Clinical trial NCT02303821
Conditions: Acute Lymphoblastic Leukemia (ALL)
Sponsor: Amgen
Start date: 2015-02-16; Completion date: 2024-06-28
Enrollment: 141 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of Phase 1b of this study is to:

* Asses the safety, tolerability and activity of carfilzomib, alone and in combination with induction chemotherapy, in children with relapsed or refractory acute lymphoblastic leukemia (ALL).
* Determine the maximum tolerated dose (MTD) and to recommend a phase 2 dose of carfilzomib in combination with induction chemotherapy.

The purpose of Phase 2 of this study is to compare the rate of complete remission (CR) of carfilzomib in combination with vincristine, dexamethasone, PEG asparaginase, daunorubicin (VXLD) at the end of induction therapy to an appropriate external control.

Detailed description:

Arms: arm 1: Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine.

Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle.

Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. arm 2: Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin.

Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. arm 3: All subjects aged ≥ 12 months at screening.

Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b.

Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. arm 4: All subjects aged \< 12 months at screening.

Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b.

Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle.
Interventions: intervention 1: Carfilzomib intervention 2: Dexamethasone intervention 3: Mitoxantrone intervention 4: PEG-asparaginase intervention 5: Vincristine intervention 6: Intrathecal (IT) Methotrexate intervention 7: Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate) intervention 8: 6-Mercaptopurine intervention 9: Cyclophosphamide intervention 10: Cytarabine intervention 11: Daunorubicin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None intervention 10: None intervention 11: None

Protocol documents:
Prot_000.pdf: 
Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140106 
Carfilzomib for Injection 
Page 1 of 243 
CONFIDENTIAL 
 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
Phase 1b/2 Study of Carfilzomib in Combination With 
Induction Chemotherapy in Children With Relapsed or 
Refractory Acute Lymphoblastic Leukemia 
Protocol Number: 
20140106 (formerly CFZ008) 
Name of Investigational 
Product: 
Carfilzomib for Injection 
IND Number: 
71,057 
EudraCT Number: 
2014-001633-84 
NCT Number: 
02303821 
Sponsor: 
Onyx Therapeutics, Inc., an Amgen Inc. subsidiary 
One Amgen Center Drive 
Thousand Oaks, California 91320 
United States 
Phone:  1-805-447-1000 
Fax:  1-805-480-4978 
Study Medical Monitor: 
, MD 
One Amgen Center Drive 
Thousand Oaks, California 91320 
United States 
 
 
Investigators: 
PHASE 1: 
, MD  
Sorbonne Paris-Cité 
 
, MD 
Medical College of Wisconsin 
 
PHASE 2: 
, MD 
University of Colorado 
 
, MD 
Children’s Hospital of Orange County 
 
, MD 
Erciyes University 
 


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Clinical Study Protocol No. 20140106 
Carfilzomib for Injection 
Page 2 of 243 
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 MD 
University Sapienza of Rome, Italy 
 
, MD/PhD 
Kid’s Cancer Centre at Sydney Children’s Hospital 
Date of Original Protocol: 11 April 2014 
Protocol Amendment 1 
31 May 2014 
Protocol Amendment 2 
23 January 2015 
Protocol Amendment 3 
20 October 2016 
Protocol Amendment 4 
22 February 2017 
Protocol Amendment 5 
11 September 2017 
Protocol Amendment 6 
24 October 2018 
Protocol Amendment 7 
19 September 2019 
Protocol Amendment 8 
13 August 2020 
Protocol Amendment 9 
04 February 2021 
Protocol Amendment 10 
03 August 2021 
Protocol Amendment 11 
04 November 2022 
Protocol Amendment 12 
28 August 2023 
Confidentiality 
Statement: 
This material is the property of Onyx Therapeutics, Inc., a 
wholly owned subsidiary of Onyx Pharmaceuticals, Inc., an 
Amgen Inc. subsidiary.  The material is highly confidential 
and is to be used only in connection with matters 
authorized by a senior representative of Onyx 
Therapeutics, Inc., and no part of it is to be disclosed to a 
third party without the express prior written permission of 
Onyx Therapeutics, Inc. 
Compliance Statement: 
This study will be conducted in accordance with 
Protocol 20140106, the International Council for 
Harmonisation (ICH), Guideline for Good Clinical Practice 
(GCP), and the applicable country and regional (local) 
regulatory requirements. 


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Clinical Study Protocol No. 20140106 
Carfilzomib for Injection 
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PROTOCOL ACCEPTANCE PAGE 
Protocol Number/Date:  Protocol 20140106, Amendment 12/28 August 2023 I have 
read this protocol for Study 20140106 entitled:  Phase 1b/2 Study of Carfilzomib in 
Combination With Induction Chemotherapy in Children with Relapsed or Refractory 
Acute Lymphoblastic Leukemia.  As investigator, I understand and agree to conduct this 
study as outlined herein. 
 
 
 
Investigator Name (print) 
 
 
Investigator Signature 
 
Date 
Signature on this page assures the sponsor that, to the best of the investigator’s 
knowledge, the affiliated Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) operates in accordance with the governing regulations, and that the investigator 
understands, and agrees to abide by, all governing regulatory obligations and the 
International Council for Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) 
and country and regional (local) requirements while conducting this clinical investigation.  
Once signed, the original of this form should be detached from the protocol and returned 
to the Sponsor or its designee (please retain a copy for your files). 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140106 
Carfilzomib for Injection 
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1. 
Synopsis 
Name of 
sponsor/company: 
Onyx Therapeutics, Inc., an Amgen Inc. subsidiary 
Name of product: 
Carfilzomib for Injection 
Title of study and 
protocol number 
and phase: 
Phase 1b/2 Study of Carfilzomib in Combination with Induction 
Chemotherapy in Children with Relapsed or Refractory Acute 
Lymphoblastic Leukemia; 20140106 (formerly CFZ008). 
Study objectives: 
The phase 1 part of the study is now closed.  Phase 2 starts from 
Section 17.11 Appendix K. 
Phase 2: 
All primary and secondary objectives will be analyzed for T-cell and 
B-cell acute lymphoblastic leukemia (ALL) populations separately, 
unless otherwise specified.  For the primary and secondary endpoint 
evaluation, response will be derived by the sponsor based upon local 
reporting of bone marrow, peripheral blood, and extramedullary 
disease status.  Minimal residual disease (MRD) status will be 
determined per central lab review of bone marrow MRD using next 
generation sequencing (NGS). 
Objectives 
Endpoints 
Primary 
 
Compare the rate of CR of 
CFZ-VXLD at the end of 
induction therapy to an 
appropriate external control.   
 
CR after induction therapy 
Secondary 
 
Evaluate the safety and 
tolerability of CFZ-VXLD  
 
Treatment-emergent and 
treatment-related adverse 
events and severe adverse 
events and laboratory 
abnormalities during the 
induction therapy and 
consolidation therapy 
 
Compare the rate of CR, 
CRp, CRh, and CRi of CFZ-
VXLD at the end of induction 
therapy relative to an 
appropriate external control 
 
CR, CRp, CRh, and CRi at 
the end of induction therapy 
 
Compare EFS for CFZ-VXLD 
to an appropriate external 
control 
 
EFS, defined as time from 
initiation of therapy until 
treatment failure (defined as 
failure to reach at least a 
CRi after consolidation or 
after induction in subjects 
that do not receive 
consolidation), relapse, or 
death from any cause 
 
Compare OS for CFZ-VXLD 
relative to an appropriate 
external control 
 
OS defined as time from 
initiation of therapy until 
death from any cause 


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 
Estimate the DOR for 
CFZ-VXLD relative to an 
appropriate external control 
 
DOR, defined as time from 
earliest of CR, CRp, CRh, or 
CRi to relapse or death from 
any cause 
 
Estimate the rate of MRD[-] 
at the end of induction in 
subjects receiving 
CFZ-VXLD 
 
MRD status using NGS less 
than 10-4 after induction 
therapy in subjects 
achieving CR  
 
Estimate the rate of MRD[-] 
bone marrow after induction 
and consolidation therapy in 
subjects with B-cell ALL or 
T-cell ALL receiving 
CFZ-VXLD 
 
MRD status using NGS less 
than 10-3 and less than 10-4 
in subjects achieving CR, 
CRp, CRh, or CRi after 
induction and consolidation 
therapy, separately 
 
Estimate the proportion of 
subjects that bridge to stem 
cell transplant or CAR-T cell 
therapy in subjects receiving 
CFZ-VXLD 
 
Occurrence of a stem cell 
transplant or CAR-T, without 
an intervening relapse after 
protocol specified therapy 
 
Estimate the rate of CR, 
CRp, CRh, and CRi of 
CFZ-VXLD at the end of 
consolidation therapy in 
subjects receiving 
CFZ-VXLD 
 
CR, CRp, CRh, and CRi 
after consolidation therapy  
 
Estimate the 
pharmacokinetics of 
carfilzomib when 
administered as part of 
VXLD regimen 
 
Carfilzomib pharmacokinetic 
parameters, including AUC, 
Cmax, and if feasible, t1/2 
AUC  area under the concentration-time curve; CAR-T  chimeric antigen 
receptor T cell therapy; CFZ-VXLD  carfilzomib combined with VXLD; 
Cmax  maximum plasma concentration; CR  complete remission; 
CRh  complete remission with partial hematologic recovery; 
CRi  complete remission with incomplete hematologic recovery; 
CRp  complete remission with incomplete recovery of platelets; 
DOR  duration of response; EFS  event-free survival; MRD  minimal 
residual disease; MRD[-]  minimal residual disease negative bone marrow; 
NGS  next generation sequencing; OS  overall survival; t1/2  half-life; 
VXLD  vincristine, dexamethasone, PEG asparaginase, daunorubicin 
Study design: 
This study is a phase 1b/2 study evaluating carfilzomib administered 
with a chemotherapy backbone.  After the maximum tolerated dose 
(MTD) or recommended phase 2 dose is identified in the phase 1 part 
of the study, dosing in the phase 2 part of the study will begin. 
The phase 1 part of the study is now closed.   
Phase 2:  The phase 2 portion of the study is a multicenter, 
single-group, externally-controlled study of carfilzomib in combination 
with vincristine, dexamethasone, polyethylene glycol 
(PEG)-asparaginase, daunorubicin (VXLD) in a minimum of 
100 subjects, unless futility is met.  Eligible subjects must be greater 
than or equal to 1 month to less than 21 years old, with their original 
diagnosis at less than 18 years of age, and must have ALL with bone 
marrow relapse (greater than or equal to 5 leukemia blasts in bone 


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marrow) or refractory relapse with or without extramedullary disease of 
the T-cell phenotype or of the B-cell phenotype after having received a 
targeted B-cell immune therapy (eg, blinatumomab, inotuzumab, or 
chimeric antigen receptor T cell [CAR-T] therapy).   
The carfilzomib dose for phase 2 will be 20 mg/m2 on day 1 of 
induction and 56 mg/m2 for subsequent doses.   
Eligible subjects will be treated with VXLD plus carfilzomib for 1 cycle 
(induction), followed by assessment of treatment response.  All 
subjects who do not show progression during induction will undergo a 
bone marrow and extramedullary disease evaluation after completion 
of induction therapy between days 29 to 45 of induction (subjects 
greater than or equal to 12 months of age) or days 36 to 50 of 
induction (subjects less than 12 months of age), based on blood count 
recovery but before the start of post-induction therapy, whichever 
comes first.  Response will be assessed per local and central 
laboratory review of bone marrow, peripheral blood and differential, 
and local assessment for sites of extramedullary disease.  MRD will be 
assessed by NGS central laboratory review and local evaluation by 
flow cytometry and/or PCR or NGS when available. 
Subjects without disease progression after induction may, at the 
investigator’s discretion, be treated with 1 cycle of consolidation 
chemotherapy plus carfilzomib.  Subjects who do not show disease 
progression during consolidation will be assessed for treatment 
response between day 29 to 45 of consolidation (subjects greater than 
or equal to 12 months of age) or days 36 to 50 of consolidation 
(subjects less than 12 months of age), based on blood count recovery 
or start of alternative therapy, whichever comes first. 
Treatment response after consolidation therapy will also be assessed 
per local and central laboratory review of bone marrow, peripheral 
blood and differential, and local assessment for sites of extramedullary 
disease.   
Infants (less than 12 months at screening) will receive a modified 
induction and consolidation based on the Interfant-06 
induction/consolidation.  The modified induction/consolidation cycles 
for infants are 35 days in duration and response assessment will occur 
between 36 to 50 days.  
When available local laboratory assessments of MRD by flow 
cytometry and/or PCR or NGS will be collected.  The consolidation 
treatment will consist of one 28-day cycle of Children’s Oncology 
group-modified Berlin-Frankfurt-Munster (BFM) therapy; 
cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, 
vincristine, and intrathecal (IT) therapy or for less than 12 months of 
age a modified infant consolidation from COG AALL15P1; 
cyclophosphamide, cytarabine, 6-mercaptopurine, and IT therapy, 
combined with carfilzomib at a dose of 56 mg/m2 (or lower if dose 
reduction was required during induction) at the same schedule as the 
induction therapy. 
After completion of study therapy, subjects will be followed for 
subsequent treatment(s), event-free and overall survival. 
For selected objectives, the treatment response to induction of 
subjects receiving CFZ-VXLD will be compared to an external control 
arm of subjects from an observational study of relapsed pediatric ALL 
(Study 20180065) that received standard-of-care (SoC) 


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chemotherapy, after appropriate adjustment.  More details will be 
included in the statistical analysis plan. 
Number of 
investigational 
sites: 
The phase 1 part of the study is now closed.   
Phase 2:  Approximately 120 sites 
Planned number of 
subjects: 
The phase 1 part of the study is now closed.   
Phase 2:  A minimum of 100 subjects will be enrolled and receive at 
least one dose of carfilzomib in the phase 2 part of the study unless 
futility is met.  A minimum of 30 subjects with T-cell ALL and 
50 subjects with B-cell ALL will be enrolled. 
Sample size 
justification: 
The phase 1 part of the study is now closed.   
Phase 2:  The sample size was determined based on practical 
considerations and limited phase 1 data.  Due to the rarity of the 
patient population, a minimum of 50 B-cell and 30 T-cell ALL subjects 
are planned to be enrolled, in order to reach more than 70 power for 
testing the primary hypothesis for at least one phenotype at 
2-sided alpha of 0.05, with an interim futility analysis. 
The external control arm is expected to include approximately 
74 B-cell ALL subjects and approximately 60 T-cell ALL subjects as 
per the primary analysis sets (B-PAS/T-PAS) included in 
Study 20180065.  More details will be presented in the 
Study 20180065 protocol which will provide the data for the external 
control arm.   
Additionally, after appropriate propensity score adjustment, the 
complete remission (CR) rate is expected to be 25 for B-cell and 
15 for T-cell subjects from the external control arm, and 
approximately 60 for B-cell and 30 for T-cell subjects from 
CFZ-VXLD arm.  As these estimates are based on data available so 
far, additional scenarios proposed for the experimental arm CR rates 
and sample sizes and the power/external control sample sizes 
expected in these cases are included in Table 27. 
Study population: 
The phase 1 part of the study is now closed.   
Phase 2:  All subjects must be greater than or equal to 1 month to less 
than 21 years of age and diagnosed prior to their 18th birthday with 
relapsed or refractory relapsed ALL.  See Sections 21.1 and 21.2 for 
additional details. 
Inclusion criteria: 
The phase 1 part of the study is now closed.   
Phase 2: 
110 
Subject’s legally acceptable representative has provided 
informed consent when the subject is legally too young to 
provide informed consent and the subject has provided written 
assent based on local regulations and/or guidelines prior to 
any study-specific activities/procedures being initiated, except 
for standard of care local testing as permitted per 
Section 21.3. 
111 
Age greater than or equal to 1 month to less than 21 years.  
Subjects greater than or equal to 18 years must have had their 
original diagnosis at less than 18 years of age. 
112 
Subjects must be diagnosed with relapsed or refractory 
relapsed ALL. 


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113 
Subjects must have a documented first remission, less than 
5 blasts in the bone marrow (M1 bone marrow) and no 
evidence of extramedullary disease. 
114 
T-cell ALL with bone marrow relapse (defined as greater than 
or equal to 5 leukemia blasts in bone marrow) or refractory 
relapse with or without extramedullary disease. 
OR 
B-cell ALL with bone marrow relapse or refractory relapse 
(defined as greater than or equal to 5 leukemia blasts in 
bone marrow) after having received a targeted B-cell immune 
therapy (eg, blinatumomab, inotuzumab, or a CAR-T therapy) 
with or without extramedullary disease. 
115 
Adequate liver function:  bilirubin less than or equal to 1.5 x 
upper limit of normal (ULN), alanine aminotransferase (ALT) 
less than or equal to 5 x ULN. 
116 
Adequate renal function:  serum creatinine less than or equal 
to 1.5 x ULN or glomerular filtration rate (GFR) greater than or 
equal to 70 mL/min/1.73 m2; or for children less than 2 years 
of age, greater than or equal to 50 mL/min/1.73 m2. 
117 
Adequate cardiac function:  shortening fraction greater than or 
equal to 30 or ejection fraction greater than or equal to 50 
118 
Karnofsky (subjects greater than or equal to 16 years of age) 
or Lansky (subjects 12 months to less than 16 years of age) 
performance status greater than or equal to 50. 
119 
Subjects must have fully recovered from the acute toxic 
effects of all previous chemotherapy, immunotherapy, or 
radiotherapy treatment before enrollment (for example: 
recovery from gastrointestinal toxicity may occur more rapidly 
than less reversible organ toxicities such as sinusoidal 
obstruction syndrome or non-infectious pneumonitis, for 
serious prior toxicities recommend discussion with Amgen 
medical monitor) 
120 
Life expectancy of greater than 6 weeks per investigator`s 
judgment at time of screening 
Exclusion criteria: 
The phase 1 part of the study is now closed.   
Phase 2: 
211 
Prior treatment with carfilzomib. 
214 
Intolerance, hypersensitivity, or inability to receive any of the 
chemotherapy components of the VXLD regimen (or 
acceptable substitutes as listed in Section 22.2.1.2).  An 
exception is allowed for allergy to asparaginase products if 
Erwinia asparaginase is unable to be administered. 
215 
Autologous hematopoietic stem cell transplantation (HSCT) 
within 6 weeks prior to start of study treatment. 
216 
Allogeneic HSCT within 3 months prior to start of study 
treatment. 
217 
Active graft versus host disease (GVHD) requiring systemic 
immune suppression.  


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218 
Less than 30 days from discontinuation of immune 
suppressive therapy administered for the treatment of acute or 
chronic GVHD. 
219 
Isolated extramedullary relapse. 
220 
Positive bacterial or fungal infection within 14 days of 
enrollment (except for documented line infection, line has 
been removed, and blood culture after line removal is negative 
for 5 days prior to first dose of induction therapy).  Antibiotics 
may be administered for prophylaxis as per institutional 
standards up to and after enrollment. 
221 
Subjects with less than 3 antibody half-lives since the last 
dose of monoclonal antibody (eg, 66 days for rituximab, 69 
days for epratuzumab, inotuzumab for 36 days), prior to first 
dose of investigational product must be discussed with the 
Amgen medical monitor and may be allowed to enroll based 
on extent of disease or evidence of rapidly rising peripheral or 
bone marrow blast counts.  
222 
Cell-based immunotherapy (eg, donor leucocyte infusion, 
CAR-T cells, tumor vaccines) within 42 days prior to first dose 
of investigational product.  If the Amgen medical monitor 
agrees, an exception may be granted to the 42-day 
requirement for subjects with rapidly rising peripheral or bone 
marrow blast counts.  
223 
Down’s syndrome. 
224 
Presence of another active cancer. 
225 
History of grade greater than or equal to 2 pancreatitis within 
6 months to screening 
226 
Unresolved toxicities from prior anticancer therapy, defined as 
not having resolved to Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 grade 1 or to levels 
dictated in the eligibility criteria apart from alopecia or toxicities 
from prior anticancer therapy that are considered irreversible 
and do not trigger another exclusion criterion (defined as 
having been present and stable for greater than 4 weeks) 
227 
Antitumor therapy (chemotherapy, investigational agents, 
molecular-targeted therapy) within 7 days of day 1 of 
induction.  Exception: hydroxyurea to control peripheral blood 
leukemic cell counts is allowed until start of investigational 
product. 
228 
Active viral infection, including but not limited to 
cytomegalovirus (CMV), Hepatitis B infection with positive 
serum hepatitis surface antigen or hepatitis B DNA, human 
immunodeficiency virus (HIV), Hepatitis C with detectable 
hepatitis C RNA.  Subjects who have previously received a 
stem cell transplant must be screened for CMV infection, 
unless both subject and donor are known to be CMV negative. 
229 
Currently receiving treatment in another investigational device 
or product study, or less than 14 days since ending treatment 
on another investigational device or product study. 
230 
Uncontrolled arrhythmias or screening ECG with corrected QT 
interval (QTc) of greater than 470 msec. 


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231 
History or evidence of any other clinically significant disorder, 
condition, or disease (with the exception of those outlined 
above) that, in the opinion of the investigator or Amgen 
physician, if consulted, would pose a risk to subject safety or 
interfere with the study evaluation, procedures or completion. 
238 
Known allergy to captisol (a cyclodextrin derivative used to 
solubilize carfilzomib; for a complete listing of Captisol-
enabled drugs, see the Ligand Pharmaceuticals, Inc. website). 
Treatment 
regimen(s) 
The phase 1 part of the study is now closed.   
Phase 2: 
Carfilzomib will be administered at a dose of 20 mg/m2 on day 1 
followed by 56 mg/m2 on days 2, 8, 9, 15, and 16 during induction and 
at 56 mg/m2 on days 1, 2, 8, 9, 15, and 16 during the optional 
consolidation. 
Induction VXLD:   
For subjects greater than or equal to 12 months of age at screening: 
 
Vincristine:  1.5 mg/m2 per dose on days 1, 8, 15, and 22 
(maximum single dose 2 mg)   
 
Daunorubicin:  60 mg/m2 per dose IV on day 2  
 
PEG-asparaginase (Erwinia Asparaginase for asparaginase 
allergic subjects):  2500 U/m2 per dose IV on days 4 and 18,   
 
Dexamethasone:  3 mg/m2 per dose twice daily on days 1 
through 21, total daily dose should be 6 mg/m2 per day 
In regions unable to source components of VXLD, alternate forms at 
equivalent dose may be used.  In addition, anthracycline may be 
omitted from the regimen, at the investigator’s discretion, for subjects 
enrolling less than 6 months from stem cell transplant or CAR-T 
therapy or subjects in third or higher relapse, or in refractory relapse if 
the subjects most recent salvage therapy included an anthracycline.  
See Section 22.1.2.1 for details. 
See Table 17 for details regarding VXLD dosing for subjects less than 
12 months of age at screening. 
Modified BFM Consolidation: 
For subjects greater than or equal to 12 months of age at screening: 
 
Cytarabine:  75 mg/m2 per dose IV or SC on days 1 through 
4 and 8 through 11  
 
6-mercaptopurine:  60 mg/m2 per day orally on days 1 through 
14  
 
Cyclophosphamide:  1 g/m2 on day 1 
 
Vincristine:  1.5 mg/m2 per dose on days 15 and 22 (maximum 
single dose 2 mg) 
 
PEG-asparaginase (Erwinia Asparaginase for asparaginase 
allergic subjects or alternative agents; see Section 22.1.2.1): 
1000 U/m2 IV on day 15 
See Table 21 for details regarding modified BFM consolidation dosing 
for subjects less than 12 months of age at screening. 
Intrathecal chemotherapy:  
For subjects greater than or equal to 12 months of age at screening: 


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 
CNS negative (at screening):  methotrexate on days 1 and 8  
 
CNS positive (at screening):  methotrexate, cytarabine, and 
hydrocortisone on days 1, 8, 15, and 22. 
 
IT therapy on day 1 of induction may include cytarabine, 
methotrexate, or triple-therapy per institutional practice 
 
Administration of IT therapy on day 29 is per institutional 
practice 
See Table 17 and Table 21 and for details regarding modified 
IT chemotherapy dosing for subjects less than 12 months of age at 
screening. 
Criteria for 
evaluation: 
The phase 1 part of the study is now closed.   
Phase 2:  Response will be assessed per local and central laboratory 
review of bone marrow, peripheral blood and differential, and local 
assessment for sites of extramedullary disease. 
Statistical methods 
and analyses: 
The phase 1 part of the study is now closed.   
Phase 2: 
Primary Analysis 
The primary analysis for each phenotype will occur when the external 
control subjects from B-PAS/T-PAS have been selected and at least 
100 enrolled subjects in the experimental arm have received at least 
one dose of carfilzomib and had the opportunity to complete a 
post-induction response evaluation.  All the available data on 
primary/secondary and exploratory endpoints will be summarized at 
this time. 
Final Analysis 
The final analysis will occur after the end of the study for all subjects.   
For each planned analysis, data will be subject to ongoing checks for 
integrity, completeness, and accuracy in accordance with the Data 
Management Plan with the expectation that all outstanding data issues 
are resolved ahead of the snapshot.  The data will be locked to 
prevent further changes, and a snapshot of the locked database will 
be used in the analysis. 
Efficacy Analyses 
Unless otherwise specified all efficacy endpoints will be analyzed for 
B-cell and T-cell phenotype independently.  The comparison analyses 
for CR, CRh, CRp, CRi, EFS, and OS endpoints will use the Primary 
Analysis Set, while for all the other efficacy endpoints the Safety 
Analysis Set will be used. 
Interim Futility Analysis 
An interim analysis for futility will be conducted independently for each 
phenotype T-cell and B-cell, respectively.  The analysis will occur 
after at least 60 subjects from the experimental arm have received 
at least one dose of carfilzomib and had the opportunity to complete a 
post induction response evaluation.  The futility criterion will be derived 
such that the probability of futility is at least 70 under H0 and the 
power loss is at most 0.01 under H1, using a Bayesian predictive 
probability approach.  Additional details are provided in the SAP. 


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Safety Analyses 
The safety analyses will be based on the Safety Analysis Set analyzed 
by each phenotype separately. 
Correlative studies: 
The phase 1 part of the study is now closed.   
Phase 2: 
For pharmacokinetic analyses 
 assessments 
refer to Sections 24.2.6 and 24.2.7. 
Samples for genomic biomarker analysis will not be collected in 
phase 2. 


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TABLE OF CONTENTS 
Phase 2 of study begins at Section 17.11.1 through Section 30 (Appendix K) 
1. 
Synopsis ................................................................................................................. 4 
2. 
List of Abbreviations and Definitions of Terms ...................................................... 23 
3. 
Background Information ........................................................................................ 26 
3.1 
Disease Background ................................................................................. 26 
3.2 
Proteasome Inhibitors ............................................................................... 29 
3.2.1 
Preclinical Background for Investigational Drug ......................... 29 
3.2.2 
Clinical Background for Investigational Drug ............................. 31 
3.3 
Dose Rationale ......................................................................................... 32 
4. 
Study Objectives ................................................................................................... 33 
4.1 
Primary Objectives .................................................................................... 33 
4.2 
Secondary Objectives ............................................................................... 33 
4.3 
Exploratory Objectives .............................................................................. 34 
5. 
Study Design ........................................................................................................ 34 
5.1 
Type/Design of Study ................................................................................ 35 
5.2 
Dose-escalation Plan ................................................................................ 36 
5.3 
Estimated Study Duration and Study Closure ............................................ 38 
6. 
Subject Eligibility ................................................................................................... 38 
6.1 
Inclusion Criteria ....................................................................................... 39 
6.2 
Exclusion Criteria ...................................................................................... 40 
7. 
Subject Screening and Enrollment ........................................................................ 41 
8. 
Dosage and Treatment Administration .................................................................. 45 
8.1 
Treatment Administration .......................................................................... 46 
8.1.1 
Carfilzomib Single-agent Lead-in Window (Dose 
Escalation 1 [R3] Only) .............................................................. 46 
8.1.2 
Induction (Dose Escalation 1 [R3] and Dose 
Escalation 2 [VXLD]) ................................................................. 47 
8.1.2.1 
Dose Escalation 1 (R3) ........................................... 50 
8.1.2.2 
Dose Escalation 2 (VXLD) ....................................... 51 
8.1.3 
Optional Consolidation .............................................................. 58 
8.1.4 
Testicular Relapse ..................................................................... 63 
8.2 
Dose-limiting Toxicity ................................................................................ 63 
8.3 
Definition of Carfilzomib Dose-limiting Toxicity .......................................... 63 
8.4 
Dose-modification Guidelines .................................................................... 64 
8.4.1 
Carfilzomib ................................................................................ 64 
8.4.2 
6-mercaptopurine ...................................................................... 65 
8.4.3 
Cyclophosphamide .................................................................... 66 


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8.4.4 
Cytarabine ................................................................................. 66 
8.4.5 
Daunorubicin or Other Anthracycline ......................................... 66 
8.4.6 
Dexamethasone ........................................................................ 67 
8.4.7 
Intrathecal Methotrexate or Triple Therapy ................................ 68 
8.4.8 
Mitoxantrone.............................................................................. 68 
8.4.9 
PEG-asparaginase or L-asparaginase ....................................... 68 
8.4.10 
Vincristine .................................................................................. 70 
8.5 
Concomitant Medications .......................................................................... 71 
8.5.1 
Required Concomitant Medications ........................................... 72 
8.5.2 
Excluded Concomitant Medications ........................................... 72 
8.5.3 
Drug-Drug Interactions .............................................................. 72 
8.6 
Product Complaints ................................................................................... 72 
9. 
Supportive Care Requirements and Guidelines .................................................... 73 
9.1 
Tumor Lysis Syndrome ............................................................................. 73 
9.2 
Blood Products .......................................................................................... 74 
9.3 
Pneumocystis Prophylaxis ........................................................................ 74 
9.4 
Fungal Prophylaxis .................................................................................... 74 
9.5 
Herpes Virus Prophylaxis .......................................................................... 74 
9.6 
Bacterial Prophylaxis ................................................................................. 75 
9.7 
Intravenous Immunoglobulin Supplementation .......................................... 75 
9.8 
Central Line Care ...................................................................................... 75 
9.9 
Fever and Neutropenia.............................................................................. 75 
9.9.1 
Definition ................................................................................... 75 
9.9.2 
Evaluation ................................................................................. 75 
9.9.3 
Treatment .................................................................................. 75 
9.9.4 
Persistent or Recurrent Symptoms ............................................ 75 
9.10 
Myeloid Growth Factors ............................................................................ 76 
9.11 
Gastritis Prophylaxis ................................................................................. 76 
9.12 
Prevention and Management of Nausea and Vomiting .............................. 76 
9.13 
Constipation Prophylaxis ........................................................................... 76 
9.14 
Contraception ............................................................................................ 77 
9.14.1 
Female of Childbearing Potential ............................................... 77 
9.14.2 
Female Subjects ........................................................................ 77 
9.14.3 
Male Subjects ............................................................................ 78 
9.14.4 
Unacceptable Methods of Birth Control for Male and 
Female Subjects ....................................................................... 79 
10. 
Study Procedures ................................................................................................. 79 
10.1 
On-study Assessments ............................................................................. 79 
10.1.1 
Lead-in Window (Dose Escalation 1 [R3] Only) ......................... 79 
10.1.2 
Induction (Dose Escalation 1 [R3] and Dose 
Escalation 2 [VXLD]) ................................................................. 80 
10.1.3 
Optional Consolidation .............................................................. 81 


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10.1.4 
Additional Procedure Details ..................................................... 82 
10.2 
Response Assessment.............................................................................. 85 
10.2.1 
Complete Remission ................................................................. 85 
10.2.2 
Complete Remission Without Platelet Recovery ........................ 85 
10.2.3 
Complete Remission With Incomplete Hematologic 
Recovery ................................................................................... 85 
10.2.4 
Partial Response ....................................................................... 86 
10.2.5 
Stable Disease .......................................................................... 86 
10.2.6 
Progressive Disease .................................................................. 86 
10.2.7 
Induction Death ......................................................................... 86 
10.2.8 
Not Evaluable ............................................................................ 86 
11. 
Study Discontinuation ........................................................................................... 86 
11.1 
Withdrawal of Subjects From Treatment ................................................... 87 
11.2 
End-of-study Assessments ........................................................................ 87 
11.3 
Study Termination ..................................................................................... 89 
12. 
Adverse Events and Serious Adverse Events (SAES) .......................................... 89 
12.1 
Adverse Event Reporting .......................................................................... 89 
12.1.1 
Definitions ................................................................................. 89 
12.2 
Causality ................................................................................................... 90 
12.3 
Adverse Events Reporting Procedures ...................................................... 91 
12.3.1 
General ..................................................................................... 91 
12.3.2 
Disease Progression ................................................................. 92 
12.4 
Serious Adverse Event Definitions ............................................................ 93 
12.5 
Serious Adverse Event Reporting and Documentation 
Requirements ............................................................................................ 93 
12.6 
Pregnancy and Lactation Reporting .......................................................... 94 
13. 
Statistics ............................................................................................................... 95 
13.1 
Study Endpoints ........................................................................................ 95 
13.1.1 
Primary Endpoints ..................................................................... 95 
13.1.2 
Secondary Endpoints ................................................................ 95 
13.1.3 
Exploratory Endpoints ............................................................... 96 
13.2 
Analysis of the Conduct of the Study ......................................................... 96 
13.3 
Independent Review Committee ............................................................... 96 
13.4 
Cohort Safety Review Committee ............................................................. 96 
13.5 
Data Monitoring Committee ....................................................................... 98 
13.6 
Statistical Methods .................................................................................... 98 
13.6.1 
Efficacy Analyses ...................................................................... 99 
13.6.2 
Safety Analysis .......................................................................... 99 
13.6.3 
Correlative Study Analyses ...................................................... 100 
13.6.3.1 
Pharmacokinetic Analysis ..................................... 100 
 
 


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13.7 
Handling of Missing Data ........................................................................ 102 
13.8 
Determination of Sample Size ................................................................. 102 
14. 
Investigational Drug ............................................................................................ 102 
14.1 
Carfilzomib Description, Packaging, and Storage .................................... 102 
14.1.1 
Physical Description ................................................................ 102 
14.1.2 
Formulation ............................................................................. 102 
14.1.3 
Packaging and Labeling .......................................................... 102 
14.1.4 
Storage and Stability ............................................................... 103 
14.2 
Study Drug Accountability ....................................................................... 103 
14.3 
Chemotherapy Backbone Description, Packaging, and Storage .............. 104 
14.4 
Chemotherapy Backbone Accountability ................................................. 104 
15. 
Ethical and Administrative Considerations .......................................................... 104 
15.1 
Compliance Statement ............................................................................ 104 
15.2 
Institutional Review Board or Independent Ethics Committee.................. 105 
15.3 
Informed Consent, Pediatric Assent, and Human Subject 
Protection ................................................................................................ 105 
15.4 
Direct Access to Source Data, Source Documents, and Study 
Records .................................................................................................. 106 
15.5 
Data Collection and Handling .................................................................. 106 
15.6 
Confidentiality ......................................................................................... 107 
15.7 
Publication Policy .................................................................................... 107 
16. 
References ......................................................................................................... 109 
17. 
Appendices ......................................................................................................... 114 
17.1 
Appendix A.  Schedule and Description of Assessments, 
Screening for Phase 1 ............................................................................. 114 
17.2 
Appendix B.  Schedule and Description of Assessments, Lead-in 
Window for Phase 1 ................................................................................ 116 
17.3 
Appendix C.  Schedule and Description of Assessments, 
Induction for Phase 1 .............................................................................. 117 
17.4 
Appendix D.  Schedule and Description of Assessments, 
Optional Consolidation for Phase 1 ......................................................... 118 
17.5 
Appendix E.  Description of End--of-study Assessments for 
Phase 1 ................................................................................................... 119 
17.6 
Appendix F.  Karnofsky and Lansky Performance Status Scales ............ 120 
17.7 
Appendix G.  Guidance for Determining Previous Cumulative 
Anthracycline Dose ................................................................................. 120 
17.8 
Appendix H.  Sample Serious Adverse Event Report Form ..................... 122 
17.9 
Appendix I.  Pregnancy Notification Form................................................ 122 
17.10 Appendix J.  Lactation Notification Worksheet ......................................... 122 
17.11 Appendix K.  Phase 2 Part of Study ........................................................ 123 


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17.11.1 
Phase 2:  Study Schema ......................................................... 123 
17.11.2 
Phase 2:  Schedule of Activities, Phase 2 ................................ 124 
18. 
Phase 2:  Introduction ......................................................................................... 153 
18.1 
Phase 2 Study Rationale ......................................................................... 153 
18.2 
Background ............................................................................................. 154 
18.2.1 
Acute Lymphoblastic Leukemia ............................................... 154 
18.2.2 
Treatment Outcomes in Pediatric Relapsed ALL ..................... 154 
18.2.2.1 
Rationale for Incorporating Proteasome 
Inhibitor with VXLD ................................................ 156 
18.2.3 
Therapeutic Needs in Relapsed or Refractory ALL .................. 156 
18.2.4 
Justification of Treatment Effect............................................... 157 
18.2.5 
Amgen Investigational Product Background:  
Carfilzomib .............................................................................. 161 
18.2.6 
Non-investigational Product Background:  VXLD, 
Modified BFM, and Intrathecal Chemotherapy......................... 161 
18.3 
Benefit/Risk Assessment ......................................................................... 161 
18.3.1 
Therapeutic Context ................................................................ 161 
18.3.2 
Key Benefits ............................................................................ 161 
18.3.3 
Key Risks ................................................................................ 162 
18.3.3.1 
Cardiac Toxicity ..................................................... 163 
18.3.3.2 
Hypertension ......................................................... 164 
18.3.3.3 
Acute Renal Failure ............................................... 165 
19. 
Phase 2:  Objectives and Endpoints ................................................................... 166 
20. 
Phase 2:  Study Design ...................................................................................... 168 
20.1 
Overall Design ........................................................................................ 168 
20.2 
Number of Subjects ................................................................................. 169 
20.2.1 
Replacement of Subjects ......................................................... 169 
20.3 
Justification for Investigational Product Dose .......................................... 169 
20.3.1 
Justification for Non-investigational Product Dose ................... 171 
20.4 
End of Study ........................................................................................... 171 
21. 
Phase 2:  Study Population ................................................................................. 171 
21.1 
Inclusion Criteria ..................................................................................... 171 
21.2 
Exclusion Criteria .................................................................................... 172 
21.3 
Subject Enrollment .................................................................................. 174 
21.4 
Screen Failures ....................................................................................... 175 
22. 
Phase 2:  Treatments ......................................................................................... 175 
22.1 
Treatment(s) Administered ...................................................................... 175 
22.1.1 
Investigational Product:  Carfilzomib ........................................ 175 
22.1.1.1 
Dosage Formulation .............................................. 175 
22.1.1.2 
Dosage, Administration, and Schedule .................. 175 
22.1.1.3 
Intravenous Prehydration ...................................... 176 


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22.1.2 
Non-investigational Product:  VXLD ......................................... 176 
22.1.2.1 
Dosage Formulation .............................................. 176 
22.1.2.2 
Dosage, Administration, and Schedule .................. 180 
22.1.3 
Non-investigational Product:  Modified BFM  ........................... 180 
22.1.3.1 
Dosage Formulation .............................................. 180 
22.1.3.2 
Dosage, Administration, and Schedule .................. 181 
22.1.4 
Non-investigational Product:  Intrathecal 
Chemotherapy ......................................................................... 181 
22.1.4.1 
Dosage Formulation .............................................. 181 
22.1.4.2 
Dosage, Administration, and Schedule .................. 181 
22.1.5 
Medical Devices ...................................................................... 181 
22.1.6 
Other Protocol-required Therapies .......................................... 182 
22.1.6.1 
Tumor Lysis Syndrome ......................................... 182 
22.1.6.2 
Blood Products ...................................................... 183 
22.1.6.3 
Pneumocystis Jiroveci Prophylaxis ........................ 183 
22.1.6.4 
Fungal Prophylaxis ................................................ 183 
22.1.6.5 
Herpes Virus Prophylaxis ...................................... 183 
22.1.6.6 
Bacterial Prophylaxis ............................................. 183 
22.1.6.7 
Intravenous Immunoglobulin 
Supplementation ................................................... 184 
22.1.6.8 
Central Line Care .................................................. 184 
22.1.6.9 
Fever and Neutropenia .......................................... 184 
22.1.6.10 Myeloid Growth Factors ........................................ 185 
22.1.6.11 Gastritis Prophylaxis .............................................. 185 
22.1.6.12 Prevention and Management of Nausea 
and Vomiting ......................................................... 185 
22.1.6.13 Constipation Prophylaxis ....................................... 185 
22.1.6.14 Mucositis ............................................................... 186 
22.1.6.15 Contraception ........................................................ 186 
22.1.7 
Product Complaints ................................................................. 188 
22.1.8 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................. 188 
22.2 
Dose Modification .................................................................................... 189 
22.2.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ................................... 189 
22.2.1.1 
Amgen Investigational Product:  
Carfilzomib ............................................................ 192 
22.2.1.2 
Amgen/Non-Amgen Non-Investigational 
Product:  VXLD, Modified BFM, and 
Intrathecal Chemotherapy ..................................... 192 
22.2.1.3 
Dose Modifications for Modified Infant 
Consolidation ........................................................ 192 
22.3 
Preparation/Handling/Storage/Accountability .......................................... 193 
22.4 
Measures to Minimize Bias:  Randomization and Blinding ....................... 193 


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22.4.1 
Method of Treatment Assignment ............................................ 193 
22.4.2 
Blinding ................................................................................... 193 
22.5 
Treatment Compliance ............................................................................ 193 
22.6 
Treatment of Overdose ........................................................................... 193 
22.7 
Prior and Concomitant Treatment ........................................................... 194 
22.7.1 
Prior Treatment ....................................................................... 194 
22.7.2 
Concomitant Treatment ........................................................... 194 
23. 
Phase 2:  Discontinuation Criteria ....................................................................... 194 
23.1 
Discontinuation of Study Treatment......................................................... 194 
23.2 
Discontinuation From the Study .............................................................. 195 
23.2.1 
Reasons for Removal From Study ........................................... 196 
23.3 
Lost to Follow-up ..................................................................................... 196 
24. 
Phase 2:  Study Assessments and Procedures .................................................. 196 
24.1 
General Study Periods ............................................................................ 197 
24.1.1 
Screening, Enrollment and/or Randomization .......................... 197 
24.1.2 
Treatment Period ..................................................................... 197 
24.1.3 
Safety Follow-up ...................................................................... 197 
24.1.4 
Long-term Follow-up ................................................................ 198 
24.1.5 
End of Study for Individual Subjects ........................................ 198 
24.2 
Description of General Study Assessments and Procedures ................... 198 
24.2.1 
General Assessments ............................................................. 198 
24.2.1.1 
Informed Consent .................................................. 198 
24.2.1.2 
Demographics ....................................................... 198 
24.2.1.3 
Medical History ...................................................... 199 
24.2.1.4 
Physical Examination ............................................ 199 
24.2.1.5 
Physical Measurements ........................................ 199 
24.2.1.6 
Substance Abuse History ...................................... 199 
24.2.1.7 
Karnofsky and Lansky Performance Status ........... 199 
24.2.2 
Efficacy Assessments .............................................................. 199 
24.2.2.1 
Response Assessment .......................................... 199 
24.2.3 
Safety Assessments ................................................................ 203 
24.2.3.1 
Vital Signs ............................................................. 203 
24.2.3.2 
Electrocardiograms (ECGs) ................................... 203 
24.2.3.3 
Echocardiograms (ECHOs) ................................... 204 
24.2.3.4 
Vital Status ............................................................ 204 
24.2.4 
Adverse Events and Serious Adverse Events .......................... 204 
24.2.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information ................ 204 
24.2.4.2 
Method of Detecting Adverse Events and 
Serious Adverse Events ........................................ 206 
24.2.4.3 
Follow-up of Adverse Events and Serious 
Adverse Events ..................................................... 206 


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24.2.4.4 
Regulatory Reporting Requirements for 
Serious Adverse Events ........................................ 206 
24.2.4.5 
Safety Monitoring Plan .......................................... 207 
24.2.4.6 
Pregnancy and Lactation ....................................... 208 
24.2.5 
Clinical Laboratory Assessments ............................................. 208 
24.2.6 
Pharmacokinetic Assessments ................................................ 209 
 
 
25. 
Phase 2:  Statistical Considerations .................................................................... 210 
25.1 
Statistical Hypotheses ............................................................................. 210 
25.2 
Sample Size Determination ..................................................................... 210 
25.3 
Analysis Sets, Subgroups, and Covariates .............................................. 212 
25.3.1 
Analysis Sets ........................................................................... 212 
25.3.1.1 
Primary Analysis Set ............................................. 212 
25.3.1.2 
Safety Analysis Set ............................................... 212 
25.3.1.3 
Per Protocol Analysis Set ...................................... 212 
25.3.1.4 
Interim Futility Analysis Set ................................... 212 
25.3.2 
Covariates ............................................................................... 212 
25.3.3 
Subgroups ............................................................................... 212 
25.3.4 
Handling of Missing and Incomplete Data ................................ 213 
25.4 
Statistical Analyses ................................................................................. 213 
25.4.1 
Planned Analyses .................................................................... 214 
25.4.1.1 
Interim Futility Analysis .......................................... 214 
25.4.1.2 
Primary Analysis ................................................... 214 
25.4.1.3 
Final Analysis ........................................................ 214 
25.4.2 
Methods of Analyses ............................................................... 214 
25.4.2.1 
General Considerations ......................................... 214 
25.4.2.2 
Efficacy Analyses .................................................. 215 
25.4.2.3 
Safety Analyses .................................................... 217 
26. 
Phase 2:  Clinical Laboratory Tests .................................................................... 218 
27. 
Phase 2:  Study Governance Considerations ...................................................... 219 
28. 
Phase 2:  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting .................................................................. 227 
29. 
Phase 2:  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information .......................................................................................... 236 
30. 
Sample Storage and Destruction ........................................................................ 242 
 
List of Tables 
Table 1.  Phase 1 Screening Assessments ................................................................... 42 
Table 2.  Phase 1 and 2 Bone Marrow Status Definitions .............................................. 44 


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Table 3.  Phase 1 and 2 CNS Status Definitions ............................................................ 45 
Table 4.  Phase 1 Schedule of Treatment and Response Assessments, 
Lead-in Window ...................................................................................... 46 
Table 5.  Phase 1 Schedule of Treatment and Response Assessments, 
Induction Cycle ....................................................................................... 48 
Table 6.  Phase 1 and 2 Age-based Dosing Guidelines ................................................. 52 
Table 7.  Phase 1 Schedule of Treatment and Response Assessment, 
Optional Consolidation Cycle .................................................................. 59 
Table 8.  Phase 1 and 2 Dose Decrements for Carfilzomib ............................................ 64 
Table 9.  Phase 1 On-study Assessments:  Lead-in Window ......................................... 80 
Table 10.  Phase 1 On-study Assessments:  Induction Cycle (Dose 
Escalation 1 [R3] and Dose Escalation 2 [VXLD]) ................................... 81 
Table 11.  Phase 1 On-study Assessments:  Optional Consolidation Cycle ................... 82 
Table 12.  Phase 1 End-of-study Assessments ............................................................. 88 
Table 13.  Toxicity Grading for Adverse Events not Covered in the 
NCI-CTCAE (Version 4.03) ..................................................................... 90 
Table 14.  Phase 2 Schedule of Activities – Induction Therapy Subjects 
Greater Than or Equal to 12 Months of Age at Screening ..................... 124 
Table 15.  Phase 2 Dosing Regimen for Induction Therapy – Subjects 
Greater Than or Equal to 12 Months of Age at Screening ..................... 129 
Table 16.  Phase 2 Schedule of Activities – Induction Therapy Subjects Less 
Than 12 Months of Age at Screening .................................................... 130 
Table 17.  Phase 2 Dose Regimen for Induction Therapy – Subjects Less 
Than 12 Months of Age at Screening .................................................... 139 
Table 18.  Phase 2 Schedule of Activities – Consolidation Therapy Subjects 
Greater Than or Equal to 12 Months of Age at Screening ..................... 141 
Table 19.  Phase 2 Dose Regimen for Consolidation Therapy – Subjects 
Greater Than or Equal to 12 Months of Age at Screening ..................... 145 
Table 20.  Phase 2 Schedule of Activities – Consolidation Therapy Subjects 
Less Than 12 Months of Age at Screening ........................................... 147 
Table 21.  Phase 2 Dose Regimen for Consolidation Therapy – Subjects Less 
Than 12 Months of Age at Screening .................................................... 151 
Table 22.  Covariate Distribution for Phase 1 Subjects ................................................ 159 
Table 23.  Dose Modification for RYLAZE ................................................................... 177 
Table 24.  Example Dose Decrements for Carfilzomib ................................................. 189 
Table 25.  Dose Modification Table for Carfilzomib ...................................................... 190 
Table 26.  Treatment Response Definitions ................................................................. 200 
Table 27.  Power Estimates Based on Various Scenarios for Sample Size 
and Hypothesized Relative Effect ......................................................... 210 
Table 28.  Phase 2 Analyte Listing .............................................................................. 219 


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List of Figures 
Figure 1.  Phase 1b Schema ......................................................................................... 35 
Figure 2.  Study 20140106 Road Map, Induction Cycle, Dose Escalation 1 
(R3) ........................................................................................................ 53 
Figure 3.  Study 20140106 Road Map, Induction Cycle, Dose Escalation 2 
(VXLD) ................................................................................................... 55 
Figure 4.  Study 20140106 Road Map, Optional Consolidation Cycle ............................ 61 
Figure 5.  Phase 2 Part - Study Schema ...................................................................... 123 
Figure 6.  Phase 2 Sample Electronic Serious Adverse Event Contingency 
Report Form (paper-based form) .......................................................... 233 
Figure 7.  Phase 2 Pregnancy and Lactation Notification Forms .................................. 240 
 


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2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALL  
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
ASCO 
American Society of Clinical Oncology 
ASH 
American Society of Hematology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BFM 
Berlin-Frankfurt-Münster 
BID 
bis in diem (twice a day) 
BLR 
Bayesian Logistic Regression 
B-PAS 
B-cell primary analysis set 
BSA 
body surface area 
BUN 
blood urea nitrogen 
Captisol 
sulfobutylether beta cyclodextrin (SBE beta CD) 
CAR-T 
chimeric antigen receptor T cell therapy 
CBC 
complete blood count 
Cmax 
maximum plasma concentration 
CMP 
carfilzomib, melphalan, prednisone 
CMV 
cytomegalovirus 
CNS 
central nervous system 
COG 
Children’s Oncology Group 
Cr 
serum creatinine 
CR 
complete remission 
CRF 
case report form 
CRh 
complete remission with partial hematologic recovery 
CRi 
complete remission with incomplete hematologic recovery 
CRp 
complete remission without platelet recovery 
CSF 
cerebral spinal fluid 
CSRC 
Cohort Safety Review Committee 


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Abbreviation 
Definition 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT-L 
chymotrypsin-like  
CYP450 
cytochrome P450  
D5W 
5 Dextrose Injection, USP 
DFS 
disease-free survival 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
End of Treatment 
EU 
European Union 
FDA 
Food and Drug Administration 
FCBP 
females of childbearing potential 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulation factor 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyltransferase 
GVHD 
graft versus host disease 
H2 
histamine 2 blocker 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HIV 
human immunodeficiency virus 
HSCT 
hematopoietic stem cell transplantation 
HSV 
herpes simplex virus 
IB 
investigator’s brochure 
IBG 
Independent Biostatistics Group 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
ID 
induction death 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IM 
intramuscular 
IMiD 
immunomodulatory drug 


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Abbreviation 
Definition 
IND 
Investigational New Drug 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IST 
investigator-sponsored trial 
IT 
intrathecal 
IUD 
intrauterine device 
IV 
intravenous(ly) 
IVIg 
intravenous immunoglobulin 
IVRS 
Interactive Voice Recognition System 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
M-W-F 
Monday, Wednesday, Friday 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCRM 
new continual reassessment method 
NE 
not evaluable 
NGS 
next generation sequencing 
NM-GRF 
nuclear magnetic-glomerular filtration rate 
ORR 
overall response rate 
PAS 
primary analysis set 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
 
 
PEG 
polyethylene glycol 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
PN 
peripheral neuropathy 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
QTc 
corrected QT interval 
R3 backbone 
dexamethasone, mitoxantrone, PEG-asparaginase, and vincristine 
RBC 
red blood cell 
 
 


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Abbreviation 
Definition 
RPLS 
reversible posterior leukoencephalopathy syndrome 
SAE 
serious adverse event 
SD 
stable disease 
SIADH 
syndrome of inappropriate secretion of antidiuretic hormone 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
TACL 
Therapeutic Advances in Childhood Leukemia & Lymphoma 
TcR 
T-cell receptor 
TLS 
Tumor Lysis Syndrome 
Tmax 
time to maximum plasma concentration 
TMP-SMX 
trimethoprim-sulphamethoxazole 
T-PAS 
T-cell primary analysis set 
TPMT 
thiopurine methyltransferase 
UK 
United Kingdom 
ULN 
upper limit of normal  
US 
United States 
VXLD 
In Section 3 BACKGROUND INFORMATION:  vincristine; dexamethasone; 
PEG-asparaginase; doxorubicin or daunorubicin 
In all other sections:  vincristine, dexamethasone, PEG-asparaginase, 
daunorubicin 
WBC 
white blood cell 
 
 
 
 
PHASE 1 PORTION OF STUDY 
3. 
Background Information 
Phase 1 is now closed, the phase 2 protocol, including the phase 2 background 
information is provided in Appendix K.   
3.1 
Disease Background 
Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood.  
Approximately 2400 children in the United States (US) are newly diagnosed with this 
disease each year.  The peak incidence occurs among 2 to 3-year-olds, with a rate of 
80 cases per million for this age group.  There is no disparity in incidence by sex, but 
white children are affected up to three-fold as often as black children (SEER Research 
Data 2013). 


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The epidemiology of pediatric ALL does not vary much among western nations, with the 
reported incidence typically approximating 3 to 4 cases per 100,000 children 
(NCIC 2004; Milne 2008; Hjalgrim 2003; Dalmasso 2005).  In some reports, the ALL 
incidence among boys slightly exceeds that in girls (Kulkarni 2011; Milne 2008).  
The overall incidence of ALL appears to be stable over time (NCIC 2004; Kulkarni 2011; 
Milne 2008; Hjalgrim 2003), however Dalmasso et al. have described a recent increase 
in pediatric ALL cases in Italy (Dalmasso 2005). 
Although the majority of children with newly diagnosed ALL will achieve a complete 
remission and enjoy long-term survival, approximately 20 will experience bone marrow 
relapse.  A 2010 report by Therapeutic Advances in Childhood Leukemia and 
Lymphoma (TACL) presented the remission rates and disease-free survival (DFS) of 
children with relapsed lymphoblastic leukemia treated between 1995 and 2004 at 
institutions participating in their consortium.  While children with either an early or late 
first bone marrow relapse fared well (83 and 93 complete remission, respectively), 
children with subsequent relapses had a progressively lower likelihood of achieving 
remission again.  Only 44 of children with a second bone marrow relapse achieved 
complete remission and their 5-year DFS was 27.  Those with a third relapse achieved 
a subsequent complete remission only 27 of the time and their 5-year DFS was a 
mere 15.  These figures clearly demonstrate the need for novel agents to improve 
outcomes for very high-risk patients. 
Salvage therapy for subjects with relapsed ALL most often involves combinations of 
agents with activity in newly diagnosed ALL, used at varying dose levels and schedules.  
Key agents in this setting include:  etoposide, vincristine, asparaginase, doxorubicin, 
mitoxantrone, cytarabine, cyclophosphamide, methotrexate, dexamethasone, and 
prednisone.  Current standard of care therapies for relapsed ALL include salvage 
regimens such as the UK R3 (R3; dexamethasone, mitoxantrone, PEG-asparaginase, 
and vincristine) and VXLD (vincristine; dexamethasone; PEG-asparaginase; and 
doxorubicin or daunorubicin) chemotherapy backbones.  The addition of a proteasome 
inhibitor to these backbones could further boost clinical response through a mechanism 
of action that differs from any of the current chemotherapy agents in the R3 or VXLD 
regimens. 
Novel agents for the treatment of pediatric ALL have been developed in recent years 
and, like proteasome inhibitors, offer promise for improved outcomes.  Clofarabine 
(Clolar), a second-generation purine analogue that received accelerated approval in the 


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US in 2004, is indicated for the treatment of patients 1 to 21 years old with ALL who 
have had at least 2 treatment regimens and for whom ALL has recurred or resisted 
treatment.  Clofarabine has considerably greater activity, both as a single agent and in 
combination, relative to first generation purine nucleoside analogue antecedents.  
Approval was based on improved response rate and no survival advantage has been 
demonstrated to date.  Nelarabine (Arranon), a nucleoside metabolic inhibitor that 
received accelerated approval in the US in 2005, is indicated for the postinduction 
treatment of patients with T-cell ALL and T-cell lymphoblastic lymphoma whose disease 
has not responded to or has relapsed following treatment with at least 2 chemotherapy 
regimens.  Nelarabine has demonstrated activity as monotherapy in T-cell ALL in the 
pediatric and adult populations.  Neither Clofarabine nor Nelarabine is currently 
approved for use in combination with induction chemotherapy.  Blinatumomab 
(Blincyto), developed by Amgen, Inc., is an antibody with specificity for both CD19 and 
CD3, and attacks B-cell lymphoblastic leukemia using bispecific T-cell-engaging 
technology.  Blinatumomab has received approval in the United States for the treatment 
of adults and children with Philadelphia chromosome-negative relapsed or refractory and 
minimal residual disease (MRD)-positive B-cell precursor ALL.  In the European Union 
(EU), approval for this indication is currently limited to adults only.  Ongoing research is 
needed to determine the best approach for incorporating these agents into the treatment 
armamentarium for relapsed and/or high-risk pediatric ALL. 
Minimal residual disease has well-established prognostic utility in pediatric ALL 
(Cavé 1998).  A matched case-control study by Sutton et al. found that bone marrow 
MRD measure by real-time polymerase chain reaction (PCR) on Day 15 of induction was 
strongly predictive of relapse (Sutton 2009).  MRD has also demonstrated prognostic 
utility prior to hematopoietic stem cell transplantation (HSCT), with poorer survival 
among those who enter HSCT with MRD positivity (Campana 2013).  The effect of 
proteasome inhibition on MRD has yet to be determined but is being explored using flow 
cytometric analysis in the Phase 2 part of a study of bortezomib in pediatric ALL.  Most 
children with multiply relapsed ALL or relapsed ALL with other high-risk features will 
proceed to allogeneic HSCT, thus reduced MRD due to proteasome inhibition could 
significantly impact prognosis beyond the effect of improving complete remission rates 
alone.  The study presented in this protocol will be the first, to our knowledge, to explore 
MRD following proteasome inhibition using a quantitative PCR technique. 


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3.2 
Proteasome Inhibitors 
The proteasome is a multicatalytic proteinase complex that is responsible for 
degradation of a wide variety of protein substrates within normal and transformed cells.  
Intracellular proteins targeted for degradation by the proteasome are first ubiquitinated 
via the ubiquitin conjugation system.  Ubiquitinated proteins are cleaved within the 
proteasome by 1 or more of 3 separate N-terminal threonine protease activities:  a 
chymotrypsin-like (CT-L) activity, a trypsin-like activity, and/or a caspase-like activity. 
Treatment with proteasome inhibitors produces an accumulation of pro-apoptotic 
proteins, promotes autophagy, and increases the stability of negative cell cycle 
regulators (Shen 2013; Zang 2012).  Data from pediatric-derived cell lines presented at 
the American Society of Hematology (ASH) meeting in December 2013, indicated 
substantial cytotoxic activity in all leukemia cells treated with carfilzomib 
(Jayanthan 2013).  This is consistent with the work of Niewerth et al. who reported the 
susceptibility of numerous patient-derived pediatric leukemia specimens to bortezomib, 
carfilzomib, and other investigational proteasome inhibitors.  A strong correlation with the 
relative proportion of immunoproteasomes to constitutive proteasomes was suggested 
and may explain the greater sensitivity to proteasome inhibition of lymphoblastic as 
compared with myeloid leukemias (Niewerth 2013).  Clinical data comes from the 
proteasome inhibitor bortezomib which shows the same maximum tolerated dose (MTD) 
as in adults, when assessed in pediatric subjects with solid tumors or acute leukemias 
(1.2 and 1.3 mg/m2, respectively) (Blaney 2004; Horton 2007).  While no evidence of 
activity was seen in subjects with solid tumors, a suggestion of a positive signal occurred 
in subjects with leukemia.  A subsequent Phase 1 study by Messinger, et al. using 
bortezomib 1.3 mg/m2 added to the chemotherapy combination of vincristine, 
dexamethasone, PEG-asparaginase, and doxorubicin (VXLD) showed activity with 
acceptable toxicity in children with relapsed ALL (Messinger 2010).  A follow-up pediatric 
Phase 2 part of the study of bortezomib-VXLD in patients with relapsed B-cell ALL 
reported 70 complete remission, a remission rate that greatly exceeded the 
approximate 40 in comparable subjects from earlier studies (Messinger 2012). 
3.2.1 
Preclinical Background for Investigational Drug 
Carfilzomib (formerly known as PR-171) is a tetrapeptide epoxyketone-based inhibitor of 
the chymotrypsin-like activity of the 20S proteasome.  Carfilzomib, which is structurally 
and mechanistically different from the dipeptide boronic acid proteasome inhibitor 
bortezomib, showed less off-target activity when measured against a broad panel of 


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proteases including metallo-, aspartyl-, and serine proteases compared to bortezomib; 
the latter showed off-target inhibitory activity in the nanomolar range against several 
serine proteases (Arastu-Kapur 2009).  This selectivity may be responsible for the 
reductions in myelosuppression and neuropathy observed in preclinical studies 
comparing carfilzomib with bortezomib. 
Based on in vitro and in vivo studies, it is anticipated that a more intense and sustained 
proteasome inhibition can be achieved with carfilzomib relative to bortezomib, resulting 
in enhanced antitumor activity.  Continuous 72-hour exposure to carfilzomib was 
associated with potent cytotoxic and pro-apoptotic activity across a broad panel of 
tumor-derived cell lines in culture (Demo 2007).  Incubation of hematologic tumor cell 
lines with carfilzomib for as little as 1 hour led to rapid inhibition of proteasome activity 
followed by accumulation of polyubiquitinated proteins and induction of apoptotic cell 
death.  Carfilzomib was also cytotoxic in bortezomib-resistant tumor cell lines 
(Suzuki 2011; Kuhn 2007). 
Preclinical studies in rats and monkeys have been performed administering carfilzomib 
intravenously (IV) for 5 consecutive days followed by 9 days of rest for 2 cycles.  
Proteasome inhibition of more than 80 was achieved, suggesting that high-level 
inhibition of the proteasome with the epoxyketone class is possible, affording new 
opportunities to escalate dose to optimize antitumor effects (Onyx data on file, and 
Yang 2011).  This finding was in contrast to preclinical testing with the boronate class of 
inhibitors that prohibited uninterrupted daily dosing due to substantial morbidity and 
mortality.  Carfilzomib has also been administered to rats and monkeys for 6 and 
9 months, respectively (once daily x 2:  once daily dosing for 2 consecutive days for 
3 weeks on a 28-day cycle).  Carfilzomib was well tolerated at doses resulting in more 
than 80 proteasome inhibition, with no behavioral or histological evidence of peripheral 
neuropathy (PN) and no neutropenia (Onyx data on file and Carfilzomib Investigator’s 
Brochure [IB]).  In contrast, rats and monkeys treated with bortezomib in chronic toxicity 
studies were shown to have reduced motor activity, convulsions, tremors, and hind-limb 
paralysis accompanied by histological degeneration in peripheral nerves, as well as 
significant neutropenia (Velcade [bortezomib] full prescribing information [Millennium 
Pharmaceuticals 2012] and Velcade Summary of Product Characteristics [SmPC] [High 
Wycombe, Bucks, UK 2012]).   


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3.2.2 
Clinical Background for Investigational Drug 
As of 10 July 2015, approximately 2921 individual subjects have been treated with 
carfilzomib as participants in Onyx-sponsored clinical studies, and 89 subjects have 
been enrolled in studies in Japan sponsored by Ono Pharmaceutical Company.  
Approximately 3549 subjects have been treated with carfilzomib through the 
76 completed or actively enrolling investigator-sponsored trials (ISTs) (Carfilzomib IB). 
There are five Phase 3 studies in multiple myeloma:  PX-171-009 (ASPIRE), 
PX-171-011 (FOCUS), 2011-003 (ENDEAVOR), 2012-005 (CLARION), and 20140355 
(A.R.R.O.W.).  Additionally, 137 subjects with solid tumors have been treated with 
carfilzomib.   
These trials have explored various doses of carfilzomib either as monotherapy or in 
combination with other agents and in the majority of studies conducted to date, 
carfilzomib has been administered on 2 consecutive days for 3 weeks in a 28-day cycle.  
Carfilzomib clinical activity has been demonstrated in these studies along with an 
acceptable safety profile.  
Higher doses of carfilzomib administered on a twice-weekly schedule have been studied.  
PX-171-007, a Phase 1b/2 study, was the first to establish the MTD of single agent 
carfilzomib administered as a 30-minute infusion in subjects with relapsed and/or 
refractory multiple myeloma (Papadopoulos 2015).  Subjects received carfilzomib 
monotherapy on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  Cycle 1 Day 1 and Day 2 
doses were 20 mg/m2 followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2.  
Carfilzomib was administered later with low-dose dexamethasone (40 mg/week) at the 
45 mg/m2 and 56 mg/m2 dose levels.  Thirty-three subjects were treated and there were 
dose-limiting toxicities (DLTs) in 2 subjects dosed at 70 mg/m2 of renal tubular necrosis 
(Grade 3) and proteinuria (Grade 3).  The MTD was determined to be 56 mg/m2.  
In the 56 mg/m2 cohort (n  24), the most common treatment-related adverse events 
(AEs) of any grade were nausea (54.2), dyspnea (50.0), fatigue (45.8), pyrexia 
(41.7), and thrombocytopenia and chills (both 37.5); a majority were Grade 1 or 2.  
At this dose, hematologic AEs of thrombocytopenia (37.5) and anemia (16.7) were 
the most common treatment-related AEs of  Grade 3.  When carfilzomib at 56 mg/m2 
was combined with dexamethasone (n  8), nausea (25), fatigue (25), and dyspnea 
and chills (each 12.5) occurred less frequently than with carfilzomib alone.  The overall 
response rate (ORR) was 50 in the 56 mg/m2 cohort where the majority of subjects 


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were refractory to IMiDs and bortezomib.  The Phase 2 PX-171-003 – Part 2 (A1) study 
with single agent carfilzomib at 20/27 mg/m2 in a similar population had an ORR of 
22.9 in the Safety population.  
Additional information on the safety and activity of carfilzomib is described in the 
Carfilzomib IB.  
3.3 
Dose Rationale 
Carfilzomib has been evaluated as a single agent and as part of a combination regimen 
for the treatment of adult subjects with multiple myeloma.  Carfilzomib has not been 
previously studied in children.  The MTD for single-agent carfilzomib administered by 
IV infusion over 30 minutes on 2 consecutive days per week has been determined to be 
56 mg/m2 (Study PX-171-007).  In combination with melphalan and prednisone, the MTD 
of carfilzomib administered on this same schedule has been determined to be 36 mg/m2 
(Kolb 2012).  Assuming no substantial differences in metabolism of carfilzomib between 
adults and children, these clinical data in adults suggest that the MTD for carfilzomib 
combined with chemotherapy is likely to occur in the range of 36 to 56 mg/m2 with twice 
weekly dosing.   The current planned dose range of 27 to 70 mg/m2 on twice weekly 
schedule spans either side of this range by 1 dose level. 
Current practice is to start with 20 mg/m2 of carfilzomib before escalating to a higher 
dose.  The approved regimen for carfilzomib monotherapy includes escalation on Day 1 
of Cycle 2.  All other ongoing clinical trials of carfilzomib escalate on Day 8 of Cycle 1. 
The first generation proteasome inhibitor, bortezomib, when used at the approved dose 
and schedule for multiple myeloma, has been shown to have clinical activity in pediatric 
subjects with ALL when used concurrently with a VXLD backbone (Messinger 2010). 
Carfilzomib is primarily metabolized by epoxide hydrolase and peptidase, which are 
expected to be fully functional in pediatric populations (Auricchio 1981; McCarver 2002; 
Omiecinski 1994).  Carfilzomib dosing will be adjusted based on body surface area 
(BSA) of the individual subject.  Pharmacokinetic (PK) simulations for likely exposure 
achieved in pediatric populations based on an adult population PK model have been 
conducted.  The simulation model supports a carfilzomib starting dose of 20 mg/m2 for 
the initial pediatric study followed by a 27, 36, and 45 mg/m2 dose-escalation scheme.  
Based on the available data in adults with multiple myeloma, we anticipated the MTD to 
be close to 36 mg/m2/dose.  However, the 45 mg/m2 dose level was recently found to be 
tolerable and to date the 56 mg/m2 dose level has yet to identify an MTD.   


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Preliminary pharmacokinetic data in children who received 20, 27, 36, 45, and 56 mg/m2 
of carfilzomib suggested that carfilzomib exposures were dose proportional across this 
range and did not differ significantly comparing ages 1 to 5, 6 to 12, and 12 years.  
Compared to adults, the geometric mean of dose normalized exposures (Cmax and AUC) 
was similar, considering the high pharmacokinetic variability observed.  Prior to protocol 
amendment 6, preliminary PK analyses on the first 3 dose levels up to 36 mg/m2 had 
found an approximate 40 reduction in exposures in children versus adults and was 
used to support protocol amendment 6 to add the current 56 and 70 mg/m2 dose levels.  
These findings suggest that the MTD is likely to be in the upper part of the 36 to 
56 mg/m2 dose range. 
Prior to Protocol Amendment 3, 11 subjects (8 of them DLT evaluable) were treated with 
carfilzomib (20 or 27 mg/m2) in combination with the R3 chemotherapy backbone 
(hereafter referred to as Dose Escalation 1); the MTD was determined to be 27 mg/m2.  
This MTD was lower than anticipated, and some of the toxicity observed is hypothesized 
to have been caused by the R3 chemotherapy backbone.  Dose Escalation 2 (combining 
carfilzomib with a VXLD [vincristine, dexamethasone, PEG-asparaginase, daunorubicin] 
chemotherapy backbone) was introduced to test this hypothesis.  Because 20 mg/m2 
(Dose Level 1) is lower than the MTD of carfilzomib in combination with the likely more 
toxic R3 chemotherapy backbone, the dose escalation of carfilzomib in combination with 
the VXLD chemotherapy backbone will start at 27 mg/m2 (Dose Level 2). 
4. 
Study Objectives 
The phase 2 protocol, including the phase 2 objectives is provided in Appendix K.   
4.1 
Primary Objectives 
The primary objectives of this study are: 
 
To assess the safety and tolerability of carfilzomib, alone and in combination with 
induction chemotherapy, for the treatment of children with relapsed or refractory 
ALL 
 
To determine the MTD of carfilzomib in combination with induction chemotherapy 
and to recommend a phase 2 dose of carfilzomib in combination with induction 
chemotherapy 
4.2 
Secondary Objectives 
The secondary objectives of this study are: 
 
To characterize the PK of carfilzomib alone and in combination with induction 
chemotherapy 


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 
To evaluate the combined rate of bone marrow CR and bone marrow CRp at the 
end of the Induction Cycle 
 
To estimate the proportion of subjects who achieve MRD status  10-3 and  10-4 
lymphoblasts at the end of the Induction Cycle 
5. 
Study Design 
The phase 2 protocol, including the phase 2 part of the study design is provided in 
Appendix K.   


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Figure 1.  Phase 1b Schema 
 
5.1 
Type/Design of Study 
This is a nonrandomized, multicenter, Phase 1b dose-escalation study of carfilzomib in 
combination with induction chemotherapy, comprising either an R3 backbone of 
dexamethasone, mitoxantrone, PEG-asparaginase, and vincristine (Dose Escalation 1) 


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or a VXLD backbone of vincristine, dexamethasone, PEG-asparaginase, and 
daunorubicin (Dose Escalation 2) in children with relapsed or refractory ALL. 
Subjects who were 21 years old or younger at the time of their initial ALL diagnosis will 
be enrolled at approximately 50 pediatric oncology centers located in the US, Canada, 
Australia, Israel, or Europe.  Approximately 18 subjects will participate in the R3 dose 
escalation and approximately 24 will participate in the second dose escalation for VXLD.  
Additional subjects may be enrolled to treat up to 12 subjects at the MTD.  
Every effort will be made to enroll a minimum of 3 subjects who fall into each of the 
following age groups at the time of their enrollment onto this study: 
 
12 to  24 months old 
 
2 to  12 years old 
 
12 to 18 years old 
 
A minimum number for subject enrollment will not be applied to subjects over 
18 years of age.  No infants ( 12 months of age) will be enrolled, although subjects 
originally diagnosed with ALL during infancy are eligible if they are at least 
12 months old at the time of study treatment initiation.   
There is no predetermined maximum number of subjects per age group, however, the 
sponsor may temporarily or permanently close enrollment to a particular age group, if 
the distribution of subjects across age groups appears imbalanced. 
During the Dose Escalation 1 (R3) portion of the study only, the Induction Cycle will be 
preceded by a 1-week carfilzomib single-agent Lead-in Window.  Subjects in both dose 
escalation portions of the study will receive a 4-week cycle of induction chemotherapy 
and have the option to receive a 4-week cycle of consolidation chemotherapy, if SD or 
better response is achieved at the end of the Induction Cycle.  Refer to the Study Design 
Schema (Figure 1) and to Section 8, Dosage and Treatment Administration, for further 
details about the treatment regimen. 
5.2 
Dose-escalation Plan 
The Phase 1b dose-escalation design will use the Bayesian 2-parameter logistic 
regression model, the new continual reassessment method (NCRM) applied to observed 
DLTs occurring during the Lead-in Window and Induction Cycle (Neuenschwander 
2008).  The prior distribution and the data available after each dose cohort are applied to 
an algorithm that computes the posterior distribution of the DLT rate at each dose level.  
The posterior probabilities of the estimated DLT rate at each dose to fall into target 


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toxicity interval (20-33) or excessive/unacceptable toxicity interval ( 33–100) will 
be used in the dose-escalation decision and the final determination of the MTD. 
A cohort size of 2 will be used in Dose Escalation 1 (R3).  The starting dose is 20 mg/m2; 
the maximum planned dose and the minimum planned dose are 45 mg/m2 and 
20 mg/m2, respectively.  One or more cohorts of 2 subjects may be enrolled to each 
dose level, depending on the toxicity observed.  The Cohort Safety Review Committee 
([CSRC]; whose membership is described in Section 13.4) will review the safety data 
and dose level recommended by the algorithm after every cohort has completed the 
4-week Induction Cycle.  The CSRC will expand the dose level by 2 subjects, advance to 
the next dose level, or de-escalate to a lower dose level, based on the available data.  
No dose-level skipping will be allowed in dose-escalation decisions.  There is no such 
constraint on de-escalation decisions.  The algorithm will stop when the sample size 
reaches 18 or when the DLT rate of the recommended MTD has a 95 posterior 
credible interval that falls within the prespecified range of 5 to 60. 
A cohort size of 3 will be used in Dose Escalation 2 (VXLD).  The starting dose level is 
27 mg/m2; the planned dose levels are 27, 36, 45, 56, and 70 mg/m2.  One or more 
cohorts of 3 subjects may be enrolled to each dose level, depending on the toxicity 
observed.  The CSRC will review the safety data and dose level recommended by the 
algorithm after every cohort has completed the 4-week Induction Cycle.  The CSRC will 
expand the dose level by 3 subjects, advance to the next dose level, or de-escalate to a 
lower dose level, on the basis of the available data.  No dose-level skipping will be 
allowed in dose-escalation decisions.  There is no such constraint on de-escalation 
decisions.  If clinically justified, CSRC may halt enrollment and recommend the MTD or 
the dose for the phase 2 part of the study based on available data.  More details are 
presented in the CSRC charter (see Section 13.4).  The algorithm will stop when the 
sample size reaches 24 or if both of the first two criteria, or the third criterion are met: 
 
The probability of the Target Toxicity interval at the candidate MTD exceeds 40 
AND 
 
A minimum of 2 cohorts (6 subjects) are accrued and treated at the candidate MTD 
OR 
 
The algorithm recommends a dose level that has been recommended twice and with 
6 subjects treated, and the CSRC agrees with the recommendation 


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A minimum of 2 subjects (1 cohort) will be enrolled at the starting dose level in Dose 
Escalation 1 (R3).  For the NCRM, the relationship between dose and the probability of 
DLT will be updated as additional subject safety information becomes available (eg, after 
the last subject in the cohort completes the Induction Cycle).  After all subjects enrolled 
at the starting dose level are DLT-evaluable, the Bayesian Logistic Regression (BLR) 
model will be updated, and the NCRM will recommend the next dose level from the 
updated probabilities for target toxicity interval and excessive/unacceptable toxicity 
interval.  The next dose level (eg, the Dose Level 2 or continuation of Dose Level 1) will 
be the dose with the highest posterior probability of having a toxicity rate in the target 
toxicity interval, which is defined as 20–33, and will be subject to the constraint that 
the probability of excessive/unacceptable toxicity, which is defined as  33-100, is 
less than 40.  The MTD will be selected based on the above criteria or the stopping 
criteria as specified in Section 5.2 and the recommendation of the CSRC. 
A minimum of 3 subjects (1 cohort) will be enrolled at the starting dose level in Dose 
Escalation 2 (VXLD).   
When the algorithm recommends an MTD, the CSRC will review the data and 
recommend a dose for the Phase 2 part of the study. 
5.3 
Estimated Study Duration and Study Closure 
The total study duration is expected to be a minimum of 48 months.  Therefore, it is 
estimated that the final analysis will occur approximately 4 months after the last subject 
is enrolled.  The study will be considered complete when the last subject has finished 
study treatment and all required follow-up assessments. 
6. 
Subject Eligibility 
The phase 2 protocol, including details on phase 2 subject eligibility are provided in 
Appendix K.   


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6.1 
Inclusion Criteria 
Inclusion criteria for the phase 1b part of the study are the following: 
1. 
Age 21 years or younger at the time of initial ALL diagnosis and age  1 year at the 
time of study treatment initiation. 
2. 
Subjects must have a diagnosis of ALL with  5 blasts in the bone marrow (M2 or 
M3 disease), with or without extramedullary disease. 
 
To be eligible, subjects must have had 1 or more prior therapeutic attempts, 
defined as: 
o Early first relapse ( 36 months from original diagnosis) after achieving a CR 
(B-ALL) or first relapse any time following the original diagnosis after 
achieving a CR (T-ALL) 
OR 
o First refractory bone marrow relapse occurring any time after original 
diagnosis after achieving a CR (ie,  1 failed attempt to induce a second 
remission) 
OR 
 
Relapse after achieving a CR following the first or subsequent relapse 
(ie,  2 relapses) 
OR 
 
Failing to achieve a CR from original diagnosis after at least 1 induction attempt 
3. 
Subjects must have fully recovered from the acute toxic effects of all previous 
chemotherapy, immunotherapy, or radiotherapy treatment before enrollment. 
4. 
Subjects must have a serum creatinine level that is  1.5 x institutional upper limit of 
normal (ULN) according to age.  If serum creatinine level is  1.5 x ULN, the subject 
must have a calculated creatinine clearance or radioisotope glomerular filtration rate 
(GFR)  70 mL/min/1.73 m2, or for children  2 years of age,  50 mL/min/1.73 m2. 
5. 
Adequate liver function, defined as both of the following: 
 
Total bilirubin  1.5 x institutional ULN, except in the presence of Gilbert 
syndrome.  For those with hyperbilirubinemia due to Gilbert syndrome, subjects 
are only eligible if they have a direct bilirubin  1.5 x institutional ULN. 
 
Alanine aminotransferase (ALT)  5 x institutional ULN 
6. 
Performance status:  Karnofsky or Lansky scores  50 for subjects  16 years old or 
 16 years old, respectively.  See Appendix F 
7. 
Females of childbearing potential (FCBP) must have a negative serum or urine 
pregnancy test within 48 hours prior to study treatment initiation. 
8. 
Females of childbearing potential and male subjects who are sexually active with a 
FCBP must agree to use a highly effective method of contraception plus a male 
condom during the study and for 6 months following the last dose of study 


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treatment.  The methods of contraception are defined in the ICF.  Where required 
by local laws, regulations and/or guidelines, additional country-specific requirements 
are outlined in a country-specific protocol supplement. 
9. 
Subjects must provide written informed consent and pediatric assent in accordance 
with federal, local, and institutional laws and regulations. 
6.2 
Exclusion Criteria 
Exclusion criteria for the phase 1b part of the study are the following: 
1. Known allergy to any of the drugs used in the study. 
(Subjects who have had a previous allergy to PEG-asparaginase are eligible and 
if able, may receive Erwinia asparaginase at the investigator’s discretion.) 
2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib; 
for a complete listing of Captisol-enabled drugs, see the Ligand Pharmaceuticals, 
Inc. website) 
3. Left ventricular fractional shortening  30 
4. History of  Grade 2 pancreatitis 
5. Active graft-versus-host disease requiring systemic treatment 
6. Positive culture for or other clinical evidence of infection with bacteria or fungus 
within 14 days of the initiation of study treatment 
7. Down Syndrome 
8. Prior therapy restrictions: 
 
Subjects must have completed therapy with granulocyte-colony stimulating 
factor (G-CSF) or other myeloid growth factors at least 7 days before study 
treatment initiation, or at least 14 days before study treatment initiation, if 
pegylated myeloid growth factors were administered. 
 
Subjects must have received the last dose of a non-monoclonal antibody 
biologic agent at least 7 days before study treatment initiation.  For agents 
that have known adverse events (AEs) occurring beyond 7 days after the last 
administration, this period must be extended beyond the time during which 
AEs are known to occur, and the Sponsor study medical monitor should be 
contacted. 
 
At least 3 antibody half-lives must have elapsed since the last dose of 
monoclonal antibody (eg, 66 days for rituximab, 69 days for epratuzumab, 
and 36 days for inotuzumab) before subjects may initiate study treatment. 
 
Subjects must have completed any type of active immunotherapy (eg, tumor 
vaccines) at least 42 days before study treatment initiation. 
 
Subjects must not have received other antineoplastic agents with therapeutic 
intent, excluding hydroxyurea and antimetabolites administered as part of 
maintenance chemotherapy, within 7 days prior to study treatment initiation. 
9. Females who are pregnant and/or breastfeeding 
10. Hepatitis B infection with positive hepatitis B DNA 


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7. 
Subject Screening and Enrollment 
The phase 2 protocol, including details on phase 2 screening and enrollment are 
provided in Appendix K.   
An informed consent form (ICF) must be signed and dated by the subject or the subject’s 
legally acceptable representative before any study-specified tests may be performed.  
A signed and dated pediatric assent form must also be obtained, in accordance with 
local laws and regulations, prior to performing any study-specified tests on a child of 
appropriate age and development.  Subjects who reach the age of majority during study 
participation must sign a new ICF, in order for study participation to continue. 
Subjects are assigned an identification number when informed consent has been 
obtained.  The subject identification number will be assigned by Interactive Web 
Response System (IWRS).  This number is used to identify the subject throughout the 
study and must appear on all study-related documentation and communications.  
Eligibility and enrollment of subjects will ultimately be determined by the investigator; 
however, in the phase 1b part of the study, the study medical monitor will first review 
results of the required screening assessments and may provide feedback to the 
investigator.  Screening assessments are presented in Table 1 and, where needed, are 
further described in the text that follows.  Evaluations performed as part of routine 
medical care may be used to satisfy the screening requirements, provided that informed 
consent for the use of these data was obtained and the evaluations took place within the 
required timeframe. 


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Table 1.  Phase 1 Screening Assessments 
Assessment 
Up to 72 Hours 
Before 
Enrollment 
Up to 7 Days 
Before Enrollment 
Complete history and physical examination 
X 
 
Bone marrow aspirate 
 
Xa 
Lumbar puncture 
 
X 
Examination for testicular involvement 
 
X 
ECG (12-lead) 
 
X 
Echocardiogram (fractional shortening) 
 
X 
Local laboratory evaluations: 
 
 
CBC with differential and platelet count 
X 
 
Serum electrolytes:  Na, K, Cl, CO2, Ca, Mg, P 
X 
 
Blood glucose 
X 
 
Renal function:  BUN, Cr; NM-GFR only if Cr 1.5 x 
ULN 
X 
 
Hepatic function: 
AST, ALT, total and direct bilirubin, ALP, albumin 
X 
 
Pancreatic function:  amylase, lipase 
X 
 
Uric acid 
X 
 
Serum or urine pregnancy test, FCBP 
X 
 
Hepatitis B testing 
 
Xb 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; anti-HBs  hepatitis B surface antibody; 
AST  aspartate aminotransferase; BUN  blood urea nitrogen; CBC  complete blood count; Cr  serum 
creatinine; ECG  electrocardiogram; FCBP  female of childbearing potential; HBV  hepatitis B virus; 
NM-GFR  nuclear magnetic-glomerular filtration rate; ULN  upper limit of normal. 
 
b Hepatitis serologies may be obtained up to 2 weeks prior to enrollment.  Testing is not required if tested 
negative within 6 months of screening and no change in the subject’s risk factors within these 6 months.  
Subjects with positive testing or a history of prior hepatitis B virus (HBV) infection should have 
consultation with a specialist and must have HBV-DNA testing at screening and again at safety follow up.  
Subjects that have received hepatitis B vaccination with only anti-HBs positivity and no clinical signs of 
hepatitis do not require HBV-DNA monitoring.   
Physical Examination 
A complete history and physical examination must include all of the following: 
 
Review of medical and surgical histories, including: 
o Prior cumulative anthracycline exposure (refer to Appendix G, Guidance 
for Determining Previous Cumulative Anthracycline Dose) 
o Known or suspected cancer predisposition syndromes 


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o Other co-morbidities which, in the investigator’s opinion, either place a 
subject at increased risk for AEs, or have potential impact on the results 
of study-specified tests.  This includes, but is not limited to: 
− Endocrinopathies 
− Gastrointestinal disorders 
− Inborn errors of metabolism 
− Congenital heart disease, repaired or unrepaired 
− Epilepsy 
o Documentation of all current medications 
 
Vital signs: 
o Temperature 
o Heart rate 
o Respiratory rate 
o Systolic and diastolic blood pressures 
 
Weight, height, and BSA 
 
Performance status assessment (Appendix F): 
o Lansky score if  16 years of age 
o Karnofsky score if  16 years of age 
 
Examination of all of the following: 
o Head 
o Ears 
o Eyes 
o Nose 
o Oropharynx 
o Neck 
o Heart 
o Lungs 
o Abdomen 
o Genitalia 
o Back 
o Extremities 
o Lymph nodes 
o Skin 
o Nervous system 
 
Determination of the baseline NCI-CTCAE (Version 4.03) grade for all abnormal 
physical examination findings 


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Bone Marrow Aspirate 
Bone marrow aspirate must be obtained and a morphologic diagnosis of relapsed or 
refractory ALL must be determined prior to study enrollment.  In the event that aspirate 
cannot be obtained, diagnosis may be made by biopsy.  It is not necessary for the 
results of immunophenotyping or cytogenetic studies to be available prior to enrollment 
or the initiation of study treatment.  Bone marrow status definitions are provided in 
Table 2. 
A portion of the bone marrow obtained during screening will be submitted to a central 
laboratory to facilitate the analysis of MRD.  Peripheral blood may be obtained prior to 
treatment and submitted in its place, only for subjects from whom sufficient bone marrow 
could not be obtained.  Instructions for the collection and submission of MRD specimens 
are provided in the Laboratory Manual. 
Note:  Although not part of the screening assessment, a sample for 
 
 must be obtained at the time of the diagnostic bone marrow aspirate for subjects 
from whom consent for these optional studies has been obtained. 
Table 2.  Phase 1 and 2 Bone Marrow Status Definitions 
Status Level 
Description 
M1 Marrow 
Less than 5 blasts in a bone marrow aspirate and at least 200 cells counted 
M2 Marrow 
5–25 blasts in a bone marrow aspirate with at least 200 cells counted 
M3 Marrow 
Greater than 25 blasts in a bone marrow aspirate with at least 200 cells 
counted 
Lumbar Puncture 
Cerebrospinal fluid must be obtained prior to the initiation of study treatment and 
examination must include: 
 
Red blood cell (RBC) count 
 
White blood cell (WBC) count 
 
Differential 
 
Cytology 
It is not necessary for central nervous system (CNS) status to be declared prior to the 
initiation of study treatment.  CNS status must be declared prior to the second scheduled 
lumbar puncture, however, as this informs the treatment regimen from that day on.  CNS 
status definitions are provided in Table 3. 


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Table 3.  Phase 1 and 2 CNS Status Definitions 
CNS Status Level 
Description 
CNS 1 
In CSF, absence of blasts on cytospin preparation, regardless of the number of 
WBCs 
CNS 2 
In CSF, presence  5 mcl WBCs and cytospin positive for blasts, or  5 mcl WBCs 
but negative by Steinherz/Bleyer algorithma: 
 
CNS 2a 
 10 mcl RBCs;  5 mcl WBCs and cytospin positive for blasts 
 
CNS 2b 
 10 mcl RBCs;  5 mcl WBCs and cytospin positive for blasts 
 
CNS 2c 
 10 mcl RBCs;  5 mcl WBCs and cytospin positive for blasts but 
negative by Steinherz/Bleyer algorithma 
CNS 3 
In CSF, presence of  5/L WBCs and cytospin positive for blasts and/or clinical 
signs of CNS leukemia: 
 
CNS 3a 
 10 mcl RBCs;  5 mcl WBCs and cytospin positive for blasts 
 
CNS 3b 
 10 mcl RBCs,  5 mcl WBCs and positive by Steinherz/Bleyer 
algorithma 
 
CNS 3c 
Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye 
involvement or hypothalamic syndrome) 
CNS  central nervous system; CSF  cerebrospinal fluid; RBC  red blood cell; WBC  white blood cell. 
a If the subject has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and contains 
 5 WBC/mcl and blasts, the following Steinherz/Bleyer algorithm should be used to distinguish between 
CNS2 and CNS3 disease: 
CSF WBC  2X Blood WBC 
 CSF RBC 
Blood RBC 
Subjects with CNS 3 leukemia will be considered to be CNS-positive throughout this 
study.  All other subjects are considered to be CNS-negative. 
The first dose of intrathecal (IT) chemotherapy may be given with the diagnostic lumbar 
puncture, in accordance with institutional practice, and is considered to be part of Day 1 
study treatment, provided that study enrollment and the remainder of Day 1 study 
treatment occur within the required timeframe. 
A single-page screening assessments reference is provided in Appendix A. 
8. 
Dosage and Treatment Administration 
The phase 2 protocol, including details on phase 2 dose and treatment administration 
are provided in Appendix K.   
Study treatment should be initiated within approximately 48 hours after enrollment.  The 
Sponsor study medical monitor should be contacted if circumstances prevent this. 


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A  1-day window is permitted for the delivery of all scheduled study treatments.  Other 
backbone chemotherapy and assessments may be aligned with carfilzomib based on 
investigator discretion. 
8.1 
Treatment Administration 
8.1.1 
Carfilzomib Single-agent Lead-in Window (Dose Escalation 1 [R3] 
Only) 
During the Dose Escalation 1 (R3) portion of the study only, the Induction Cycle will be 
preceded by a 1-week carfilzomib single-agent Lead-in Window.  The schedule of 
treatment and response assessments for the Lead-in Window is presented in Table 4. 
Table 4.  Phase 1 Schedule of Treatment and Response Assessments, Lead-in 
Window 
Study Drug 
Cycle Days 
1 
2 
8 
Systemic Treatment 
 
 
 
Carfilzomib 
X 
X 
 
Premedication with dexamethasone 
X 
X 
 
Prehydration 
X 
X 
 
CNS Treatment 
 
 
 
Chemotherapy with Diagnostic Lumbar Puncturea 
X 
 
 
Response Assessment 
 
 
X 
Note:  Lead-in Window will only occur in the Dose Escalation 1 (R3) portion of the study. 
a Intrathecal chemotherapy per institutional practice; may include cytarabine, methotrexate, or triple therapy 
(cytarabine, hydrocortisone, and methotrexate). 
Carfilzomib 
Carfilzomib will be given as an IV infusion over approximately 30 ( 5) minutes on 
Days 1 and 2 of the carfilzomib single-agent Lead-in Window.  Subjects in all cohorts will 
receive 20 mg/m2 of carfilzomib on Day 1 of the Lead-in Window; the Day 2 carfilzomib 
infusions will be given at the assigned dose level for each cohort: 
 
Dose Level 1:  20 mg/m2 
 
Dose Level 2:  27 mg/m2 
 
Dose Level 3:  36 mg/m2 
 
Dose Level 4:  45 mg/m2 
Subjects with a BSA  2.2 m2 will receive a dose calculated based on a BSA of 2.2 m2.  
Premedication with 3 mg/m2 of dexamethasone (oral or IV) will be administered 
approximately 30 minutes prior to the start of each carfilzomib infusion. 


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Adequate hydration is required to mitigate the risks for TLS and pre-renal azotemia, 
which have been associated with carfilzomib.  Prehydration with at least 125 mL/m2/hour 
of IV fluid is required for 1 hour prior to carfilzomib administration; hydration 
management is otherwise at the investigator’s discretion and should be appropriate for 
the clinical situation.  Detailed supportive care guidelines regarding TLS are provided in 
Section 9.1. 
Central Nervous System Treatment (According to age-based dosing presented in 
Table 6) 
Preservative-free forms of cytarabine, hydrocortisone, and methotrexate should be used 
for IT administration. 
 
Intrathecal chemotherapy in accordance with institutional practice given within 
7 days before enrollment or on Day 1 
Disease Progression During the Carfilzomib Single-agent Lead-in Window 
If the subject has a greater than 25 increase in circulating blasts during the carfilzomib 
single-agent Lead-in Window and the investigator deems them no longer suitable for 
single-agent therapy, the subject will be advanced to Day 1 of the Induction Cycle and 
will begin combination chemotherapy.  Should this occur, Days 1 and 2 carfilzomib 
doses during the Induction Cycle will be eliminated and the subject will receive 6, rather 
than 8, total doses of carfilzomib prior to the end-of-induction response assessment.  
8.1.2 
Induction (Dose Escalation 1 [R3] and Dose Escalation 2 [VXLD]) 
The Induction Cycle consists of a 4-week cycle of treatment that includes carfilzomib and 
a combination chemotherapy backbone (R3 in Dose Escalation 1 or VXLD in Dose 
Escalation 2).  During the Dose Escalation 1 portion of the study, the Induction Cycle 
begins on Day 8 of the carfilzomib single-agent Lead-in Window and there are no 
minimum blood cell count requirements in order to begin.  During the Dose Escalation 2 
portion of the study, induction is the first cycle of therapy that the subject will receive. 
The schedule of treatment and response assessments for the Induction Cycle is 
presented in Table 5.  Induction Cycle Road Maps for Dose Escalation 1 and Dose 
Escalation 2 are provided in Figure 2 and Figure 3 respectively. 
 


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Table 5.  Phase 1 Schedule of Treatment and Response Assessments, Induction Cycle 
Page 1 of 2 
Footnotes defined on next page 
Study Drug 
Cycle Days 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 
22 
23 24 25 26 27 
28 
29 
Systemic Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carfilzomiba 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication with 
dexamethasone 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prehydration 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
R3 Chemotherapy 
Backbone (Dose 
Escalation 1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dexamethasone 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Mitoxantrone 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEG-asparaginase  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vincristine 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
VXLD Chemotherapy 
Backbone (Dose 
Escalation 2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daunorubicin 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Dexamethasone 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PEG-asparaginase  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vincristine 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 


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Table 5.  Phase 1 Schedule of Treatment and Response Assessments, Induction Cycle 
Study Drug 
Cycle Days 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 
22 
23 24 25 26 27 
28 
29 
CNS Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy with 
Diagnostic Lumbar 
Punctureb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Escalation 1 
(R3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Escalation 2 
(VXLD) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IT Methotrexate  
(CNS-negative) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Escalation 1 
(R3) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Escalation 2 
(VXLD) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IT Triple Therapyc 
(CNS-positive) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Escalation 1 
(R3) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dose Escalation 2 
(VXLD) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Response Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Page 2 of 2 
CNS  central nervous system; IT  intrathecal; PEG  polyethylene glycol. 
a For dose escalation 2 (VXLD) carfilzomib administration may be within  1 days for each scheduled dose.  Other backbone chemotherapy and assessments may be 
aligned with carfilzomib based on investigator discretion. 
b Intrathecal chemotherapy per institutional practice; may include cytarabine, methotrexate, or triple therapy (cytarabine, hydrocortisone, and methotrexate). 
c Triple therapy comprises cytarabine, hydrocortisone, and methotrexate. 


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8.1.2.1 
Dose Escalation 1 (R3) 
Carfilzomib 
Carfilzomib will be given as an intravenous infusion over 30  5 minutes on Days 1, 2, 8, 
9, 15, and 16 of the Induction Cycle.  Subjects with a BSA  2.2 m2 will receive a dose 
calculated based on a BSA of 2.2 m2.  On the days on which the treatment regimen 
includes carfilzomib, but not dexamethasone (Days 8 and 9 of the Induction Cycle of 
Dose Escalation 1 [R3]), premedication with 3 mg/m2 of dexamethasone (oral or IV) will 
be administered approximately 30 minutes prior to the start of the carfilzomib infusion. 
Adequate hydration is required to mitigate the risks for TLS and pre-renal azotemia, 
which have been associated with carfilzomib.  Prehydration with at least 125 mL/m2/h of 
IV fluid is required for 1 hour prior to carfilzomib administration; hydration management 
is otherwise at the investigator’s discretion and should be appropriate for the clinical 
situation.  Detailed supportive care guidelines regarding TLS are provided in Section 9.1. 
During Dose Escalation 1 (R3), carfilzomib infusions will be given at the assigned dose 
level for each cohort: 
 
Dose Level 1:  20 mg/m2 
 
Dose Level 2:  27 mg/m2 
 
Dose Level 3:  36 mg/m2 
 
Dose Level 4:  45 mg/m2 
Induction Chemotherapy Backbone for Dose Escalation 1 (R3) 
 
Dexamethasone 10 mg/m2 given orally twice daily on Days 1–5 and 15–19 
o IV administration is acceptable, if the subject is unable to tolerate oral 
administration. 
o Round the calculated dosage up to the nearest one-half tablet or 0.1 mL. 
 
Mitoxantrone, 10 mg/m2 IV on Days 1 and 2 
o Infuse over 10−15 minutes in 5 Dextrose Injection, USP (D5W) 
 
PEG-asparaginase 1000 U/m2 IV on Days 3 and 18 
o Infuse over 1–2 hours in D5W or normal saline. 
o Rapid access to emergency medications (ie, epinephrine and 
methylprednisolone) during and for approximately 24 hours following 
dosage administration is strongly recommended. 
o See Section 8.4.9 for information regarding the substitution of Erwinia for 
PEG-asparaginase. 
 
Vincristine 1.5 mg/m2 (maximum 2-mg dose) IV on Days 3, 10, 17, and 24 
o Administer as an IV push over 1 minute or as an infusion, in accordance 
with institutional practice. 


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8.1.2.2 
Dose Escalation 2 (VXLD) 
Carfilzomib 
Carfilzomib will be dosed twice weekly over 30  5 minutes, on days 1, 2, 8, 9, 15, and 
16 of each 28-day cycle. Subjects with a BSA  2.2 m2 will receive a dose calculated 
based on a BSA of 2.2 m2.  The administration may be within  1 days for each 
scheduled dose.  Adequate hydration is required to mitigate the risks for TLS and 
pre-renal azotemia, which have been associated with carfilzomib.  Prehydration with at 
least 125 mL/m2/h of IV fluid is required for 1 hour prior to carfilzomib administration; 
hydration management is otherwise at the investigator’s discretion and should be 
appropriate for the clinical situation.  Detailed supportive care guidelines regarding TLS 
are provided in Section 9.1. 
During Dose Escalation 2 (VXLD), subjects will receive 20 mg/m2 of carfilzomib on Day 1 
of the Induction Cycle.  From Day 2 of the Induction Cycle on, carfilzomib will be infused 
at the assigned dose level for each cohort: 
 
Dose Level 2:  27 mg/m2 
 
Dose Level 3:  36 mg/m2 
 
Dose Level 4:  45 mg/m2 
 
Dose Level 5:  56 mg/m2 
 
Dose Level 6:  70 mg/m2 
Induction Chemotherapy Backbone for Dose Escalation 2 (VXLD) 
For phase 2 (Appendix K), the dose of daunorubincin has been adjusted and acceptable 
substitutions for components of VXLD have been incorporated based on local availability 
and standard practice.  In addition, a separate VXLD schedule is provided for infants.  
Section 22.1.2 provides details for the backbone dose and schedule for children 
 12 months and for infants  12 months (see also Table 15 and Table 17, respectively).   
Backbone therapy for phase 1 is described below.  If carfilzomib window is adjusted, 
scheduled backbone therapy may be adjusted  1 day to align with carfilzomib at 
investigator’s discretion. 
 
Daunorubicin, 25 mg/m2 IV on Days 1, 8, 15, and 22 
o Administer into a large vein as an IV push or as an infusion over 
1-15 minutes, or longer as required by institutional practice. 
o Administration in conjunction with rapidly infusing D5W or normal saline is 
recommended. 
o Protect from sunlight. 


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 
Dexamethasone 6 mg/m2 per day BID - given orally (3 mg/m2 per dose given 
twice daily) on Days 1-21 
o IV administration is acceptable, if the subject is unable to tolerate oral 
administration. 
o Round the calculated dosage up to the nearest one-half tablet or 0.1 mL. 
 
PEG-asparaginase 2500 U/m2 IV on Days 4 and 18 
o Infuse over 1–2 hours in D5W or normal saline. 
o Rapid access to emergency medications (ie, epinephrine and 
methylprednisolone) during and for approximately 24 hours following 
dosage administration is strongly recommended. 
o See Section 8.4.9 for information regarding the substitution of Erwinia for 
PEG-asparaginase. 
 
Vincristine 1.5 mg/m2 (maximum 2-mg dose) IV on Days 1, 8, 15, and 22 
o Administer as an IV push over 1 minute or as an infusion, in accordance 
with institutional practice. 
CNS Treatment (According to age-based dosing presented in Table 6) 
Preservative-free forms of cytarabine, hydrocortisone, and methotrexate should be used 
for intrathecal administration.   
 
CNS Treatment for Dose Escalation 1 (R3): 
 
CNS-negative subjects:  IT methotrexate given on Day 1 
 
CNS-positive subjects:  IT Triple Therapy (cytarabine, hydrocortisone, and 
methotrexate) given on Days 1, 8, 15, and 29 
 
CNS Treatment for Dose Escalation 2 (VXLD): 
 
Intrathecal (IT) chemotherapy in accordance with institutional practice given 
within 7 days before enrollment or on Day 1 
 
CNS-negative subjects:  IT methotrexate given on Day 8 
 
CNS-positive subjects:  IT Triple Therapy (cytarabine, hydrocortisone, and 
methotrexate) given on Days 8, 15, 22, and 29 
Table 6.  Phase 1 and 2 Age-based Dosing Guidelines 
Age (years) 
Dose 
Cytarabine (mg) 
Hydrocortisone (mg) 
Methotrexate (mg) 
1 to 1.99  
16 
8 
8 
2 to 2.99 
20 
10 
10 
3 to 8.99 
24 
12 
12 
 9 
30 
15 
15 


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Figure 2.  Study 20140106 Road Map, Induction Cycle, Dose Escalation 1 (R3) 
Section 8.1.2 Induction Cycle (Dose Escalation 1 [R3]) 
The Induction Cycle lasts for 4 weeks 
_________________________________ 
________________ 
Patient name or initials 
DOB 
 
Drug 
Route 
Dosage 
Days 
Important notes 
Methotrexate (MTX) 
(CNS negative) 
IT 
Age-based dosing (see table below) Day 1 
 
IT Triple Therapy (ITT) 
(CNS positive) 
IT 
Age-based dosing: 
Days 1, 8, 15, 
29 
IT Triple Therapy comprises: 
cytarabine (ARAC) 
hydrocortisone (HC) 
methotrexate (MTX) 
Age 
(yrs) 
ARAC HC MTX 
1 to 1.99 
16 
8 
8 
2 to 2.99 
20 
10 
10 
3 to 8.99 
24 
12 
12 
 9 
30 
15 
15 
Carfilzomib (CFZ) 
IV over 
30  5 min 
Dose Level 1:  20 mg/ m2 
Dose Level 2:  27 mg/ m2 
Dose Level 3:  36 mg/ m2 
Dose Level 4:  45 mg/ m2 
Days 1, 2, 8, 9, 
15, 16 
Prehydrate with 125 mL/ m2/hour x 1 hour prior to CFZ. 
Premedicate with 3 mg/ m2 of Dex (oral or IV)  30 minutes prior 
to CFZ on Days 8 and 9 only. 
If BSA  2.2 m2, base dose on a BSA of 2.2 m2. 
Dexamethasone (Dex) 
PO, IV 
10 mg/m2, twice daily 
Days 1–5, 
15–19 
Round the calculated dosage up to the nearest ½ tablet or 
0.1 mL. 
Mitoxantrone (Mito) 
IV over 10–15 min 
10 mg/ m2 
Days 1, 2 
 
PEG-asparaginase(PEG) IV over 1–2 hours 
1000 U/ m2 
Days 3, 18  
Rapid access to emergency medications (ie, epinephrine and 
methylprednisolone) for 24 hours following dosage 
administration is strongly recommended. 
Vincristine (VCR) 
IV push over 1 min 
1.5 mg/ m2 
Days 3, 10, 17, 
24 
2 mg maximum dose. 
Administration by infusion is acceptable. 
 


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Ht______cm 
Wt______kg 
BSA______m2 
Date 
Due 
Date 
Given 
Study 
Day 
CFZ 
____mg 
Dex 
____mg 
Mito 
____mg 
PEG 
____U 
VCR 
____mg 
Complete as applicable 
Comments (include any held 
doses, or dose modifications) 
IT MTX 
____mg 
ITT 
__mg/__mg/__mg 
ARAC/HC/MTX 
 
 
 
Enter calculated dose above and actual dose administered below. 
 
 
 
1 
____mg 
_____mg 
_____mg 
____mg 
 
 
____mg 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
 
 
 
2 
____mg 
_____mg 
_____mg 
____mg 
 
 
 
 
 
 
 
3 
 
_____mg 
_____mg 
 
____U 
____mg 
 
 
 
 
 
4 
 
_____mg 
mg 
 
 
 
 
 
 
 
 
5 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
8 
____mg 
 
 
 
 
 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
 
 
 
9 
____mg 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
____mg 
 
 
 
 
 
15 
____mg 
_____mg 
_____mg 
 
 
 
 
ARAC ____mg 
HC      ____mg 
MTX   
mg 
 
 
 
16 
____mg 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
17 
 
_____mg 
_____mg 
 
 
____mg 
 
 
 
 
 
18 
 
_____mg 
_____mg 
 
____U 
 
 
 
 
 
 
19 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
24 
 
 
 
 
____mg 
 
 
 
 
 
29 
 
 
 
 
 
 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
 
 
 
 
DOSE MODIFICATION GUIDELINES are provided in Section 8.4. 
If stable disease or better response is achieved at the end of the Induction Cycle, patients have the opportunity to participate in the Optional Consolidation 
Cycle.  A new Informed Consent Form, and pediatric assent (when applicable), must be obtained. 


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Figure 3.  Study 20140106 Road Map, Induction Cycle, Dose Escalation 2 (VXLD) 
Section 8.1.2 Induction Cycle (Dose Escalation 2 [VXLD]) 
The Induction Cycle lasts for 4 weeks 
_________________________________ 
________________ 
Patient name or initials 
DOB 
 
Drug 
Route 
Dosage 
Days 
Important notes 
Initial IT Chemotherapy 
IT 
Age-based dosing (see table below) or 
per institutional guidelines 
Day 1 or with 
diagnostic LP 
May include MTX, ITT, or ARAC. 
Methotrexate (MTX) 
(CNS negative) 
IT 
Age-based dosing (see table below) 
Day 8 
 
IT Triple Therapy (ITT) 
(CNS positive) 
IT 
Age-based dosing: 
Days 8, 15, 22, 29 IT Triple Therapy comprises: 
cytarabine (ARAC) 
hydrocortisone (HC) 
methotrexate (MTX) 
Age (yrs) ARAC 
HC 
MTX 
1 to 1.99 
16 
8 
8 
2 to 2.99 
20 
10 
10 
3 to 8.99 
24 
12 
12 
 9 
30 
15 
15 
Carfilzomib (CFZ) 
IV over 
30  5 min 
 
20 mg/m2 
 
Day 1 
Prehydrate with 125 mL/m2/hour x 1 hour prior to CFZ. 
If BSA  2.2 m2, base dose on a BSA of 2.2 m2. 
 
Administration may be within  1 days for each scheduled dose.  Other 
backbone chemotherapy and assessments may be aligned with 
carfilzomib based on investigator discretion. 
Dose Level 2:  27 mg/ m2 
Dose Level 3:  36 mg/ m2 
Dose Level 4:  45 mg/ m2 
Dose Level 5:  56 mg/m2 
Dose Level 6:  70 mg/m2 
Days 2, 8, 9, 15, 
16 
Daunorubicin (DNR) 
IV over 1–15 min 
25 mg/m2 
Days 1, 8, 15, and 
22 
Administration in conjunction with rapidly infusing D5W or normal saline 
is recommended. 
Protect from sunlight. 
Dexamethasone (Dex) 
PO, IV 
6 mg/m2 per day BID (3 mg/m2 per dose 
given twice daily) 
Days 1–21 
Round the calculated dosage up to the nearest ½ tablet or 0.1 mL. 
PEG-asparaginase(PEG) 
IV over 1–2 hours 
2500 U/m2 
Days 4, 18  
Rapid access to emergency medications (ie, epinephrine and 
methylprednisolone) for approximately 24 hours following dosage 
administration is strongly recommended.  
Vincristine (VCR) 
IV push over 1 min 
1.5 mg/m2 
Days 1, 8, 15, 22 
2 mg maximum dose. 
Administration by infusion is acceptable. 


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Ht______cm 
Wt______kg 
BSA______m2 
Date 
Due 
Date 
Given 
Study 
Day 
CFZ 
Day 1 
____mg 
Days 2 
onward 
____mg 
Dex 
____mg 
DNR 
____mg 
PEG 
____U 
VCR 
____mg 
Complete as applicable 
Comments (include any held 
doses, or dose modifications) 
IT MTX 
____mg 
ITT 
__mg/__mg/__mg 
ARAC/HC/MTX 
IT ARAC 
_____mg 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
____mg 
_____mg 
_____mg 
____mg 
 
____mg 
____mg 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
____mg 
_________ 
Date first IT  
chemotherapy given 
 
 
2 
____mg 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
3 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
4 
 
_____mg 
_____mg 
 
____U 
 
 
 
 
 
 
 
5 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
6 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
7 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
8 
____mg 
_____mg 
_____mg 
____mg 
 
____mg 
____mg 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
 
 
 
 
9 
____mg 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
10 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
11 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
12 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
13 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
14 
 
_____mg 
_____mg 
 
 
 
 
 
 
 


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Date 
Due 
Date 
Given 
Study 
Day 
CFZ 
Day 1 
____mg 
Days 2 
onward 
____mg 
Dex 
____mg 
DNR 
____mg 
PEG 
____U 
VCR 
____mg 
Complete as applicable 
Comments (include any held 
doses, or dose modifications) 
IT MTX 
____mg 
ITT 
__mg/__mg/__mg 
ARAC/HC/MTX 
IT ARAC 
_____mg 
 
 
15 
____mg 
_____mg 
_____mg 
____mg 
 
____mg 
 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
 
 
 
 
16 
____mg 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
17 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
18 
 
_____mg 
_____mg 
 
____U 
 
 
 
 
 
 
 
19 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
20 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
21 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
 
22 
 
 
____mg 
 
____mg 
 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
ARAC ____mg 
HC      
mg 
MTX   ____mg 
 
 
 
 
 
DOSE MODIFICATION GUIDELINES are provided in Section 8.4. 
If stable disease or better response is achieved at the end of the Induction Cycle, patients have the opportunity to participate in the Optional Consolidation 
Cycle.  A new Informed Consent Form, and pediatric assent (when applicable), must be obtained. 
 


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8.1.3 
Optional Consolidation 
Subjects with SD or better response at the end of the Induction Cycle will be offered an 
optional cycle of consolidation chemotherapy.  A new ICF and, where applicable, a new 
pediatric assent form will be required. 
The Optional Consolidation Cycle begins on Day 36 of the Induction Cycle (7 days after 
the Day 29 response assessment) or when absolute neutrophil count (ANC) is  750/mcl 
and platelet count is  75,000/mcl, whichever comes later.  Subjects with SD, partial 
response (PR), CRp, or complete remission with incomplete hematologic recovery (CRi) 
at the end of the Induction Cycle who are not expected to fully recover their blood counts 
may begin the optional cycle of consolidation on Day 36 of the Induction Cycle. 
The Optional Consolidation Cycle is composed of a single 4-week cycle of carfilzomib in 
combination with a Children’s Oncology Group (COG)-modified Berlin-Frankfurt-Münster 
(BFM) chemotherapy backbone (6-mercaptopurine, cyclophosphamide, cytarabine, 
PEG-asparaginase, vincristine), and appropriate CNS therapy administered according to 
the schedule of treatment and response assessments presented in Table 7. 
All drugs in the optional consolidation treatment regimen should be dosed based on 
weight, height, and BSA determined within 7 days of the start of the cycle. 
The Optional Consolidation Cycle Road Map is provided in Figure 4.  


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Table 7.  Phase 1 Schedule of Treatment and Response Assessment, 
Optional Consolidation Cycle 
Event 
Cycle Days 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 22 29 
Systemic treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carfilzomib 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
Premedication 
with 
dexamethasone 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
Chemotherapy 
Backbone 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-mercaptopurine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Cyclophosphamide X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytarabine 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
PEG-asparaginase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Vincristine  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
CNS treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IT Methotrexate 
(CNS-negative) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
IT Triple Therapya 
(CNS-positive) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Response 
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CNS  central nervous system; IT  intrathecal; PEG  polyethylene glycol. 
a Triple therapy comprises cytarabine, hydrocortisone, and methotrexate. 
Carfilzomib 
In phase 2 (Appendix K), consolidation for children  12 months will follow the structure 
below and is detailed in Table 19.  For infants  12 months, the consolidation dose and 
schedule is detailed in Table 21.  Permitted substitutions are listed in Section 22.1.2.1. 
Subjects who participate in the Optional Consolidation Cycle will receive carfilzomib as 
an IV infusion over 30  5 minutes on Days 1, 2, 8, 9, 15, and 16.  Carfilzomib will be 
administered at the same dose level to which the subject was assigned during the 
Lead-in Window and/or Induction Cycle.  Subjects with a BSA  2.2 m2 will receive a 
dose calculated based on a BSA of 2.2 m2.  For subjects in dose escalation 2 (VXLD) 
carfilzomib administration may be within  1 days for each scheduled dose.  
Premedication with 3 mg/m2 of dexamethasone (oral or IV) will be administered 
30 minutes prior to the start of each carfilzomib infusion. 
Prehydration is not required during the Optional Consolidation Cycle unless the subject 
remains at risk for TLS. 


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Consolidation Backbone 
 
6-mercaptopurine, 60 mg/m2 given orally on Days 1 to 14 
o Actual dose per day should be varied, as needed, to yield a weekly dose 
as close to 420 mg/m2 as possible. 
o See Section 8.4.2 for management of subjects with thiopurine 
methyltransferase (TPMT) polymorphisms. 
o Enteral administration is acceptable if the subject is unable to tolerate oral 
administration. 
o Administer at least 1 hour before and 2 hours after intake of food or drink, 
except for water. 
 
Cyclophosphamide 1000 mg/m2 IV on Day 1 
o Infuse over 30 to 60 minutes. 
o There are no requirements for hydration or mesna administration, unless 
the subject has a history of hematuria; see Section 8.4.3. 
 
Cytarabine 75 mg/m2 IV or subcutaneously on Days 1 to 4 and 8 to 11 
o IV administration should be infused over 1 to 30 minutes. 
o Subcutaneous administration sites should be rotated among the thighs, 
abdomen, and flanks. 
 
PEG-asparaginase 1000 U/m2 IV on Day 15 
o Infuse over 1 to 2 hours in D5W or normal saline. 
o Rapid access to emergency medications (ie, epinephrine and 
methylprednisolone) during and for approximately 24 hours following 
dose administration is strongly recommended. 
o See Section 8.4.9 for information regarding the substitution of Erwinia for 
PEG-asparaginase. 
 
Vincristine 1.5 mg/m2 (maximum 2 mg per dose) IV on Days 15 and 22 
o Administer as an IV push over 1 minute or as an infusion, in accordance 
with institutional practice. 
CNS Treatment (According to age-based dosing presented in Table 6) 
Preservative free forms of cytarabine, hydrocortisone, and methotrexate should be used 
for intrathecal administration.   
 
CNS-negative subjects:  IT methotrexate given on Days 1, 8, 15, and 22 
 
CNS-positive subjects:  IT Triple Therapy (cytarabine, hydrocortisone, and 
methotrexate) given on Days 1, 8, 15, and 22 
 


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Figure 4.  Study 20140106 Road Map, Optional Consolidation Cycle 
Section 8.1.3 Optional Consolidation Cycle 
The Optional Consolidation Cycle lasts for 4 weeks 
_________________________________ 
________________ 
Patient name or initials 
DOB 
 
Drug 
Route 
Dosage 
Days 
Important notes 
Methotrexate (MTX) 
(CNS negative) 
IT 
Age-based dosing (see table below) 
Days 1, 8, 15, 22 
 
IT Triple Therapy (ITT) 
(CNS positive) 
IT 
Age-based dosing: 
Days 1, 8, 15, 22 
IT Triple Therapy comprises: 
cytarabine (ARAC) 
hydrocortisone (HC) 
methotrexate (MTX) 
Age (yrs) 
ARAC 
HC 
MTX 
1 to 1.99 
16 
8 
8 
2 to 2.99 
20 
10 
10 
3 to 8.99 
24 
12 
12 
 9 
30 
15 
15 
Carfilzomib (CFZ) 
IV over 
30  5 min 
Patients to receive dose level to which they 
were assigned during the Lead-in Window 
and/or Induction Cycle 
Days 1, 2, 8, 9, 15, 
16 
Premedicate with 3 mg/m2 of Dex (oral or IV)  30 minutes prior 
to each CFZ dose. 
If BSA  2.2 m2, base dose on a BSA of 2.2 m2. 
6-mercaptopurine (6-MP) 
PO 
60 mg/m2 
Days 1–14 
Administer on an empty stomach. 
Actual dose per day should be varied, as needed, to yield a 
weekly dose as close to 420 mg/m2 as possible. 
Cyclophosphamide (CPM) 
IV over 30–60 min 
1000 mg/m2 
Day 1 
 
Cytarabine (ARAC) 
IV over 1–30 min or SC 
75 mg/m2 
Days 1–4, 8–11 
 
PEG-asparaginase(PEG) 
IV over 1–2 hours 
1000 U/m2 
Day 15  
Rapid access to emergency medications (ie, epinephrine and 
methylprednisolone) for approximately 24 hours following 
dosage administration is strongly recommended.   
Vincristine (VCR) 
IV push over 1 min 
1.5 mg/m2 
Days 15, 22 
2 mg maximum dose. 
Administration by infusion is acceptable. 
 


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Ht______cm 
Wt______kg 
BSA______m2 
* 
Date 
Given 
Study 
Day 
CFZ 
____mg 
6-MP 
____mg 
CPM 
____mg 
ARAC 
____mg 
PEG 
____U 
VCR 
____mg 
Complete as applicable 
Comments (include any held 
doses, or dose modifications) 
IT MTX 
____mg 
ITT 
__mg/__mg/__mg 
ARAC/ HC / MTX 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
____mg 
____mg 
____mg 
____mg 
 
 
____mg 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
 
 
 
2 
____mg 
____mg 
 
____mg 
 
 
 
 
 
 
 
3 
 
____mg 
 
____mg 
 
 
 
 
 
 
 
4 
 
____mg 
 
____mg 
 
 
 
 
 
 
 
5 
 
____mg 
 
 
 
 
 
 
 
 
 
6 
 
____mg 
 
 
 
 
 
 
 
 
 
7 
 
____mg 
 
 
 
 
 
 
 
 
 
8 
____mg 
____mg 
 
____mg 
 
 
____mg 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
 
 
 
9 
____mg 
____mg 
 
____mg 
 
 
 
 
 
 
 
10 
 
____mg 
 
____mg 
 
 
 
 
 
 
 
11 
 
____mg 
 
____mg 
 
 
 
 
 
 
 
12 
 
____mg 
 
 
 
 
 
 
 
 
 
13 
 
____mg 
 
 
 
 
 
 
 
 
 
14 
 
____mg 
 
 
 
 
 
 
 
 
 
15 
____mg 
 
 
 
____U 
____mg 
____mg 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
 
 
 
16 
____mg 
 
 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
____mg 
____mg 
ARAC ____mg 
HC      ____mg 
MTX   ____mg 
 
 
 
 
DOSE MODIFICATION GUIDELINES are provided in Section 8.4. 


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8.1.4 
Testicular Relapse 
The management of testicular relapse is at the investigator’s discretion, however, 
radiotherapy may not be administered concurrent with participation in this study. 
8.2 
Dose-limiting Toxicity 
Carfilzomib will be immediately omitted for any DLT.  Subjects may continue with the 
remainder of the backbone therapy, at the investigator’s discretion, should this occur.  
Carfilzomib may be reintroduced at a lower dose, in accordance with the information 
presented in Section 8.4.1.  If carfilzomib is not reintroduced, the subject is considered to 
be withdrawn from study treatment. 
Subjects who discontinue treatment, receive a dose modification, or miss doses of 
carfilzomib because of a non-dose-limiting toxicity adverse event or deviation from the 
protocol will be replaced. 
8.3 
Definition of Carfilzomib Dose-limiting Toxicity 
A DLT is defined as any of the following toxicities assessed by the investigator as 
possibly, probably, or definitely attributable to carfilzomib during the Lead-in Window or 
Induction Cycle:   
 
Any Grade 4 nonhematologic toxicity, excluding: 
o Alopecia 
o Infection 
o TLS 
o Fever and neutropenia 
o Fatigue 
o Nausea or vomiting 
o Sensory or motor neuropathy or neuropathic pain 
o In the absence of associated clinical and radiological criteria evocative of 
pancreatitis, Grade 4 laboratory elevation of lipase in the absence of 
Grade 4 laboratory elevation of amylase or Grade 4 laboratory elevation 
of amylase in the absence of Grade 4 laboratory elevation of lipase 
o The following, provided there is a return to Grade 1 status or subject’s 
baseline by the time of induction treatment course completion and blood 
count recovery (no later than Day 42 of the Induction Cycle): 
− Electrolyte abnormalities 
− Hyper- or hypoglycemia 
− Elevations of AST, ALT, gamma-glutamyl transferase (GGT), 
triglycerides, or bilirubin 


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 
 Grade 4 neutropenia or  Grade 3 thrombocytopenia persisting beyond 
Day 45 (Day 42 prior to Protocol Amendment 3) of the Induction Cycle in a 
subject who otherwise has a CR 
Serious adverse events and grade 4 adverse events considered unrelated or unlikely to 
be related to carfilzomib are not considered DLTs and do not require stopping 
carfilzomib.  If carfilzomib is temporarily stopped for an event that the investigator does 
not attribute to carfilzomib, it may be resumed within the allowed administration window, 
at the previous dose, based on the investigators risk benefit assessment. 
8.4 
Dose-modification Guidelines 
8.4.1 
Carfilzomib 
The dose decrements for carfilzomib are presented in Table 8.   
Carfilzomib must be permanently discontinued for subjects requiring more than 1 dose 
level reduction. 
Table 8.  Phase 1 and 2 Dose Decrements for Carfilzomib 
Original Carfilzomib Dose 
Reduced Carfilzomib Dose 
20 mg/m2 
15 mg/m2 
27 mg/m2 
20 mg/m2 
36 mg/m2 
27 mg/m2 
45 mg/m2 
36 mg/m2 
56 mg/m2 
45 mg/m2 
70 mg/m2 
56 mg/m2 
The following dose modifications are required for subjects who experience a DLT during 
the Lead-in or Induction Cycles.  For subjects who continue on to the Optional 
Consolidation Cycle, these same requirements must be applied for any subject who 
experiences a toxicity that would have been defined as dose limiting, had it occurred 
during the earlier cycles. 
See Section 8.3 for the definition of DLT. 
 
Omit until improved to  Grade 2 status 
 
Resume at a reduced dose level according to Table 8 at the investigator’s discretion 
o If the investigator determines that reintroducing carfilzomib therapy is not in the 
subject’s best interest, the subject will be considered withdrawn from study 
treatment. 
o If the toxicity recurs, discontinue carfilzomib treatment 


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 
Subjects continuing on to the Optional Consolidation Cycle may be re-challenged 
with their original dose of carfilzomib at the investigator’s discretion 
o If the toxicity recurs after the subject is re-challenged, omit until improved 
to  Grade 2 status and then resume at the reduced dose 
Posterior Reversible Encephalopathy Syndrome 
Posterior reversible encephalopathy syndrome (PRES), formerly termed reversible 
posterior leukoencephalopathy syndrome (RPLS), is a neurological disorder, which can 
present with seizure, headache, lethargy, confusion, blindness, altered consciousness, 
and other visual and neurological disturbances, along with hypertension, and the 
diagnosis is confirmed by neuro-radiological imaging.  Cases of PRES have been 
reported in patients receiving carfilzomib.  Discontinue carfilzomib if PRES is suspected.  
The safety of reinitiating carfilzomib therapy in patients previously experiencing PRES is 
not known.  
Subjects who are diagnosed with PRES should not be re-challenged with carfilzomib.  
8.4.2 
6-mercaptopurine 
Absolute neutrophil count and cytopenias: 
 
Do not modify the dose based on ANC. 
 
Do not modify, delay, or omit doses in response to cytopenias. 
Liver Dysfunction: 
 
Omit if the AST and/or ALT are  20 x ULN. 
 
If AST and/or ALT are  5 x ULN, but  20 x ULN, measure serum direct bilirubin 
 
Direct bilirubin  2 mg/dL ( 34.2 micromol/L):  Omit until resolved. 
 
Direct bilirubin  2 mg/dL ( 34.2 micromol/L):  Do not omit. 
 
If direct bilirubin is  2 mg/dL ( 34.2 micromol/L):  Omit until resolved, even if 
AST and ALT are  5 x ULN. 
 
Do not replace missed doses. 
TPMT polymorphisms: 
 
Provide 10 of the dose to subjects with known homozygous activity-reducing 
polymorphisms of TPMT. 
 
TPMT genotyping is not required. 
 
Measurement of TPMT metabolites is not required. 


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8.4.3 
Cyclophosphamide 
History of Hematuria: 
 
Hydrate per institutional practice and document urine specific gravity  1.010 
prior to the dose. 
 
Provide IV hydration at a rate of 125 mL/m2/h for 24 hours following the dose. 
o Monitor urine output per institutional guidelines and adjust the rate of 
hydration as needed to maintain urine output  3 mL/kg/h. 
 
Administer 600 mg/m2 total of mesna on either of the following schedules: 
o 200 mg/m2 given 15 minutes prior to, or in conjunction with, 
cyclophosphamide administration, followed by 200 mg/m2/dose at 4 hours 
and 8 hours following the start of cyclophosphamide administration, 
OR 
o Continuous administration of 600 mg/m2/24 h, beginning 15 minutes prior 
to, or in conjunction with, cyclophosphamide administration. 
8.4.4 
Cytarabine 
Cytarabine Syndrome: 
 
Administer systemic hydrocortisone or dexamethasone, in accordance with 
institutional guidelines. 
 
Withhold for  Grade 3 rash or conjunctivitis. 
o Treat conjunctivitis with dexamethasone ophthalmic drops, in accordance 
with institutional practice. 
o Resume and make up missed doses, once resolved. 
 
Withhold for  Grade 3 infection 
o Obtain cultures as appropriate, based on presentation. 
o Provide antimicrobial therapy, as appropriate. 
o Resume and make up missed doses, once resolved. 
 
Do not withhold for fever in the absence of presumed or proven serious infection. 
 
Do not withhold for myelosuppression that begins after consolidation therapy has 
commenced. 
8.4.5 
Daunorubicin or Other Anthracycline 
Cardiac Toxicity 
 
Discontinue for cardiomyopathy, as defined by LVFS  27, LVEF  50, or 
Grade  3 systolic dysfunction 
Extravasation 
 
Discontinue administration, if extravasation occurs 
 
Manage the effects of the extravasation per institutional practice 


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Hyperbilirubinemia 
 
If direct bilirubin is: 
o  5.0 mg/dL ( 85.5 micromol/L):  Discontinue until resolved 
o 3.1–5.0 mg/dL (51.3–85.5 micromol/L):  Give 25 of the dose 
o 1.2–3.0 mg/dL (20.5–51.3 micromol/L):  Give 50 of the dose 
o  1.2 mg/dL ( 20.5 micromol/L):  Give the full dose 
 
Do not make up missed doses 
8.4.6 
Dexamethasone 
Hyperglycemia:  
 
Do not reduce the dose. 
 
Insulin therapy may be initiated at the investigator’s discretion. 
Hypertension:  
 
Do not reduce the dose. 
 
Antihypertensive therapy may be initiated at the investigator’s discretion. 
 
Sodium intake may be restricted at the investigator’s discretion. 
Osteonecrosis:  
 
Grade 1:  Do not reduce the dose. 
 
Grade 2:  Dose modification is permitted at the investigator’s discretion. 
Pancreatitis:  
 
Grade 3:  Discontinue until resolved. 
o Stress dose steroids may be provided at the investigator’s discretion. 
 
Grade 2:  Do not reduce the dose. 
Severe infection:  
 
If steroids need to be discontinued in the opinion of the investigator, it is 
recommended that the study medical monitor be contacted for discussion before 
such discontinuation. 
Severe psychosis:  
 
Dose may be reduced by 50 at the investigator’s discretion. 


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8.4.7 
Intrathecal Methotrexate or Triple Therapy 
Acute neurotoxicity: 
 
Dose modifications following an acute neurotoxic event are at the investigator’s 
discretion, if thought temporally related to administration of IT methotrexate. 
o Temporally related events commonly occur 9 to 11 days following IT 
administration. 
 
Acceptable dose modifications include: 
o Eliminating the next dose 
o Substituting IT cytarabine for the next dose 
 
Leucovorin or citrovorin may be provided at the investigator’s discretion. 
Administration via an Ommaya Catheter: 
 
Give 50 of the age-based dose. 
Systemic toxicity: 
 
Do not reduce the dose. 
 
Leucovorin or citrovorin may be provided at the investigator’s discretion. 
o Do not provide leucovorin or citrovorin without evidence of systemic 
toxicity. 
Viral, bacterial, or fungal meningitis:  
 
Omit until resolved. 
 
Do not make up missed doses. 
8.4.8 
Mitoxantrone 
Hyperbilirubinemia:  
 
If total bilirubin is:  
o  12 mg/dL ( 205.2 micromol/L):  Discontinue until resolved. 
o  9 mg/dL and  12 mg/dL ( 153.9 micromol/L and  205.2 micromol/L): 
Give 25 of the dose. 
o  5 mg/dL and  9 mg/dL ( 85.5 micromol/L and  153.9 micromol/L): 
Give 50 of dose. 
o  5 mg/dL ( 85.5 micromol/L):  Give 100 of dose. 
8.4.9 
PEG-asparaginase or L-asparaginase 
 Grade 3 Anaphylaxis or  Grade 2 Systemic Allergic Reaction: 
 
Discontinue immediately. 
Manage the reaction in accordance with institutional practice. 


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 
Substitute Erwinia for all future doses. 
If Erwinia is not available, investigators may discontinue asparaginase therapy or 
consider desensitization procedure acceptable to the site. 
 
If a subject develops a  Grade 2 allergy to Erwinia asparaginase, discontinue 
future asparaginase therapy or consider desensitization procedure acceptable to 
the site. 
Given the lack of data available at this time to inform the optimal Erwinia asparaginase 
schedule, the dose-modification guidelines for ALL trials recommend the substitution or 
replacement of Erwinia asparaginase for either native or PEG-asparaginase according to 
the following schedule: 
Phase(s) of Treatment 
Replacement Schedule for Erwinia asparaginase 
Standard Induction, Consolidation, Interim 
Maintenance, Delayed Intensification. 
25,000 IU/m2/dose IM M/W/F x 6 doses for each dose 
of pegaspargase. 
IM  intramuscular. 
NOTES:  Should IV administration of Erwinia be approved by the applicable regulatory agency for a site 
participating in this study, IV administration of Erwinia will be permitted at the investigator’s discretion. 
If a subject develops a Grade 3 or higher anaphylaxis to Erwinia, discontinue future asparaginase 
therapy. 
Coagulopathy: 
 
Symptomatic:  Discontinue until resolved. 
 
Asymptomatic:  Do not reduce the dose. 
 
Blood products and/or factor replacement may be provided at the investigator’s 
discretion. 
 
Hyperbilirubinemia:  L-asparaginase may need to be withheld in subjects with an 
elevated bilirubin, since asparaginase has been associated with hepatic toxicity.  
No specific guidelines are available. 
Hyperglycemia:  
 
Do not reduce the dose. 
 
Insulin therapy may be initiated at the investigator’s discretion. 
Hyperlipidemia:  
 
Do not reduce the dose. 
Intracranial bleed, thrombosis, or infarction:  
 
Discontinue until resolved. 
 
Management of the intracranial event is at the investigator’s discretion.  
 
Resume full dose therapy at the investigator’s discretion. 


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Ketoacidosis:  
 
Discontinue until resolved. 
 
Management of ketoacidosis is at the investigator’s discretion. 
Pancreatitis: 
 
 Grade 3:  Discontinue. 
o Do not resume after pancreatitis has resolved. 
 
Grade 2:  Discontinue until resolved. 
o Resume at full dose after pancreatitis has resolved. 
Thrombosis:  
 
Discontinue until resolved. 
 
Laboratory aberrations without evidence of thrombosis are not an indication for 
discontinuation. 
 
Management of thrombosis is at the investigator’s discretion. 
8.4.10 
Vincristine 
Constipation, ileus, or typhlitis ( Grade 3): 
 
During the Induction Cycle: 
o Do not reduce or omit the dose. 
o Stool softeners and/or laxatives should be administered to prevent 
constipation (as described in Section 9.13). 
 
During the Optional Consolidation Cycle: 
o Discontinue until resolved. 
o Constipation must be treated aggressively, to facilitate ongoing vincristine 
administration. 
o Resume at 50 of the dose, when symptoms resolve. 
o Escalate to full dose therapy as tolerated. 
Direct Hyperbilirubinemia: 
 
If direct bilirubin is: 
o  6 mg/dL (102.6 micromol/L):  Omit the dose. 
o  5 and  6 mg/dL ( 87.2 micromol/L and  102.6 micromol/L): 
Give 25 of the dose. 
o  3.1 and  5 mg/dL ( 53 micromol/L and  85.5 micromol/L):  Give 50 of 
the dose. 
o  3.1 mg/dL (53 micromol/L):  Do not reduce the dose. 
 
Do not make up missed doses. 


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 
Repeat direct bilirubin measurement within 48 hours before the next dose is due 
and calculate the dose based on this measurement. 
Foot Drop, Paresis: 
 
 Grade 3:  Do not reduce the dose. 
 
 Grade 3:  Dose modification is strongly discouraged. 
o If the investigator determines that dose modification is justified: 
− Give 50 of the dose. 
− Resume full dose therapy as soon as possible. 
 
Provide physical therapy at the investigator’s discretion. 
Hyponatremia/syndrome of inappropriate secretion of antidiuretic hormone (SIADH): 
 
Do not reduce the dose. 
Jaw Pain:  
 
Do not reduce the dose. 
 
Provide analgesia at the investigator’s discretion. 
Severe Neuropathic Pain ( Grade 3):  
 
Dose modification is strongly discouraged. 
 
If the investigator determines that dose modification is justified: 
o Give 50 of the dose. 
o Resume full dose therapy as soon as possible. 
 
Provide analgesia at the investigator’s discretion. 
Vocal Cord Paralysis:  
 
Discontinue until symptoms subside. 
 
Resume at 50 of the dose. 
 
Escalate to full dose therapy as tolerated. 
8.5 
Concomitant Medications 
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements.   
All concomitant medications must be recorded on the subject’s electronic case report 
form (eCRF) from signing of the ICF to 30 days following the last dose of study drug. 


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Blood products are not considered concomitant medications and must be recorded on 
the appropriate eCRF from signing of the ICF to 30 days following the last dose of study 
drug. 
8.5.1 
Required Concomitant Medications 
All required and recommended concomitant medications are provided in Section 9, 
Supportive Care Requirements and Guidelines. 
8.5.2 
Excluded Concomitant Medications 
 
Marketed or investigational anticancer therapeutics that are not a component of 
this treatment regimen 
 
Radiotherapy 
 
Investigational agents for non-neoplastic conditions 
 
See Section 9.4 and Section 9.9.4, and Section 9.10 for instructions about azole 
antifungal agents and myeloid growth factors, respectively, as their 
administration is restricted to certain circumstances. 
8.5.3 
Drug-Drug Interactions 
 
Carfilzomib is primarily metabolized through peptidase and epoxide hydrolase 
activities. 
 
Cytochrome P450 (CYP450)–mediated mechanisms play a minor role in the 
overall metabolism of carfilzomib.  The PK profile of carfilzomib is unlikely to be 
affected by concomitant administration of cytochrome P450 inhibitors and 
inducers. 
 
Carfilzomib is a P-glycoprotein (P-gp) substrate.  The PK profile of carfilzomib is 
unlikely to be affected by P-gp inhibitors or inducers, given that carfilzomib is 
administered IV and is extensively metabolized. 
8.6 
Product Complaints 
A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  
This includes any drug(s), device(s), or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the Investigational Product Instruction Manual 
(IPIM). 


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9. 
Supportive Care Requirements and Guidelines 
For sites outside of the US, equivalent medications for all agents listed in this section are 
acceptable.  The sections below describe requirements for the phase 1 portion of this 
study; other therapies required for the phase 2 portion of the study are provided in 
Section 22.1.6. 
9.1 
Tumor Lysis Syndrome 
Subjects at high risk of tumor lysis should be assessed rapidly for evidence of 
symptomatic hyperleukocytosis, TLS, and coagulopathy.  
 
Relevant laboratory tests from the screening period include: 
o Complete blood count (CBC) 
o Serum electrolytes, including calcium and phosphorus 
o Creatinine 
o Blood urea nitrogen (BUN) 
o Uric acid 
Continued monitoring of these laboratory values at intervals suitable to the clinical 
condition is required, until abnormalities have resolved or the risk has abated.  The risk 
for serious acute TLS usually subsides within the first 72 hours after initiation of therapy. 
 
If coagulopathy is suspected, monitoring of the following additional laboratory 
tests is strongly recommended: 
o Prothrombin and activated partial thromboplastin times 
o Fibrinogen 
o D-dimer 
 
To manage hyperuricemia, hyperkalemia, hyperphosphatemia and 
hypocalcemia, the following is required: 
o Begin allopurinol 
− Institutional guidelines for dosing and administration should be 
followed. 
− Continue until peripheral blasts and extramedullary disease have 
been reduced.  
o Treatment with Rasburicase should be considered for subjects with severe 
hyperuricemia, oliguria, or severe renal dysfunction. 
− Screening for glucose-6-phosphate dehydrogenase deficiency prior to 
Rasburicase administration is strongly recommended. 
− Institutional guidelines for dosing and administration should be 
followed. 
o Hydrate at least 100-125 mL/m²/h to maintain urine output  3 mL/kg/h 


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− Continue until peripheral blasts and extramedullary disease have 
been reduced. 
− Institutional guidelines for administration should be followed. 
o If institutional practice includes alkalinization, alkalinize urine to maintain 
urine pH 6.5–7.5. 
− The regimen for alkalinizing urine is at the investigator’s discretion. 
− Institutional guidelines for dosing and administration should be 
followed. 
− Alkalinization is not recommended when treating with Rasburicase. 
9.2 
Blood Products 
 
Blood products are provided at the discretion of the investigator. 
 
Institutional guidelines for administration should be followed. 
9.3 
Pneumocystis Prophylaxis 
 
Pneumocystis prophylaxis (PCP) must be provided throughout the study period. 
 
Oral administration of trimethoprim-sulfamethoxazole (TMP-SMX) is preferred, 
but alternative agents may be provided if there is a documented contraindication 
to TMP-SMX. 
 
Institutional guidelines for dosing and administration should be followed. 
 
For subjects with delayed recovery of peripheral blood counts investigators 
should consider replacing TMP-SMX after day 22 of induction with alternative 
therapy until recovery of bone marrow function, Atovoquone, aerosolized or IV 
pentamidine, dapsone, or other agent per institutional standards may be 
considered as short term alternative to TMP-SMX. 
9.4 
Fungal Prophylaxis 
 
Fungal prophylaxis must be provided during periods of neutropenia from the 
Induction Cycle through the end of study treatment. 
 
Echinocandin (ie, caspofungin or micafungin) or amphotericin agents are 
acceptable. 
o Institutional guidelines for dosing and administration should be followed. 
o Provide treatment level doses, rather than prophylactic doses. 
 
Azole antifungal agents (ie, fluconazole, itraconazole, voriconazole) given 
concurrently with vincristine may increase risk of neurotoxicity and their use as 
prophylaxis is not permitted. 
9.5 
Herpes Virus Prophylaxis 
 
Herpes simplex virus (HSV) prophylaxis must be provided throughout the study 
period for subjects with a history of documented or suspected HSV or 
varicella-zoster virus infection. 
 
Acyclovir or valacyclovir are acceptable. 
 
Institutional guidelines for dosing and administration should be followed. 


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9.6 
Bacterial Prophylaxis 
 
Bacterial prophylaxis during periods of neutropenia is strongly recommended, 
due to the high risk for serious bacterial infections in this population.   
 
Institutional guidelines for dosing and administration should be followed. 
9.7 
Intravenous Immunoglobulin Supplementation 
 
Intravenous immunoglobulin (IVIg) supplementation for subjects with 
hypogammaglobulinemia ( 500 mg/dL) is recommended, due to the high risk for 
infections in this population.  IV Ig infusions should use concentrations no greater 
than 5 g/dL to avoid renal toxicity. 
 
Institutional guidelines for dosing and administration should be followed. 
9.8 
Central Line Care 
 
Measures to minimize the risk for catheter-associated serious bacterial infections 
must be taken throughout the study period. 
 
The specific regimen for central line care should be consistent with institutional 
guidelines. 
9.9 
Fever and Neutropenia 
9.9.1 
Definition 
 
Fever and neutropenia is defined as a temperature  38.5C on a single 
occasion, or  38C on 2 occasions within 2 hours, and an ANC  0.50 x 109/L. 
9.9.2 
Evaluation 
 
Blood cultures should be obtained from all lumens. 
 
Additional cultures (urine, cerebral spinal fluid [CSF], respiratory, etc.) are 
obtained at the investigator’s discretion and should be based on the specific 
clinical presentation. 
 
Chest radiographs and other imaging studies are obtained at the investigator’s 
discretion and should be based on the specific clinical presentation. 
9.9.3 
Treatment 
 
Broad spectrum coverage for both gram-negative and gram-positive infection 
must be provided IV as soon as possible. 
 
Additional gram-negative coverage and glycopeptide agents are at the 
investigator’s discretion and should be based on the specific clinical presentation. 
 
Antifungal, antiviral, and other additional agents are at the investigator’s 
discretion and should be based on the specific clinical presentation. 
 
Institutional guidelines for dosing and administration should be followed. 
9.9.4 
Persistent or Recurrent Symptoms 
 
If fever persists for  96 hours or recurs after 3 days of treatment, surveillance for 
fungal infections or other occult infections is strongly recommended. 
o Studies to consider include, but are not limited to: 


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− Computed tomography (chest, sinuses, abdomen, etc.) 
− Bronchoalveolar lavage 
− Viral PCR (adenovirus, Epstein-Barr virus, cytomegalovirus, etc) 
 
If not already part of the treatment regimen, treatment dose antifungal therapy 
should be initiated. 
o Although prohibited for prophylaxis, azoles may be provided at the investigator’s 
discretion. 
o Institutional guidelines for dosing and administration should be followed. 
 
The addition of other antimicrobial agents should be seriously considered and is 
at the investigator’s discretion. 
o Institutional guidelines for dosing and administration should be followed. 
9.10 
Myeloid Growth Factors 
 
Granulocyte colony stimulating factors may be administered starting 24 hours 
after the last dose of cytotoxic chemotherapy per investigators discretion and are 
recommended for subjects that are likely to have delayed neutrophil recovery, 
such as multiply relapsed, a history of prior stem cell transplant, or a history of 
delayed neutrophil recovery after cytotoxic chemotherapy.  Institutional 
guidelines for dosing and administration should be followed. 
 
Administration of myeloid growth factors in response to severe infection or fever 
and neutropenia is at the investigator’s discretion 
9.11 
Gastritis Prophylaxis 
 
Prophylaxis with either a histamine 2 (H2) blocker or proton pump inhibitor is 
required during the Induction Cycle. 
 
Continued administration of gastritis prophylaxis during the optional cycle of 
consolidation therapy is at the investigator’s discretion. 
9.12 
Prevention and Management of Nausea and Vomiting 
 
Prophylactic antiemetic administration is strongly recommended when 
emetogenic chemotherapy, including IT therapy, is administered. 
 
The precise antiemetic regimen is at the investigator’s discretion. 
 
Corticosteroid administration as part of the antiemetic regimen is prohibited. 
 
Institutional guidelines for dosing and administration should be followed. 
 
Intravenous fluids and/or nutrition support should be provided, if nausea or 
vomiting prevent adequate intake of fluids or nutrients. 
9.13 
Constipation Prophylaxis 
 
Administration of stool softeners and/or laxatives to prevent constipation is 
strongly recommended. 
 
The precise bowel regimen is at the investigator’s discretion. 
 
Institutional guidelines for dosing and administration should be followed. 


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9.14 
Contraception 
The phase 2 protocol, including the contraception requirements for the phase 2 is 
provided in Appendix K.   
9.14.1 
Female of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered of child bearing potential: 
1. Premenopausal female with 1 of the following: 
a.  Documented hysterectomy 
b.  Documented bilateral salpingectomy 
c.  Documented bilateral oophorectomy 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject medical records, 2) subject medical examination, or 
3) subject medical history interview. 
2. Premenarchal female 
3. Postmenopausal female 
a. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
b. Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they 
wish to continue their HRT during the study.  Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
9.14.2 
Female Subjects  
Female subjects of childbearing potential must agree to use one highly effective method 
of contraception (as described in the table below) during treatment and for an additional 
12 months after the last dose of protocol-required therapies.  Contraception must be in 
place at least 2 weeks prior to the first study treatment. 


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Highly Effective Contraceptive Methods for Female Subjects 
Failure rate of 1 per year when used consistently and correctly. 
 
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments.  The reliability of sexual 
abstinence must be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject.) 
If a female subject is suspected of being pregnant, the protocol-required therapies must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed. 
9.14.3 
Male Subjects 
If the male’s sole sexual partner is of non-childbearing potential or has had a bilateral 
tubal ligation/occlusion, he is not required to use additional forms of contraception during 
the study.  The definition of non-childbearing potential is provided above.    
Male subjects with a partner of childbearing potential must agree to not father a child 
during treatment and for an additional 12 months after the last dose of protocol-required 
therapies.   
Contraceptive options for male subjects include:   
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies).  The reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject.  or  
 
Use a condom during treatment and for an additional 12 months after the last dose of 
protocol-required therapies.  
The female partner is to use an acceptable method of effective contraception such as:  
hormonal, IUD, IUS, female barrier method (diaphragm, cervical cap, contraceptive 
sponge [a female condom is not an option because there is a risk of tearing when both 


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partners use a condom]).  Male subjects must not donate sperm during treatment and for 
an additional 12 months after the last dose of protocol-required therapies. 
Male subjects with a pregnant partner must practice sexual abstinence or wear a 
condom to prevent exposure of the unborn child to study drugs through semen. 
9.14.4 
Unacceptable Methods of Birth Control for Male and Female 
Subjects 
Birth control methods that are considered unacceptable in clinical trials include:  periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method. 
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to fetus if they become pregnant or father a child 
during treatment and for 6 months after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception for an increased length of time.  In addition, male subjects may 
also be required to alter the duration and methods of contraception.  The investigator 
must discuss these topics with subjects. 
10. 
Study Procedures 
The phase 2 protocol, including phase 2 part of the study procedures, is provided in 
Appendix K.   
10.1 
On-study Assessments 
All required and optional procedures to take place during the Lead-in Window, Induction 
Cycle, and Optional Consolidation Cycle are provided in the following sections and, 
where needed, are further described in the text that follows.  Single-page assessment 
guides are provided in Appendix B, Appendix C, and Appendix D. 
10.1.1 
Lead-in Window (Dose Escalation 1 [R3] Only) 
Refer to Section 8.1.1, Table 4, for treatment and response assessment details during 
the Lead-in Window. 


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Table 9.  Phase 1 On-study Assessments:  Lead-in Window 
Assessment 
Cycle Day 
1 
2 
8 
Physical examination 
X 
 
X 
Lumbar puncture 
 
 
 
CNS-negative 
Xa 
 
X 
CNS-positive 
Xa 
 
X 
Local laboratory evaluations 
 
 
 
CBC with differential and platelet count 
Xa 
 
X 
Electrolytes:  Na, K, Cl, CO2, Ca, Mg, P 
Xa 
 
X 
Blood glucose 
Xa 
 
X 
Renal function:  BUN, Cr 
Xa 
 
X 
Hepatic function:  AST, ALT, total and direct 
bilirubin, ALP, albumin 
Xa 
 
X 
Pancreatic function:  amylase, lipase 
Xa 
 
X 
Uric acid 
Xa 
 
X 
Bone-specific ALP 
X 
 
 
Correlative study measurements 
 
 
 
Pharmacokinetic studies 
X 
 
 
 
 
 
 
) 
 
 
 
Response assessment/bone marrow 
aspirate (including MRD) 
 
 
X 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; 
BUN  blood urea nitrogen; CBC  complete blood count; CNS  central nervous system; Cr  serum 
creatinine; ECG  electrocardiogram; MRD  minimal residual disease; NM-GFR  nuclear 
magnetic-glomerular filtration rate; ULN  upper limit of normal. 
a Assessments from the screening period must have been obtained within 72 hours before enrollment (or 
for lumbar puncture, within 7 days before enrollment) and no repeat Day 1 study assessments are 
required, except for repeat assessments of the blood when the initiation of study treatment occurs 
 48 hours after these labs were obtained or at the discretion of the investigator. 
10.1.2 
Induction (Dose Escalation 1 [R3] and Dose Escalation 2 [VXLD]) 
Refer to Section 8.1.2, Table 5, for treatment and response assessment details during 
the Induction Cycle. 




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10.1.3 
Optional Consolidation  
Refer to Section 8.1.3, Table 7, for treatment and response assessment details during 
the Optional Consolidation Cycle. 
Table 11.  Phase 1 On-study Assessments:  Optional Consolidation Cycle 
Assessment 
Cycle Day 
1 
2 
8 
15 
22 
29 
Physical examination 
X 
 
X 
X 
X 
X 
Lumbar puncture 
 
 
 
 
 
 
CNS-negative 
X 
 
X 
X 
X 
 
CNS-positive 
X 
 
X 
X 
X 
Xa 
Local laboratory evaluations 
 
 
 
 
 
 
CBC with differential and platelet count 
X 
 
X 
X 
X 
X 
Electrolytes:  Na, K, Cl, CO2, Ca, Mg, P 
X 
 
X 
X 
X 
X 
Blood glucose 
X 
 
X 
X 
X 
X 
Renal function:  BUN, Cr 
X 
 
X 
X 
X 
X 
Hepatic function:  AST, ALT, total and direct bilirubin, 
ALP, albumin 
X 
 
X 
X 
X 
X 
Pancreatic function:  amylase, lipase 
X 
 
X 
X 
X 
X 
Response assessment/bone marrow aspirate (including 
MRD) 
 
 
 
 
 
X 
 ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase;  
BUN  blood urea nitrogen; CBC  complete blood count; CNS  central nervous system; Cr  serum 
creatinine; MRD  minimal residual disease 
a Required only for subjects who remain CNS-positive on Day 22. 
10.1.4 
Additional Procedure Details 
Physical Examination 
During study treatment, a physical examination must include all of the following and be 
completed prior to the delivery of study treatment on the days indicated in Table 9, 
Table 10, and Table 11: 
 
Updated documentation of all current medications 
 
Vital Signs 
o Temperature:  The temperature location selected for a subject should be the 
same that is used throughout the study and documented on the vital signs case 
report form (CRF).   
o Heart Rate 
o Respiratory Rate 
o Systolic and Diastolic Blood Pressures:  Subject should be in a rested and calm 
state for at least 5 minutes before blood pressure measurements are conducted.  
The position selected for a subject should be the same that is used throughout 
the study and documented on the vital signs CRF.   


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 
Weight  
 
Height and BSA (only required prior to beginning the Optional Consolidation Cycle; 
see Section 8.1.3) 
 
Examination of all of the following: 
o Head 
o Ears 
o Eyes 
o Nose 
o Oropharynx 
o Heart 
o Lungs 
o Abdomen 
o Extremities 
o Lymph Nodes 
o Skin 
o Nervous System 
 
Determination of the updated NCI-CTCAE (Version 4.03) grade for all abnormal 
physical examination findings. 
o Clinically significant abnormal findings that are new or represent a worsening 
after the signature of the ICF must be reported as adverse events. 
Laboratory Evaluations 
Laboratory evaluations of the blood must be obtained and results reviewed prior to the 
delivery of study treatment on the days indicated in Table 9, Table 10, and Table 11 but 
may be obtained as early as 48 hours in advance. 
The first blood sample for bone-specific ALP must be collected prior to the initiation of 
study treatment; however, results are not required for study treatment to begin. 
All hepatitis testing will be performed locally.  All subjects will be tested at screening for 
hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and 
hepatitis B core antibody (anti-HBc), unless performed within 6 months of screening  and 
there was no change in the subject’s risk factors within these 6 months (Table 1).  
Subjects with positive testing or a history of prior HBV infection should have consultation 
with a specialist and must have HBV-DNA testing at screening and again at safety follow 
up.  Subjects that have received Hepatitis B vaccination with only anti--HBs positivity 
and no clinical signs of hepatitis do not require HBV-DNA monitoring. 


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Pharmacokinetic Studies 
Blood samples will be collected from all subjects for determination of plasma 
concentrations of carfilzomib on Day 1 of the Lead-in Window (Dose Escalation 1 only) 
and Day 8 of the Induction Cycle (Dose Escalation 1 [R3] and Dose Escalation 2 
[VXLD]) at the following time points: 
 
Predose 
 
15 minutes after the start of infusion 
 
Immediately (within 2 minutes before the end of infusion) 
 
10 minutes, 30 minutes, and 1, 2, and 4 hours after the end of the infusion 


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10.2 
Response Assessment 
The Lead-in Window Day 8 (for Dose Escalation 1 [R3]), the Induction Cycle Day 29 (for 
Dose Escalation 1 [R3] and Dose Escalation 2 [VXLD]), and the Optional Consolidation 
Cycle Day 29 (when applicable) response assessments will be performed by the 
investigator.  Bone marrow aspiration, lumbar puncture, physical examination (including 
testicular examination), and CBC with differential and platelets will be performed to 
assess the disease status.  Lumbar puncture to assess disease status will not be 
required after the second lumbar puncture for subjects who are CNS-negative.  Subjects 
who are CNS-positive must have 2 consecutive lumbar punctures without evidence of 
leukemia, before lumbar puncture is no longer required for assessment of disease 
status. 
A portion of the bone marrow collected at the time of these response assessments will 
be submitted to a central laboratory, for determination of MRD.  Instructions for collection 
and submission are provided in the Laboratory Manual. 
The criteria for determining treatment response are defined in the sections that follow.  
See Appendix K for response definitions for phase 2. 
10.2.1 
Complete Remission  
Complete remission (CR) is defined as the attainment of M1 bone marrow status with no 
evidence of circulating blasts or extramedullary disease and with recovery of peripheral 
counts (ANC  750 mcl and platelet count  75,000 mcl).  Qualifying marrow and 
peripheral counts should be performed within 1 week of each other. 
10.2.2 
Complete Remission Without Platelet Recovery  
Complete remission without platelet recovery (CRp) is defined as the attainment of M1 
bone marrow status with no evidence of circulating blasts or extramedullary disease and 
with recovery of ANCs (ANC  750 mcl), but with insufficient recovery of platelets 
( 75,000 mcl). 


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10.2.3 
Complete Remission With Incomplete Hematologic Recovery 
Complete remission with incomplete hematologic recovery (CRi) is defined as the 
attainment of M1 bone marrow status with no evidence of circulating blasts or 
extramedullary disease and with no recovery of ANCs (ANC  750/mcl), with or without 
insufficient recovery of platelets ( 75,000/mcl). 
10.2.4 
Partial Response 
Partial response (PR) is defined as the complete disappearance of circulating blasts and 
achievement of M2 bone marrow status, without new sites of extramedullary disease, 
and with recovery of ANCs (ANC  750 mcl). 
10.2.5 
Stable Disease  
Stable disease is defined as the subject not satisfying the criterion for progressive 
disease (PD), or has recovery of ANC  750 mcl and fails to qualify for CR, CRp, or PR. 
10.2.6 
Progressive Disease 
Progressive Disease is defined as an increase of at least 25 in the absolute number of 
circulating leukemic cells or bone marrow blasts, development of new sites of 
extramedullary disease, or other laboratory or clinical evidence of PD, with or without 
recovery of ANC or platelets. 
10.2.7 
Induction Death 
An induction death (ID) is defined as any death that occurs during the Lead-in Window 
or as any death that occurs up to Day 42 of the Induction Cycle, provided that 
subsequent therapy has not been administered and the death occurred prior to response 
evaluation, or the death occurred after response evaluation but prior to subsequent 
therapy in a subject that did not demonstrate persistent leukemia (stable or progressive 
disease). 
10.2.8 
Not Evaluable 
A subject considered to be not evaluable (NE) is one who does not satisfy the criteria for 
PD or ID, having had no marrow evaluation or inadequate marrow cell count. 
11. 
Study Discontinuation 
The phase 2 protocol, including details on study discontinuation in phase 2, is provided 
in Appendix K.   


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11.1 
Withdrawal of Subjects From Treatment 
Subjects may withdraw from study treatment at any time. 
Subjects are considered to have reached the planned end of study treatment when the 
Induction or Optional Consolidation Cycles are completed.  The investigator must 
remove a subject from study treatment prior to the planned end of treatment for the 
following reasons: 
 
Unacceptable toxicity 
 
Subject or their legally acceptable representative withdraws consent for study 
treatment 
 
Requirement for alternative therapy 
 
Noncompliance with study procedures, including administration of prohibited 
medications 
 
Pregnancy 
With the exception of those who withdraw consent for further follow-up, all subjects must 
be followed for 30 days after their final dose of study treatment or until all 
carfilzomib-related toxicity has resolved or stabilized, whichever is longer. 
Subjects determined to be not evaluable may be replaced.  Decisions regarding subject 
replacement will be made by the Sponsor and will be based on the need for additional 
subjects to do 1 or more of the following: 
 
Determine the MTD. 
 
Ensure a minimum of 3 subjects in a particular age group. 
11.2 
End-of-study Assessments 
The End-of-Study Assessments must be completed 30 days ( 4 days) following the last 
dose of study treatment.  For subjects who complete the End-of-Study Assessment less 
than 30  4 days following the last dose of study treatment, a follow-up of ongoing AEs 
should be attempted by telephone and documented in the subject’s source file.  All AEs 
must be followed until resolution, unless the investigator has determined that the event 
has stabilized or is not expected to improve.  The End-of-Study Assessments are 
presented in Table 12 and described in the text below. 


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Table 12.  Phase 1 End-of-study Assessments 
Assessment 
30 Days ( 4 Days) After Last 
Dose of Study Treatment 
Physical examination 
X 
Local laboratory evaluations 
X 
CBC with differential and platelet count 
X 
Electrolytes:  Na, K, Cl, CO2, Ca, Mg, P 
X 
Blood glucose 
X 
Renal function:  BUN, Cr 
X 
Hepatic function:  AST, ALT, total and direct bilirubin, ALP, 
albumin 
X 
Hepatitis B testing 
Xa 
Pancreatic function:  amylase, lipase 
X 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; 
BUN  blood urea nitrogen; CBC  complete blood count; Cr  serum creatinine; HBV  hepatitis B virus 
a Only in subjects with positive hepatitis B serology at screening or past history of HBV infection. 
Physical Examination 
A complete history and physical examination must include all of the following: 
 
Review of medical and surgical histories, including: 
o Documentation of all current medications 
 
Vital Signs: 
o Temperature 
o Heart Rate 
o Respiratory Rate 
o Systolic and Diastolic Blood Pressures 
 
Weight, Height, and BSA 
 
Performance Status Assessment (Appendix F): 
o Lansky score if  16 years of age 
o Karnofsky score if  16 years of age 
 
Examination of all of the following: 
o Head 
o Ears 
o Eyes 
o Nose 
o Oropharynx 
o Neck 
o Heart 
o Lungs 
o Abdomen 


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o Genitalia 
o Back 
o Extremities 
o Lymph Nodes 
o Skin 
o Nervous System 
 
Determination of the updated NCI-CTCAE (Version 4.03) grade for all 
abnormal physical examination findings. 
11.3 
Study Termination 
The Sponsor has the right to terminate this study or a study site from participating in a 
study at any time. 
Reasons for terminating the study overall or at a specific study site may include, but are 
not limited to, the following: 
 
The incidence or severity of AEs in this or other carfilzomib studies indicates 
a potential health hazard to subjects 
 
Subject enrollment is unsatisfactory 
 
Data recording is inaccurate or incomplete 
 
Investigator does not adhere to the protocol or applicable regulatory 
requirements in conducting the study 
 
The Data Monitoring Committee (DMC) recommends termination of the study 
12. 
Adverse Events and Serious Adverse Events (SAES) 
The phase 2 protocol, including details regarding adverse events and serious adverse 
events, is provided in Appendix K.  . 
12.1 
Adverse Event Reporting 
12.1.1 
Definitions 
An AE is any untoward medical occurrence in a study subject administered an 
investigational product(s) regardless of the causal relationship with treatment.  For the 
purposes of this study, an AE is defined as any untoward medical occurrence that takes 
place following the signing of the ICF. 
An AE, therefore, can be any unfavorable and unintended sign (including laboratory 
finding), symptom or disease temporally associated with participation in an 
investigational study, whether or not considered drug-related.  In addition to new events, 
any increase in the severity or frequency of a pre-existing condition that occurs after the 
subject or the subject’s legally acceptable representative signs the ICF for participation 
is considered an AE.  This includes any side effect, injury, toxicity, or sensitivity reaction.  


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All reported AEs will be coded using the current version of Medical Dictionary for 
Regulatory Activities (MedDRA).  The NCI-CTCAE version 4.03 will be used to describe 
the event and to assess the severity of AEs.  For AEs not adequately addressed in the 
NCI-CTCAE Version 4.03 (Table 13) will be used. 
Table 13.  Toxicity Grading for Adverse Events not Covered in the NCI-CTCAE 
(Version 4.03) 
Severity 
Description 
GRADE 1 - Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
GRADE 2 – Moderate 
Minimal, local, or noninvasive intervention indicated, limiting 
age-appropriate instrumental ADL 
GRADE 3 – Severe 
Medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL 
GRADE 4 – Life-threatening 
Life-threatening consequences; urgent intervention indicated 
GRADE 5 – Fatal 
Death 
ADL  activities of daily living 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
current IB as an adverse drug reaction or is not listed at the specificity or severity that 
has been observed.  AEs or suspected adverse reactions that are mentioned in the IB as 
occurring with a class of drugs or as anticipated from the pharmacological properties of 
the drug but are not specifically mentioned as occurring with a particular study drug are 
considered “unexpected.”  For example, an event more specific or more severe than 
described in the IB would be considered “unexpected.”  Any condition, laboratory 
abnormality, or physical finding with an onset date prior to the subject or their legally 
acceptable representative signing the ICF is considered to be pre-existing in nature and 
part of the subject’s medical history. 
12.2 
Causality 
A suspected adverse event means any AE for which there is reasonable possibility that 
the study drug caused the AE.  “Reasonable possibility” means that there is evidence to 
suggest a causal relationship between the drug and the AE. 
The relationship of the AE to the study drug should be assessed using the following 
criteria: 
YES; the event is suspected to be related if:  


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 
There is a clinically plausible time sequence between the AE onset and 
administration of study treatment; and/or 
 
There is a biologically plausible mechanism for the study treatment to cause or 
contribute to the AE; and/or 
 
The event responds to withdrawal of the study medication (de-challenge) and/or 
recurs or worsens with re-challenge (when clinically feasible); and/or 
 
The AE cannot be reasonably attributed to concurrent or underlying illness, other 
drugs, or procedures 
NO; the event is not suspected to be related if: 
 
The AE is more likely to be explained by the subject’s clinical state, underlying 
disease, concomitant medical, study or non-study procedure; and/or 
 
The time occurrence of the AE is not reasonably related to administration of study 
treatment; and/or 
 
The event is not related to the investigational product(s) 
In the event of a possible drug-related AE, the investigator should, to the best of his/her 
ability, assess its relationship to each of the study drugs:  carfilzomib, dexamethasone, 
mitoxantrone, PEG-asparaginase, vincristine, 6-mercaptopurine, cyclophosphamide, 
cytarabine, or IT hydrocortisone, cytarabine, or methotrexate. 
12.3 
Adverse Events Reporting Procedures 
12.3.1 
General 
All AEs (eg, any new event or worsening in severity or frequency of a pre-existing 
condition or laboratory finding) with an onset date after the subject or their legally 
acceptable representative signs the informed consent for participation in the clinical trial 
through 30 days after any study drug in the combination was received must be promptly 
documented on the AE eCRF via the electronic data capture (EDC) system.  AEs that 
are laboratory findings that do not result in a clinical action or alter treatment do not 
require reporting as AEs, unless the investigator considers the laboratory finding to be 
clinically significant.  Details of the event must include severity, relationship to study 
drug(s), duration, action taken, and outcome.  Whenever possible, reporting specific 
diagnosis is preferred when reporting AEs in the AE eCRF rather than reporting 
individual signs and symptoms.  Serious adverse events will be recorded on the AE 
eCRF and on the SAE reporting form (see Section 12.5, Serious Adverse Event 
Reporting and Documentation Requirements).  In addition, the investigator should report 
any AEs that may occur after this time period which are assessed to have a reasonable 
possibility of being associated with study drug.  If the subject is enrolled but discontinues 


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participation in the study prior to receiving study drug, AEs must be reported through the 
End-of-Study Assessment. 
If initiation of new anticancer therapy occurs within 30 days following the last dose of 
study drug(s), the date of new anticancer therapy will be recorded on the appropriate 
eCRF.   
All AE severity changes must be recorded on the AE CRF as separate events.  Every 
AE severity grade change must be recorded on the AE CRF.  All AEs that are 
considered related to study drug and all SAEs regardless of relationship to study drug 
must be followed to resolution or stabilization if improvement is not expected.  AEs which 
completely resolve and then recur should be recorded as a new AE.  For subjects who 
complete the End-of-Study Assessment less than 30 days following the last dose of 
study drug, a follow-up of ongoing AEs should be attempted by telephone and 
documented in the subject’s source file.  AEs continuing at 30 days after the last dose of 
study treatment should have a comment in the source file by the investigator that the 
event has stabilized or is not expected to improve. 
The investigator is responsible for evaluating all AEs, obtaining supporting source 
documents, and determining that documentation of the event is adequate.  
The investigator may delegate these duties to sub-investigators and must ensure that 
these sub-investigators are qualified to perform these duties under the supervision of the 
investigator and that they are listed on the FDA Form 1572. 
12.3.2 
Disease Progression 
Disease progression will be documented in an eCRF intended to capture PD 
information.  Signs and symptoms related to disease progression should be reported in 
the appropriate case report form (CRF) as an AE or as an SAE (if the event in question 
meets the criteria for seriousness).  Verbatim terms such as “disease progression,” 
“progressive disease,” etc. should not be reported as AEs or SAEs unless the 
investigator considers the progression to be atypical, accelerated, or caused by the 
study drug.  Similarly, deaths occurring as a result of disease progression should be 
reported on the eCRF intended to capture death information and should not be reported 
as SAEs. 


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12.4 
Serious Adverse Event Definitions 
An SAE is an AE that meets 1 or more of the following criteria: 
 
Death 
 
Life-threatening experience defined as any adverse experience that places the 
subject, in the view of the sponsor or investigator, at immediate risk of death at 
the time of occurrence; ie, it does not include a reaction that, had it occurred in a 
more severe form, might have caused death 
 
Requires inpatient hospitalization or prolongation of an existing hospitalization 
(except scheduled hospitalizations for a nonacute, unrelated cause such as 
elective surgery) 
 
Results in persistent or significant disability/incapacity (ie, substantial disruption 
in a subject’s ability to conduct normal activities of daily living) 
 
Is a congenital anomaly/ birth defect in the offspring of an exposed female 
subject or offspring of a female partner of a male subject 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered SAEs when, based on appropriate medical judgment, 
they jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
12.5 
Serious Adverse Event Reporting and Documentation Requirements 
Amgen Global Patient Safety must be notified of the occurrence of any SAE within 
24 hours of the investigator, designee, or site personnel’s knowledge of the event.  
The SAE will be reported by completing and submitting the SAE report form through the 
EDC system.  In the event that the EDC system is not available, paper SAE report forms 
may be used to report the SAE to Amgen Global Patient Safety (Appendix H).  Please 
refer to the SAE Reporting Guidelines in the study reference manual. 
Follow-up reports must be submitted in a timely fashion as additional information 
becomes available. 
The investigator is responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committees (IEC) in accordance with local regulations, of all SAEs.  
The sponsor may request for additional source documentation pertaining to the SAE 
from the investigational site.  If a subject is permanently withdrawn from the study due to 
an SAE, this information must be included in the initial or follow-up SAE report in the 
eCRF. 
The sponsor is responsible for notifying the appropriate global health authorities of 
SAEs, when required, and in accordance with applicable laws and regulations. 


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All SAEs occurring from the time that the subject signs consent for study participation 
and through 30 days after the last administered dose of study drug will be reported on 
the AE eCRF, regardless of whether new chemotherapy regimens are initiated.  
(Additional information is provided in Section 12.3.1).  All SAEs, regardless of 
relationship to study drug, must be followed to resolution or to stabilization if 
improvement or resolution is not expected. 
12.6 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant or a male subject fathers a child while the subject 
is taking protocol-required therapies, report the pregnancy to Amgen Global Patient 
Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur 6 months after the last dose of protocol-required therapies.  
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix I).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested.  
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant. 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event.  
If a female breastfeeds while taking protocol-required therapies, report the lactation case 
to Amgen as specified below.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix J).  Amgen Global Patient Safety will follow-up with the 
investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 


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If the subject becomes pregnant while taking an Amgen drug, the study drugs will be 
immediately discontinued.  The investigator will discuss the risks and concerns of 
investigational drug exposure to a developing fetus and counsel the subject and/or 
pregnant partner (or ensure that such counseling is provided).  
Newborns should be followed for a minimum of 12 weeks.  
13. 
Statistics 
The phase 2 protocol, including the statistical considerations for phase 2, is provided in 
Appendix K.   
13.1 
Study Endpoints 
13.1.1 
Primary Endpoints 
The primary endpoints for this study are: 
 
Safety and tolerability of carfilzomib alone and in combination with induction 
chemotherapy as defined by the type, incidence, severity, and outcome of AEs; 
changes from baseline in key laboratory analytes, vital signs, and physical 
findings.  Time to toxicity will be evaluated to differentiate single-agent 
carfilzomib from carfilzomib in combination with induction chemotherapy 
 
Determination of the MTD as the dose that has the highest posterior probability 
of having a DLT rate within the target toxicity interval (20–33), while the 
posterior probability of excessive/unacceptable toxicity ( 33–100) is less 
than 40 (per BLRM algorithm), or the stopping rules as specified in Section 5.2, 
and per CSRC recommendation. 
13.1.2 
Secondary Endpoints 
The secondary endpoints for this study are: 
 
Pharmacokinetic parameters, principally maximum plasma concentration (Cmax) 
and area under the curve (AUC), alone and in combination with induction 
chemotherapy, derived from levels of carfilzomib assayed in PK samples 
 
Combined proportion of subjects who achieve CR or CRp at the end of the 
Induction Cycle 
 
Proportion of subjects who achieve MRD status  10-3 and  10-4 lymphoblasts at 
the end of the Induction Cycle as assessed by next generation sequencing 
(NGS) 


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13.2 
Analysis of the Conduct of the Study 
Subject enrollment, treatment, duration of follow-up, and discontinuation from the study 
(including reasons for discontinuation) will be summarized by dose levels. 
13.3 
Independent Review Committee 
There will not be an Independent Review Committee for this study. 
13.4 
Cohort Safety Review Committee 
The Cohort Safety Review Committee (CSRC) activities were governed by a separate 
charter (on file) for the R3 dose escalation and first 4 cohorts of the VXLD dose 
escalation.  This section replaces the prior charter and governs the activities of the 
CSRC for all remaining cohorts of the VXLD dose escalation.  
The primary objective of the study is to determine the MTD of carfilzomib in combination 
with standard of care backbone chemotherapy (VXLD).  The CSRC is a cross-functional 
team whose purpose is to ensure the safety of subjects being treated with carfilzomib in 
combination with VXLD by reviewing safety data and DLTs after each cohort has 
completed the induction cycle, and to make recommendations on the next dose level to 
be evaluated based on that review and the recommendations of the Bayesian logistic 
regression model. 
The voting members of the CSRC include the 2 lead investigators (1 representative from 
each consortium partnering on the study), the Amgen medical monitor, and the Amgen 


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global safety officer.  Additional required non-voting members include the Amgen clinical 
trial manager and biostatistician.  Optional attendees may include, but are not limited to 
the clinical program manager(s) and the investigators (or their designees) for the 
subjects under review.  If a lead investigator is not available, the Amgen medical monitor 
will contact them and provide a summary of the meeting.  The absent member will be 
allowed to vote post-meeting. 
The CSRC will meet after each cohort of 3 DLT evaluable subjects have completed the 
induction and DLT evaluation periods.  The Bayesian logistic regression model will be 
updated, and the NCRM will recommend the next dose level from the updated 
probabilities for the target toxicity interval and the excessive-unacceptable toxicity 
interval.  The DLT evaluation period starts with the first dose of planned induction 
therapy (whether carfilzomib or backbone chemotherapy) and continues for at least 
29 days and up to 45 days from the first dose of therapy.  The conditions ending the DLT 
evaluable period are identified in Section 8.3.  A CSRC meeting may be called by the 
Amgen medical monitor after 2 subjects have been enrolled if a safety concern is 
identified.  Subjects who discontinue treatment, receive a dose modification, or miss 
doses of carfilzomib because of a non-dose-limiting toxicity adverse event or deviation 
from the protocol will be replaced, but their safety information will be considered in the 
CSRC’s decisions. 
All available study data, including data collected after the DLT evaluable period, and 
including eligibility, demographics, investigational product administration, medical and 
surgical history, prior leukemia therapy, concomitant medications, adverse events, vital 
signs, laboratory data, and available PK data will be reviewed.  The database will not be 
cleaned, an as-is snapshot of the database will be used in the analysis.  In addition to 
DLTs, all  grade 3 toxicities not meeting DLT criteria and serious adverse events (of all 
grades) will be reviewed and may be considered along with the dose level 
recommended by the Bayesian logistic regression model in CSRC decisions. 
The following decisions may be made by the CSRC: 
 
Increase the dose level by 1 step or decrease the dose level by 1 or more steps 
 
Note:  No dose level skipping will be allowed in dose escalation decisions.  There 
is no constraint on de-escalation decisions. 
 
Expand the current dose level by 3 subjects 
 
Halt enrollment, recommend the MTD based on available data, and recommend 
the dose for phase 2 if the Bayesian algorithm stopped because of the stopping 


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rules listed in Section 5.2 or because a safety signal is identified that in the 
opinion of the CSRC warrants stopping the trial 
If the CSRC decision results in a tie vote, the available study data will be provided to the 
Amgen Hematology/Oncology Therapeutic Area head for final determination. 
All other operational aspects of the CSRC meetings will follow Amgen processes for 
Dose Level Review Meetings. 
The CSRC activities will stop after the end of the phase 1 part of the study. 
13.5 
Data Monitoring Committee  
An independent DMC will be convened for this study and will act in an advisory capacity 
to the sponsor with respect to safeguarding the interests of study subjects, assessing 
interim safety and efficacy data, and monitoring the overall conduct of the study.  The 
database will not be cleaned, an as-is snapshot of the database will be used in this 
analysis.  To enhance the integrity of the study, the DMC may also formulate 
recommendations relating to the eligibility, recruitment, and retention of subjects, their 
management, improving adherence to protocol treatment, and the procedures for data 
management and quality control. 
The details of the DMC, including the roles and responsibilities of the involved parties, 
will be described in the DMC Charter.  The DMC will meet to review safety data no less 
frequently than every 6 months.  Unplanned safety review meetings of the DMC may be 
called at any time if earlier review of safety data is warranted.   
Details of the DMC for the phase 2 portion of the study are provided in Section 27. 
13.6 
Statistical Methods 
Descriptive statistics will be used to summarize enrollment, subject demographic and 
baseline characteristics, and discontinuation from the study.  Eligibility exceptions and 
important protocol deviations will be summarized. 
Data from Dose Escalation 1 (R3) and Dose Escalation 2 (VXLD) will be analyzed 
separately. 
Amgen will set a final analysis data cut-off date for safety, efficacy, and other analyses in 
anticipation of the date when all subjects have completed the study.  At that time the 
database will be cleaned, processed and a locked database will be used in the analysis.  
The final analysis will address all the study objectives. 


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13.6.1 
Efficacy Analyses 
The primary efficacy analysis will be based on subject data collected through study 
discontinuation or at the end of maximal treatment duration plus 30 days of safety 
follow-up, whichever occurs first.  Primary analyses will be based on the Safety 
Evaluable Population, defined as subjects receiving treatment with any amount of the 
study treatment regimen (chemotherapy backbone, carfilzomib, and any IT 
chemotherapy drugs).  Additional efficacy analyses will be performed using the Efficacy 
Evaluable Population, defined as subjects who are included in the safety evaluable 
population, and have a baseline disease assessment and at least 1 postbaseline 
disease assessment, or dropped out due to AE prior to the postbaseline disease 
assessment. 
All summaries will be presented by the overall Safety Population and by the assigned 
dose level.  Response assessment data including the status of CR/CRp and the 
proportion of subjects who achieve MRD status  10-3 and  10-4 lymphoblasts will be 
listed. 
13.6.2 
Safety Analysis 
The safety analyses will be based on the safety evaluable population, which is defined 
as all subjects who receive any amount of the study treatment regimen (chemotherapy 
backbone, carfilzomib, and any IT chemotherapy drugs).  
Safety and tolerability will be assessed through summaries of study drug administration, 
DLTs, AEs, changes in selected laboratory analytes, vital signs, and physical findings by 
dose level, and for all subjects. 
The number of DLTs and AEs at each dose level will be summarized separately for the 
carfilzomib single-agent Lead-in Window and the Induction Cycle.  Adverse events will 
also be summarized separately for subjects who receive the optional cycle of 
consolidation chemotherapy. 
Means and standard deviations will be used to summarize the total dose for each 
component of study drug received.  All summaries will be presented by the assigned 
dose level and for all subjects. 
All AE data will be listed by study site, dose level, subject identification number, and 
study day.  All AEs will be summarized by preferred term and NCI-CTCAE 
(Version 4.03) toxicity grade.  In addition, all SAEs, including deaths, will be listed 
separately and summarized. 


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Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, and blood 
pressure) data will be displayed by visit and time (when available), with NCI-CTCAE 
(Version 4.03) Grade 3 and 4 values identified where appropriate.  Additionally, all 
laboratory data will be summarized by NCI-CTCAE grade. 
13.6.3 
Correlative Study Analyses 
13.6.3.1 
Pharmacokinetic Analysis 
Blood samples will be collected from all subjects for determination of plasma 
concentrations of carfilzomib.  Actual collection times will be recorded and used in the 
analysis.  Individual and mean plasma concentration-versus-time data will be tabulated 
and plotted by dose level.  The PK parameter estimates for carfilzomib will be 
summarized, including total plasma exposure (AUC), Cmax, time to maximum plasma 
concentration (Tmax), total plasma clearance, and plasma terminal half-life (as 
appropriate for data collected).  Estimates for these parameters will be tabulated and 
summarized (ie, mean, standard deviation). 
Unless otherwise specified, the PK parameter will be estimated based on 
noncompartmental methods.  These estimates will be summarized descriptively by dose 
level and by single-agent or combined therapy.  
 
 
 
In addition to noncompartmental PK analysis, the population modeling program will be 
used to fit a nonlinear mixed effects model to estimate PK parameters including 
clearance and volume of distribution, the inter- and intra-subject variability and the 
population variability in the parameter estimates.  The PK concentrations obtained from 
subjects in the Dose Escalation 1 (R3) and Dose Escalation 2 (VXLD) portions of the 
study, along with results from adult carfilzomib studies, will be used in the development 
of a structural model.  The best model will be evaluated by goodness-of-fit statistics and 
reduction in the objective function and posterior predictive checks.  Subject 
characteristics such as age, gender, body weight, BSA, and race will be included in the 
model to identify potential covariates affecting PK of carfilzomib in pediatric populations.  
Results from the population PK modeling will be reported separately. 
 
 


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13.7 
Handling of Missing Data 
Missing data for partial dates on AEs or concomitant medication may be imputed 
according to prespecified, conservative imputation rules.  The details of the imputation 
rules will be defined in the statistical analysis plan. 
13.8 
Determination of Sample Size 
The estimated sample size for the study is based on the N-CRM.  A cohort size of 2 will 
be used and a minimum of 1 cohort (DLT-evaluable subjects) will be enrolled before the 
trial stops in the Dose Escalation 1 (R3) portion of the study.  A cohort size of 3 will be 
used and a minimum of 1 cohort (DLT-evaluable subjects) will be enrolled before the trial 
stops in the Dose Escalation 2 (VXLD) portion.  With a maximum of 18 subjects in dose 
escalation 1 and 24 in dose escalation 2, the algorithm was able to find MTD with 
reasonable probability under various dose toxicity distribution and prior assumptions 
based on simulation results. 
14. 
Investigational Drug 
The phase 2 protocol, including details for investigation products, is provided in 
Appendix K.   
14.1 
Carfilzomib Description, Packaging, and Storage 
14.1.1 
Physical Description 
Carfilzomib is a synthetic small molecule peptide bearing the chemical name 
(2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-ph
enylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide
.  The molecular formula is C40H57N5O7 and the molecular weight is 719.91. 
14.1.2 
Formulation 
Carfilzomib for Injection will be provided as a lyophilized powder which, when 
reconstituted, contains a 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM 
sodium citrate buffer (pH 3.5) containing 10 (w/v) sulfobutylether-beta-cyclodextrin 
Captisol (SBE-beta-CD). 
14.1.3 
Packaging and Labeling 
Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use vials 
packaged in multivial cartons.  Institutional pharmacies will be supplied with open stock 
vials with full-disclosure labels.   


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Reordering clinical drug supplies will be managed through the Interactive Voice 
Recognition System (IVRS) or IWRS; details are provided in the IPIM and/or the IWRS 
Site User Manual. 
14.1.4 
Storage and Stability 
Study drug should be stored in a securely locked area with access limited to appropriate 
study personnel.  Lyophilized Carfilzomib for Injection must be stored at 2C–8C 
(36F−46F).  Vials must be kept in cartons to protect contents from light until ready for 
reconstitution.  Additional details are provided in the IPIM. 
14.2 
Study Drug Accountability 
The Sponsor (or designee) and the investigator will maintain records of each shipment of 
Carfilzomib for Injection.  Upon receipt of Carfilzomib for Injection, the designated 
recipient at the study site will inspect the shipment, verify the number and condition of 
the vials, and prepare an inventory or drug accountability record.  The records will 
document shipment dates, method of shipment, batch numbers, product presentation, 
quantity of vials contained in the shipment, and dispensation to individual subjects using 
the subject identification number. 
Responsibility for drug accountability at the study site rests with the investigator; 
however, the investigator may assign drug accountability duties to an appropriate 
pharmacist or designee.  Inventory and accountability records must be readily available 
for inspection by the study monitor and are open to inspection at any time by any 
applicable regulatory authorities. 
The investigator must ensure that the investigational products are used in accordance 
with the protocol.  The investigator will also maintain records adequately documenting 
that the subjects were provided the treatment specified and reconciling all investigational 
products. 
Remaining supplies will be retained by the pharmacy at the end of the study, and after 
verification of the final drug accountability by the study monitor, discarded or destroyed 
according to institutional Standard Operating Procedures (SOPs).  Documentation of 
destruction of unused study medication will be maintained by the site.  For each subject, 
the site pharmacy personnel will be required to record and document proper per protocol 
dispensing of carfilzomib. 


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14.3 
Chemotherapy Backbone Description, Packaging, and Storage 
Standard-of-care chemotherapy that is commercially available will not be provided or 
reimbursed by the Sponsor (except if required by local regulations).  The investigator will 
be responsible for providing these agents and any ancillary supplies needed for 
chemotherapy administration.  Administration of the chemotherapy backbone should be 
in accordance with the schedules provided in Sections 8.1.2 and 8.1.3. 
The chemotherapy drugs used in the induction backbones (daunorubicin, 
dexamethasone, mitoxantrone, PEG-asparaginase, and vincristine), the chemotherapy 
drugs used in the consolidation backbone (6-mercaptopurine, cyclophosphamide, 
cytarabine, PEG-asparaginase, and vincristine), and the CNS treatment drugs 
(hydrocortisone, cytarabine, and methotrexate) are considered to be standard of care 
and are commercially available. 
The description, how supplied, and storage instructions for each drug product are 
available in the associated prescribing information.  The study staff is advised to refer to 
the prescribing information that is specific to the brand or formulation of the drug product 
being administered to subjects at their site. 
14.4 
Chemotherapy Backbone Accountability 
Sites will be required to record and document subject compliance with the induction 
backbones (dexamethasone, mitoxantrone, PEG-asparaginase, and vincristine; or 
vincristine, dexamethasone, PEG-asparaginase, and daunorubicin), the consolidation 
backbone (6-mercaptopurine, cyclophosphamide, cytarabine, PEG-asparaginase, and 
vincristine), and the CNS treatment drugs (hydrocortisone, cytarabine, and 
methotrexate).  Additional details are provided in the IPIM. 
15. 
Ethical and Administrative Considerations 
The phase 2 protocol, including ethical and administrative considerations, is provided in 
Appendix K.   
15.1 
Compliance Statement 
This study will be conducted in accordance with the protocol and with US FDA, and the 
ICH Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki, and any 
applicable local health authority and Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) requirements.  The investigator is responsible for ensuring that this 
protocol, the site’s informed consent form, and any other information that will be 
presented to potential subjects are reviewed and approved by the appropriate IRB or 
IEC prior to the enrollment of any study subjects. 


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15.2 
Institutional Review Board or Independent Ethics Committee 
The investigator will submit this protocol, the informed consent, IB, and any other 
relevant supporting information to the appropriate IRB or IEC and the local regulatory 
agency for review and approval prior to study initiation. 
Amendments to the protocol must also be approved by the IRB/IEC and the local 
regulatory agency, as appropriate, prior to the implementation of changes in this study.  
No protocol deviations are allowed.  However, the investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the 
study subjects without prior IRB/IEC/Sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it, and, if appropriate, the 
proposed protocol amendment, should be submitted to the IRB/IEC/Sponsor.  Any 
deviations from the protocol must be fully explained and documented by the investigator. 
15.3 
Informed Consent, Pediatric Assent, and Human Subject Protection 
No investigator may involve a human being as a subject in research unless the 
investigator has obtained the legally effective informed consent and pediatric assent of 
the subject or the subject’s legally acceptable representative.  An investigator shall seek 
such consent and assent only under circumstances that provide the prospective subject 
or the subject’s legally acceptable representative sufficient opportunity to consider 
whether or not to participate, and that minimize the possibility of coercion or undue 
influence.  The information that is given to the subject or the representative shall be in a 
language understandable to the subject or representative. 
The Sponsor or its designated representative will provide the investigator with sample 
consent and assent forms.  Local and/or institutional requirements may require 
disclosure of additional information in the ICF.  Any changes to the consent or assent 
forms must be submitted to the sponsor or its designated representative for acceptance, 
prior to submission to the IRB/IEC.  The IRB/IEC will review the consent and assent 
forms for approval.  A copy of the approved forms must be submitted to the sponsor or 
its designated representative for its approval prior to initiation of the study.  Before 
implementing any study procedure on a particular subject, informed consent and assent 
shall be documented in such subject’s case histories and by the use of written consent 
and assent forms approved by the Sponsor and the IRB/IEC and signed and dated by 
the subject or the subject’s legally acceptable representative at the time of consent and 
assent.  Copies of the signed informed consent and assent forms will be given to the 
subject or subject’s legally acceptable representative.  The original signed consent and 
assent forms must be maintained by the investigator and available for inspection by the 


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Sponsor, its designated representative, or regulatory authority representatives at any 
time. 
15.4 
Direct Access to Source Data, Source Documents, and Study 
Records 
The study will be carried out in keeping with applicable local laws and regulations.  
This may include an inspection by Sponsor representatives/designees, and/or regulatory 
authority representatives at any time.  The investigator/institution must agree to the 
inspection of study-related records by the regulatory authority/Sponsor 
representatives/designees and must allow direct access to source documents to the 
regulatory authority/Sponsor representatives/designees/IRB/IEC.  The investigator must 
allocate time (investigator and study staff) to discuss findings and relevant issues with 
the regulatory authority/Sponsor representatives. 
15.5 
Data Collection and Handling 
As part of the responsibilities assumed by participating in the study, the investigator 
agrees to maintain adequate case histories for the subjects treated as part of the 
research under this protocol.  The investigator agrees to maintain accurate eCRFs (or 
paper Case Report Forms [CRFs]) and source documentation as part of the case 
histories.  These source documents may include subject diaries, laboratory reports, and 
other documents.  The Sponsor will supply the eCRF (or CRF), which will be completed 
in English. 
Data collection will involve the use of the EDC system, to which only authorized 
personnel will have access. 
The investigator or designee must enter all results collected during the clinical study into 
eCRFs (or CRFs).  Guidelines for completion of eCRFs (or CRFs) will be reviewed with 
study site personnel at the site initiation visits.  Investigators are responsible for approval 
of the entered/corrected data.  Detailed instructions may be found in the other 
study-specific documents. 
All entries made on the eCRF (or CRF), must be verifiable against source documents.  
In addition to periodic monitoring occurring within the system by study monitors, 
programmatic edit checks and data listings will be used to review the data for 
completeness, logic, and adherence to study protocol.  As a result of this monitoring and 
these checks, queries may be electronically issued to the clinical study sites and 
electronically resolved by those sites. 


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All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records.  Also, data will be stored 
and evaluated in such a way as to assure subject confidentiality in accordance with the 
legal and regulatory requirements applying to protected health information.  Study 
records (eg, copies of eCRFs, regulatory documents) will be retained at the study site, 
along with adequate source documentation.  The study file and all source data should be 
retained for the time period required by applicable regulatory requirements and will not 
be destroyed until written notification is given by the sponsor or designee for destruction. 
15.6 
Confidentiality 
All records identifying the subject will be kept confidential and, in accordance with the 
applicable laws and/or regulations, will not be made publicly available. 
Subject names will not be supplied to the sponsor.  Only the subject number will be 
recorded on the CRF.  If the subject name appears on any other document 
(eg, pathologist report) or study materials (eg, biopsy tissue slides), then that information 
must be redacted before a copy of the document is supplied to the sponsor.  Study data 
stored on a computer will be stored in accordance with local data protection laws and 
regulations.  Subjects will be informed in writing that representatives of the sponsor, 
IRB/IEC, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will 
be handled in strictest confidence and in accordance with local data protection laws and 
regulations. 
If the results of the study are published, the subject’s identity will remain confidential. 
The investigator will maintain a list to enable subjects’ records to be identified in 
accordance with applicable laws and regulations and according to the terms and agreed 
upon in such subjects’ signed consent forms. 
15.7 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 


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not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) Recommendations for 
the Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical 
Journals, which states: 
 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 1, 
2, 3 and 4. 
 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 


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Auricchio S, Stellato A, DeVisia B. Development of brush border peptidases in human 
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Blade J, Rosinol L. Renal, hematologic and infectious complications in multiple 
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Blaney S, Bernstein M, Neville K, et al. Phase I study of the proteasome inhibitor 
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Campana D, Leung W. Clinical significance of minimal residual disease in patients with 
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17. 
Appendices 
17.1 
Appendix A.  Schedule and Description of Assessments, Screening for Phase 1 
Schedule of Screening Assessments 
Assessment 
Up to 
72 Hours 
Before 
Enrollment 
Up to 7 Days 
Before 
Enrollment 
Complete history and physical examination 
X 
 
Bone marrow aspirate 
 
Xa 
Lumbar puncture 
 
X 
Examination for testicular involvement 
 
X 
ECG (12-lead) 
 
X 
Echocardiogram (fractional shortening) 
 
X 
Local laboratory evaluations: 
 
 
CBC with differential and platelet count 
X 
 
Serum electrolytes: 
Na, K, Cl, CO2, Ca, Mg, P 
X 
 
Blood glucose 
X 
 
Renal function:  BUN, Cr; NM-GFR only if Cr 
1.5 x ULN 
X 
 
Hepatic function:  AST, ALT, total and direct 
bilirubin, ALP, albumin 
X 
 
Pancreatic function:  amylase, lipase 
X 
 
Uric acid 
X 
 
Serum or urine pregnancy test, females of 
reproductive potential 
X 
 
Hepatitis B testing 
 
Xb 
anti-HBs  hepatitis B surface antibody; CBC  complete blood count; ECG  
electrocardiogram; HBV  hepatitis B virus; ULN  upper limit of normal. 
An ICF and, where applicable, a pediatric assent form must be signed before 
any study-specified tests may be performed. 
A complete history and physical examination must include all of the following: 
 
Review of medical and surgical histories, including: 
o 
Prior cumulative anthracycline exposure 
o 
Known or suspected cancer pre-disposition syndromes 
o 
Other co-morbidities which, in the investigator’s opinion, either 
place a subject at increased risk for adverse events, or have 
potential impact on the results of study-specified tests, including, 
but is not limited to:  Endocrinopathies, gastrointestinal disorders, 
inborn errors of metabolism, congenital heart disease (repaired or 
unrepaired), epilepsy. 
o 
Documentation of all current medications 
 
Vital signs:  temperature, heart rate, respiratory rate, systolic and 
diastolic blood pressures 
 
Weight, height, and body surface area 
 
Performance status assessment:  Lansky score if 16 years of age; 
Karnofsky score if 16 years of age 
 
Examination of all of the following:  head, ears, eyes, nose, oropharynx, 
neck, heart, lungs, abdomen, genitalia, back, extremities, lymph nodes, 
skin, nervous system 
 
Determination of the baseline NCI-CTCAE (Version 4.03) grade for all 
abnormal physical examination findings 
Bone marrow aspirate must be obtained and a morphologic diagnosis of 
relapsed or refractory acute lymphoblastic leukemia must be determined prior 
to study enrollment.  In the event that aspirate cannot be obtained, diagnosis 
may be made by biopsy.  It is not necessary for the results of 
immunophenotyping or cytogenetic studies to be available prior to enrollment 
or the initiation of study treatment. 
 
Cerebrospinal fluid must be obtained prior to the initiation of study treatment 
and examination must include:  RBC count, WBC count, differential, cytology. 


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for other assessments. 
b Hepatitis serologies may be obtained up to 2 weeks prior to enrollment.  
Testing is not required if tested negative within 6 months of screening and no 
change in the subject’s risk factors within these 6 months.  Subjects with 
positive testing or a history of prior HBV infection should have consultation 
with a specialist and must have HBV-DNA testing at screening and again at 
safety follow up.  Subjects that have received hepatitis B vaccination with only 
anti-HBs positivity and no clinical signs of hepatitis do not require HBV-DNA 
monitoring. 


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17.2 
Appendix B.  Schedule and Description of Assessments, Lead-in Window for Phase 1 
On-Study Assessments:  Lead-in Window 
Assessment 
Cycle Day 
1 
2 
8 
Physical examination 
X 
 
X 
Lumbar puncture 
 
 
 
CNS- negative 
Xa 
 
X 
CNS- positive 
Xa 
 
X 
Local laboratory evaluations 
 
 
 
CBC with differential and platelet count 
Xa 
 
X 
Electrolytes:  Na, K, Cl, CO2, Ca, Mg, P 
Xa 
 
X 
Blood glucose 
Xa 
 
X 
Renal function:  BUN, Cr 
Xa 
 
X 
Hepatic function:  AST, ALT, total and direct 
bilirubin, ALP, albumin 
Xa 
 
X 
Pancreatic function:  amylase, lipase 
Xa 
 
X 
Uric acid 
Xa 
 
X 
Bone-specific ALP 
X 
 
 
Correlative study measurements 
 
 
 
Pharmacokinetic studies 
X 
 
 
 
 
 
 
) 
 
 
 
Response assessment/bone marrow aspirate 
(including MRD) 
 
 
X 
a Assessments from the screening period must have been obtained within 72 hours 
before enrollment (or for lumbar puncture, within 7 days before enrollment) and no 
repeat Day 1 study assessments are required, except for repeat evaluations of the 
blood when the initiation of study treatment occurs 48 hours after these labs were 
obtained or at the discretion of the investigator. 
 
Physical examination during study treatment must include all of the 
following: 
 Updated documentation 
of all current medications 
 
Examination of all of the following: 
head, ears, eyes, nose, oropharynx, 
heart, lungs, abdomen, extremities, 
lymph nodes, skin, and nervous 
system 
 
Weight, height, and body 
surface area 
 Vital Signs:  temperature, 
heart rate, respiratory 
rate, and systolic and 
diastolic blood pressures 
 
Determination of the updated CTCAE 
(v. 4.03) grade for all abnormal 
physical examination findings.  
Clinically significant abnormal findings 
that are new or represent a worsening 
after the signature of the ICF must be 
reported as AEs. 
Local laboratory evaluations of the blood must be obtained and results 
reviewed prior to the delivery of study treatment and may be obtained as 
early as 48 hours in advance.  The blood sample for bone-specific ALP 
must be collected prior to the initiation of study treatment. 
Blood samples for PK studies must be collected from all subjects for 
determination of plasma concentrations of carfilzomib at the following time 
points:  predose; 15 minutes after the start of infusion; immediately (within 
2 minutes before the end of infusion); and at 10 minutes, 30 minutes, and 1, 
2, and 4 hours after the end of the infusion. 
Blood samples for PDn studies must be collected predose and 
approximately 1 hour following the Day 1 and Day 2 carfilzomib dose. 
Response assessment includes physical examination, CBC, lumbar 
puncture, and bone marrow aspiration.  A lumbar puncture is not required 
after the second lumbar puncture for subjects who are CNS-negative.  
CNS-positive subjects must have 2 consecutive lumbar punctures without 
evidence of leukemia, before lumbar puncture is no longer required. 




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17.4 
Appendix D.  Schedule and Description of Assessments, Optional Consolidation for Phase 1 
On-Study Assessments:  Optional Consolidation Cycle 
Assessment 
Cycle Day 
1 
8 
15 
22 
29 
Physical examination 
X 
X 
X 
X 
X 
Lumbar puncture 
 
 
 
 
 
CNS- negative  
X 
X 
X 
X 
 
CNS- positive 
X 
X 
X 
X 
Xa 
Local laboratory evaluations 
 
 
 
 
 
CBC with differential and platelet count 
X 
X 
X 
X 
X 
Electrolytes:  Na, K, Cl, CO2, Ca, Mg, 
P 
X 
X 
X 
X 
X 
Blood glucose 
X 
X 
X 
X 
X 
Renal function:  BUN, Cr 
X 
X 
X 
X 
X 
Hepatic function:  AST, ALT, total and 
direct bilirubin, ALP, albumin 
X 
X 
X 
X 
X 
Pancreatic function:  amylase, lipase 
X 
X 
X 
X 
X 
Response assessment/bone marrow 
aspirate (including MRD) 
 
 
 
 
X 
a Required only for subjects who remain CNS-positive on Day 22. 
 
 
A new ICF and, where applicable, a new pediatric assent form is 
required for participation in this cycle. 
Physical examination during study treatment must include all of 
the following: 
 
 Updated 
documentation of all 
current medications 
 Examination of all of the 
following: 
head, ears, eyes, nose, 
oropharynx, heart, lungs, 
abdomen, extremities, lymph 
nodes, skin, and nervous system 
 Weight, height, and 
body surface area 
 Vital Signs:  
temperature, heart 
rate, respiratory rate, 
and systolic and 
diastolic blood 
pressures 
 Determination of the updated 
CTCAE (v. 4.03) grade for all 
abnormal physical examination 
findings.  Clinically significant 
abnormal findings that are new or 
represent a worsening after the 
signature of the ICF must be 
reported as AEs 
Local laboratory evaluations of the blood must be obtained and 
results reviewed prior to the delivery of study treatment and may 
be obtained as early as 48 hours in advance.   
Response assessment includes physical examination, CBC, 
lumbar puncture, and bone marrow aspiration.  A lumbar puncture 
is not required after the second lumbar puncture for subjects who 
are CNS-negative.  CNS-positive subjects must have 2 
consecutive lumbar punctures without evidence of leukemia, 
before lumbar puncture is no longer required. 


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17.5 
Appendix E.  Description of End--of-study Assessments for Phase 1 
End-of-Study Assessments 
Assessment 
30 Days ( 4 Days) After Last 
Dose of Study Treatment 
Physical examination 
X 
Local laboratory evaluations 
X 
CBC with differential and platelet count 
X 
Electrolytes:  Na, K, Cl, CO2, Ca, Mg, P 
X 
Blood glucose 
X 
Renal function:  BUN, Cr 
X 
Hepatic function:  AST, ALT, total and direct 
bilirubin, ALP, albumin 
X 
Hepatitis B testing 
Xa 
Pancreatic function:  amylase, lipase 
X 
HBV  hepatitis B virus 
a Only in subjects with positive hepatitis B serology at screening or past history of 
HBV infection. 
 
A complete history and physical examination must include all of the 
following: 
 
Review of medical and surgical histories, including documentation of 
all current medications 
 
Vital Signs: 
o 
Temperature 
o 
 Heart rate 
o 
Respiratory rate 
o 
Systolic and diastolic blood pressures 
 
Weight, height, and body surface area 
 
Performance status assessment: 
o 
Lansky score if  16 years of age 
o 
Karnofsky score if  16 years of age 
 
Examination of all of the following: 
 
Head, ears, eyes, nose, oropharynx, neck, heart, lungs, abdomen, 
genitalia, back, extremities, lymph nodes, skin, nervous system. 
 
Determination of the updated NCI-CTCAE (Version 4.03) grade for 
all abnormal physical examination findings. 
The End-of-Study Assessments must be completed 30 days ( 4 days) 
following the last dose of study treatment.  For subjects who complete 
the End-of-Study Assessment less than 30  4 days following the last 
dose of study treatment, a follow-up of ongoing AEs should be attempted 
by telephone and documented in the subject’s source file.  All AEs must 
be followed until resolution, unless the investigator has determined that 
the event has stabilized or is not expected to improve. 
 


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17.6 
Appendix F.  Karnofsky and Lansky Performance Status Scales 
Performance Status Criteria 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
Karnofsky 
Lansky 
Score 
Description 
Score 
Description 
100 
Normal, no complaints, no evidence 
of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity, 
minor signs or symptoms of disease. 
90 
Minor restrictions in physically 
strenuous activity. 
80 
Normal activity with effort, some 
signs or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self.  Unable to carry on 
normal activity or to do active work. 
70 
Both greater restriction of, and less 
time spent in, active play. 
60 
Requires occasional assistance, but 
is able to care for most of his needs. 
60 
Up and around, but minimal active 
play; keeps busy with quieter 
activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around much 
of the day; no active play; able to 
participate in all quiet play and 
activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet 
activities. 
30 
Severely disabled, hospitalization is 
indicated although death not 
imminent. 
30 
In bed; needs assistance even for 
quiet play. 
20 
Hospitalization necessary, very sick, 
active supportive treatment 
necessary. 
20 
Often sleeping; play entirely limited 
to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
0 
Dead. 
0 
Unresponsive. 
Sources:  Karnofsky 1949; Lansky 1987. 


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17.7 
Appendix G.  Guidance for Determining Previous Cumulative 
Anthracycline Dose 
Total Anthracycline Calculation Worksheet 
Instructions: 
In order to calculate the total anthracycline received by a subject, you will need to review the subject’s 
previous treatment.  You will need to document each dose of anthracycline chemotherapy prescribed and 
received by the subject. 
Step 1: Indicate which drug the subject received.  (Contact the investigator if drug not listed) 
Step 2: Enter the prescribed dose for that drug per the chemotherapy roadmap/orders.  Be sure to list all 
doses. 
Step 3: Enter the corresponding conversion factor for the drug given. 
Step 4: Multiply the prescribed dose by the conversion factor and enter the result in the Total 
Anthracycline column. 
Step 5: After you have completed this worksheet for all doses, add all the total doses to obtain the Total 
Cumulative Dose. 
Drug 
Prescribed Dose 
The prescribed dose is the dose of 
chemotherapy written in the protocol.  
It will be listed as mg/m2.  (It is not 
the actual dose received by the 
subject) 
Conversion Factor 
Doxorubicin  1 
Daunorubicin  0.5 
Idarubicin  2.5 
Mitoxantrone  2.5 
Total 
Anthracycline 
EXAMPLE: 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
10 mg/m2 
2.5 
25 mg/m2 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 
Total Cumulative Dose 
 


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17.8 
Appendix H.  Sample Serious Adverse Event Report Form 
Phase 1b of the study is closed.  See Section 28 Figure 6 for phase 2 serious adverse 
event report forms. 
17.9 
Appendix I.  Pregnancy Notification Form 
Phase 1b of the study is closed.  See Section 29 Figure 7 for phase 2 Pregnancy 
Notification Form. 
17.10 
Appendix J.  Lactation Notification Worksheet 
Phase 1b of the study is closed.  See Section 29 Figure 7 for phase 2 Lactation 
Notification Form. 


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17.11 
Appendix K.  Phase 2 Part of Study 
17.11.1 
Phase 2:  Study Schema 
Figure 5.  Phase 2 Part - Study Schema 
Subject ≥12 
months of age
Days 29-45
Subject < 12 
months of age
Days 36-50
Subject ≥12 
months of age
Days 29-45
Subject < 12 
months of age
Days 36-50
Day 45
Consolidation
Day 28 
Consolidation
Day 1 
Consolidation
Day 28
Induction
Day 1
Induction
Day -7
SCREENING (7 DAYS)
ENROLLMENT N = 100
INDUCTION THERAPY
VXLD + Carfilzomib
Carfilzomib 20 mg/m2 day 1, 56 mg/m2
days 2, 8, 9, 15, 16
Assess 
Disease 
Response
Assess 
Disease 
Response
(OPTIONAL)
CONSOLIDATION THERAPY
Modified BFM backbone + 
Carfilzomib
Carfilzomib 56 mg/m2 days 1, 2, 8, 9, 
15, 16
SAFETY FOLLOW-UP
LONG-TERM 
FOLLOW-UP 
 
 
 


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17.11.2 
Phase 2:  Schedule of Activities, Phase 2 
Table 14.  Phase 2 Schedule of Activities – Induction Therapy Subjects Greater Than or Equal to 12 Months of Age at Screening 
 
Screeninge 
Treatment Period  
(Induction Therapy Subjects  
Greater Than or Equal to 12 Months of Age) 
SFUa 
LTFU 
(every 
12 weeks)b 
Comments 
Study Day 
(up to 7 days 
before day 1) 
1 
2 
4 
8 
9 15 16 18 22 29-45c 
 
 
 
General and Safety 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent and 
assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Physical 
measurements 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight and height at screening; weight at SFU 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance use history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Includes tobacco exposure 
ECGe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHOe 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Subjects with clinical symptoms of congestive 
heart failure during or after induction should 
have an ECHO to evaluate cardiac function 
before initiation of the optional consolidation. 
Vital signs 
X 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
 
Temperature, heart rate, respiratory rate, and 
systolic and diastolic blood pressures.  On 
days 29 to 45, assessment only required at time 
of bone marrow assessment. 
Karnofsky or Lansky 
Performance status 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Lansky if less than 16 years of age; Karnofsky if 
greater than or equal to 16 years of age 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collected from time of signing of the ICF.  
Details regarding the reporting of adverse 
events are provided in Section 24.2.4. 


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Screeninge 
Treatment Period  
(Induction Therapy Subjects  
Greater Than or Equal to 12 Months of Age) 
SFUa 
LTFU 
(every 
12 weeks)b 
Comments 
Study Day 
(up to 7 days 
before day 1) 
1 
2 
4 
8 
9 15 16 18 22 29-45c 
 
 
 
Serious adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collected from time of signing of the ICF.  
Details regarding the reporting of serious 
adverse events are provided in Section 24.2.4. 
Concomitant therapies 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collected from time of signing of the ICF.  
Details regarding the reporting of concomitant 
therapies are provided in Section 22.7.2. 
LABORATORY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(females of 
childbearing potential 
only)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine.  Additional on-treatment 
pregnancy testing may be performed at the 
investigator’s discretion if there is suspicion that 
a female subject is pregnant or per local laws 
and regulations. 
Coagulatione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
INR, aPTT  
Hematologye 
X 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
 
See Table 28 for analytes.  On days 29 to 45, 
assessment to be performed weekly, at the time 
of bone marrow assessment, and on day 45 in 
subjects that have not yet proceeded to next 
therapy.  Samples obtained on day of bone 
marrow and within 1 week after the bone 
marrow will be assessed locally and a stained 
slide must be sent to central lab, unless subject 
has already started next therapy at the time the 
sample is obtained. 
Chemistrye 
X 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
 
See Table 28 for analytes.  In addition to 
chemistries in the complete metabolic panel, 
include adjusted calcium, ALP, magnesium, 
phosphorous, serum albumin, and total protein if 
not part of standard panel; direct bilirubin if total 
bilirubin is elevated; and uric acid until 
normalized for 2 consecutive measurements.   
On days 29 to 45, assessment only required at 
time of bone marrow assessment.   
Pancreatic functione 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Amylase and lipase 


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Screeninge 
Treatment Period  
(Induction Therapy Subjects  
Greater Than or Equal to 12 Months of Age) 
SFUa 
LTFU 
(every 
12 weeks)b 
Comments 
Study Day 
(up to 7 days 
before day 1) 
1 
2 
4 
8 
9 15 16 18 22 29-45c 
 
 
 
Hepatitis B screeninge 
X 
 
 
 
 
 
 
 
 
 
 
Xd 
 
All hepatitis testing will be performed locally.  All 
subjects will be tested at screening for HBsAg, 
anti-HBs, and anti-HBc, unless testing was 
previously performed within 6 months of 
screening and there was no change in the 
subject’s risk factors within these 6 months.  
CMV PCR testinge 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Recommended for all subjects, but only required 
for subjects who are known to be CMV positive 
or who previously received a bone marrow 
transplant. 
STUDY-SPECIFIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate/biopsye 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
On days 29 to 45, perform assessment when 
peripheral blood counts recover (defined as 
ANC greater than or equal to 1000/L, platelets 
greater than or equal to 100 000/L) or as 
clinically indicated, to assess for CR, by day 45, 
or as clinically indicated.  MRD BMA using NGS 
has priority over MRD BMA flow cytometry or 
PCR.  Bone marrow will be assessed locally and 
stained slides will be submitted to central 
laboratory for histological examination. 
Lumbar puncture with 
or without ITe 
X 
X 
 
 
X 
 
X 
 
 
X 
X 
 
 
If IT therapy is administered during screening 
(within 7 days of day 1), repeat of IT on day 1 is 
not required.  Lumbar puncture performed on 
days 15 and 22 only if CNS3 (Table 3).  On 
days 29 to 45, assessment only required at time 
of bone marrow assessment. 
Testicular 
ultrasound/physical 
exam (males with 
testicular mass only)e 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Remission is to be determined by the same 
technique used at screening 




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c The timing of assessments on days 29 to 45 and when/if a subject proceeds to the consolidation phase is to be determined by the investigator based on the subject’s 
peripheral blood count recovery or the start of alternate therapy, whichever comes first.  Assessments may be repeated multiple times within this window at the 
discretion of the investigator as needed to assess for response or progression.  If peripheral blood counts recover within 7 days of an M1 bone marrow assessment a 
repeat bone marrow is not required to confirm CR. 
d Subjects with positive testing or a history of prior HBV infection should have consultation with a specialist and must have HBV-DNA testing at screening and again at 
safety follow-up.  Subjects that have received hepatitis B vaccination with only anti-HBs positivity and no clinical signs of hepatitis do not require HBV-DNA 
monitoring.  
e Evaluations performed within 7 days of enrollment as part of routine medical care (eg, bone marrow aspirate/biopsy) may be used for screening assessments.   


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Table 15.  Phase 2 Dosing Regimen for Induction Therapy – Subjects Greater Than or Equal to 12 Months of Age at Screening 
CNS = central nervous system; IT = intrathecal therapy; IV = intravenous; PEG = polyethylene glycol  
 
Screening 
Treatment Period (Induction Therapy Subjects  
Greater Than or Equal to 12 Months of Age) 
Comments 
Study Day 
(up to 7 days before day 1) 
1 
2 
4 
8 
9 
15 
16 
18 
22 
29-45 
 
STUDY TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
Carfilzomib 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
20 mg/m2 on day 1, 56 mg/m2 for subsequent 
doses.  Administer IV over 30  5 minutes 
Prehydration 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
Greater than or equal to 125 mL/m2/hour of IV 
fluid is required for 1 hour prior to carfilzomib 
administration 
Vincristine 
 
X 
 
 
X 
 
X 
 
 
X 
 
1.5 mg/m2 per dose (maximum single dose 
2 mg).  Administer as IV push over 1 min or 
infusion per institutional policy. 
Dexamethasone 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
3 mg/m2 per dose twice daily (total daily dose 
6 mg/m2) on days 1 through 21.  Administer 
orally or as IV.  Given 4 hours to 30 minutes 
prior to carfilzomib doses.  See 
Section 22.1.2.1 for acceptable alternatives. 
PEG-asparaginase 
 
 
 
X 
 
 
 
 
X 
 
 
2500 U/m2 per dose.  Administer IV.  See 
Section 22.1.2.1 for acceptable alternatives.  
Daunorubicin 
 
X 
 
 
 
 
 
 
 
 
60 mg/m2 per dose.  Administer as an infusion 
over 15 to 60 minutes per institutional practice.  
See Section 22.1.2.1 for acceptable 
alternatives. 
IT – CNS Negative at 
Screening 
X 
 
 
 
X 
 
 
 
 
 
day 29 Methotrexate, dose is age dependent (see 
Figure 3).  IT therapy may be performed on 
day 29 per institutional standard practice.  See 
Section 22.1.4 for acceptable alternatives. 
IT – CNS Positive 
(CNS 3) at Screening 
X 
 
 
 
X 
 
X 
 
 
X 
day 29 Methotrexate, cytarabine, and hydrocortisone 
doses are age dependent (see Figure 3).  IT 
therapy may be performed on day 29 per 
institutional standard practice.  See 
Section 22.1.4 for acceptable alternatives. 


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Table 16.  Phase 2 Schedule of Activities – Induction Therapy Subjects Less Than 12 Months of Age at Screening 
 
Screeninge 
Treatment Period  
(Induction Therapy Subjects Less Than 12 Months of Age) 
SFUa 
LTFU 
(every 
12 weeks)b 
Comments 
Study Day 
(up to 
7 days 
before 
day 1) 
1 2 3-7 8 
9 
10-11 12 13-14 15 
16 
17-
21 
22 
23-
27 
28 29 
36-
50c 
 
 
GENERAL AND 
SAFETY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
and assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Physical 
measurements 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight and height at 
screening; weight at 
SFU 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance use 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes tobacco 
exposure 
ECGe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHOe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Subjects with clinical 
symptoms of 
congestive heart 
failure during or after 
induction should have 
an ECHO to evaluate 
cardiac function before 
initiation of the 
optional consolidation. 


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Screeninge 
Treatment Period  
(Induction Therapy Subjects Less Than 12 Months of Age) 
SFUa 
LTFU 
(every 
12 weeks)b 
Comments 
Study Day 
(up to 
7 days 
before 
day 1) 
1 2 3-7 8 
9 
10-11 12 13-14 15 
16 
17-
21 
22 
23-
27 
28 29 
36-
50c 
 
 
Vital signs 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
Temperature, heart 
rate, respiratory rate, 
and systolic and 
diastolic blood 
pressures.  On 
days 36 to 50, 
assessment only 
required at time of 
bone marrow 
assessment. 
Adverse events 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collected from time of 
signing of the ICF.  
Details regarding the 
reporting of adverse 
events are provided in 
Section 24.2.4. 
Serious adverse 
events 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
Collected from time of 
signing of the ICF.  
Details regarding the 
reporting of serious 
adverse events are 
provided in  
Section 24.2.4. 
Concomitant 
therapies review 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collected from time of 
signing of the ICF.  
Details regarding the 
reporting of 
concomitant therapies 
are provided in  
Section 22.7.2. 
LABORATORY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulatione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR, aPTT  


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Screeninge 
Treatment Period  
(Induction Therapy Subjects Less Than 12 Months of Age) 
SFUa 
LTFU 
(every 
12 weeks)b 
Comments 
Study Day 
(up to 
7 days 
before 
day 1) 
1 2 3-7 8 
9 
10-11 12 13-14 15 
16 
17-
21 
22 
23-
27 
28 29 
36-
50c 
 
 
Hematologye 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
See Table 28 for 
analytes.  On days 36 
to 50, assessment to 
be performed weekly 
starting on day 36, at 
the time of bone 
marrow assessment, 
and on day 50 in 
subjects that have not 
yet proceeded to next 
therapy, samples 
obtained on day of 
bone marrow and 
within 1 week after the 
bone marrow will be 
assessed locally and a 
stained slide must be 
sent to central lab, 
unless subject has 
already started next 
therapy at the time the 
sample is obtained. 


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Screeninge 
Treatment Period  
(Induction Therapy Subjects Less Than 12 Months of Age) 
SFUa 
LTFU 
(every 
12 weeks)b 
Comments 
Study Day 
(up to 
7 days 
before 
day 1) 
1 2 3-7 8 
9 
10-11 12 13-14 15 
16 
17-
21 
22 
23-
27 
28 29 
36-
50c 
 
 
Chemistrye 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
See Table 28 for 
analytes.  In addition 
to chemistries in the 
complete metabolic 
panel, include 
adjusted calcium, ALP, 
magnesium, 
phosphorous, serum 
albumin, and total 
protein if not part of 
standard panel; direct 
bilirubin if total bilirubin 
is elevated; and uric 
acid until normalized 
for 2 consecutive 
measurements.   
On days 36 to 50, 
assessment only 
required at time of 
bone marrow 
assessment. 
Pancreatic 
functione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Amylase and lipase 


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Screeninge 
Treatment Period  
(Induction Therapy Subjects Less Than 12 Months of Age) 
SFUa 
LTFU 
(every 
12 weeks)b 
Comments 
Study Day 
(up to 
7 days 
before 
day 1) 
1 2 3-7 8 
9 
10-11 12 13-14 15 
16 
17-
21 
22 
23-
27 
28 29 
36-
50c 
 
 
Hepatitis B 
screeninge 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
All hepatitis testing will 
be performed locally.  
All subjects will be 
tested at screening for 
HBsAg, anti-HBs, and 
anti-HBc, unless 
testing was previously 
performed within 
6 months of screening 
and there was no 
change in the subject’s 
risk factors within 
these 6 months.  
CMV PCR testinge 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recommended for all 
subjects, but only 
required for subjects 
who are known to be 
CMV positive or who 
previously received a 
bone marrow 
transplant. 


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Screeninge 
Treatment Period  
(Induction Therapy Subjects Less Than 12 Months of Age) 
SFUa 
LTFU 
(every 
12 weeks)b 
Comments 
Study Day 
(up to 
7 days 
before 
day 1) 
1 2 3-7 8 
9 
10-11 12 13-14 15 
16 
17-
21 
22 
23-
27 
28 29 
36-
50c 
 
 
STUDY-SPECIFIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate/biopsye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
On days 36 to 50, 
perform assessment 
when peripheral blood 
counts recover 
(defined as ANC 
greater than or equal 
to 1000/L, platelets 
greater than or equal 
to 100 000/L) or as 
clinically indicated, to 
assess for CR, by 
day 50, or as clinically 
indicated.  MRD BMA 
using NGS has priority 
over MRD BMA flow 
cytometry or PCR.  
Bone marrow will be 
assessed locally and 
stained slides will be 
submitted to central 
laboratory for 
histological 
examination. 


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Screeninge 
Treatment Period  
(Induction Therapy Subjects Less Than 12 Months of Age) 
SFUa 
LTFU 
(every 
12 weeks)b 
Comments 
Study Day 
(up to 
7 days 
before 
day 1) 
1 2 3-7 8 
9 
10-11 12 13-14 15 
16 
17-
21 
22 
23-
27 
28 29 
36-
50c 
 
 
Lumbar puncture 
with or without ITe 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
If IT therapy is 
administered during 
screening (within 
7 days of day 1) 
repeat of IT on day 1 
is not required.  On 
days 36 to 50, 
assessment only 
required at time of 
bone marrow 
assessment. 
Testicular 
ultrasound/physical 
exam (males with 
testicular mass 
only)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Remission is to be 
determined by the 
same technique used 
at screening 
Chest imaging (if 
mediastinal mass 
is present at 
screening only)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
On days 36 to 50, 
assessment, by same 
technique as at 
screening, only 
required at time of 
bone marrow 
assessment. 
Other 
extramedullary 
disease 
assessmente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Only if clinically 
indicated, response 
should be assessed 
using same method 
used at screening 
Vital status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 




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ALL = acute lymphoblastic leukemia; ALP = alkaline phosphatase; ANC = absolute neutrophil count; anti-HBs = hepatitis B core antibody; anti-HBs = hepatitis B 
surface antibody; aPTT = activated partial thromboplastin time; BMA = bone marrow aspirate; CMV = cytomegalovirus; CNS = central nervous system; CR = complete 
remission; ECG = electrocardiogram; ECHO = echocardiogram; EOI = end of infusion; HBsAg = hepatitis B surface antigen; ICF = informed consent; 
INR = international normalized ratio; IT = intrathecal therapy; LTFU = long term follow-up; MRD = minimal residual disease; NGS = next generation sequencing; 
PCR = polymerase chain reaction; SFU = safety follow-up 
a The safety follow-up visit is to be performed 30 days after the last dose of protocol specified systemic anti-leukemia therapy in induction or consolidation whichever is 
later, or prior to next therapy following induction if not proceeding to optional consolidation, or prior to next therapy after consolidation. 
b After the safety follow-up visit, subjects are to continue follow-up every 12 weeks for up to 2 years.   
c The timing of assessments on days 36 to 50 and when/if a subject proceeds to the consolidation phase is to be determined by the investigator based on the subject’s 
peripheral blood count recovery or the start of alternate therapy, whichever comes first.  Assessments may be repeated multiple times within this window at the 
discretion of the investigator as needed to assess for response or progression.  If peripheral blood counts recover within 7 days of an M1 bone marrow assessment a 
repeat bone marrow is not required to confirm CR. 
d Subjects with positive testing or a history of prior HBV infection should have consultation with a specialist and must have HBV-DNA testing at screening and again at 
safety follow-up.  Subjects that have received hepatitis B vaccination with only anti-HBs positivity and no clinical signs of hepatitis do not require HBV-DNA 
monitoring. 
e Evaluations performed within 7 days of enrollment as part of routine medical care (eg, bone marrow aspirate/biopsy) may be used for screening assessments. 


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Table 17.  Phase 2 Dose Regimen for Induction Therapy – Subjects Less Than 12 Months of Age at Screening 
 
Treatment Period  
(Induction Therapy Subjects Less Than 12 Months of Age) 
Comments 
Study Day 
1 2 3-7 
8 
9 10-11 12 13-14 15 16 17-21 22 23-27 
28 
29 
36-50  
STUDY 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carfilzomib 
X X 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
 
20 mg/m2 on day 1, 56 mg/m2 for subsequent 
doses.  Administer IV over 30  5 minutes 
Prehydration 
X X 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
 
Greater than or equal to 125 mL/m2/hour of IV fluid 
is required for 1 hour prior to carfilzomib 
administration 
Vincristine 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Less than 6 months of age:  1 mg/m2  
Greater than or equal to 6 months of age:  
1.2 mg/m2  
Administer as IV push over 1 min or infusion per 
institutional policy.  Dose should be rounded to 
nearest 0.01 mg and maximum single dose is 
2 mg. 
Prednisolone 
X X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Less than 6 months of age:  13 mg/m2/dose TID 
(total daily dose = 39 mg/m2) 
Greater than or equal to 6 months of age:  
15 mg/m2/dose TID (total daily dose = 45 mg/m2) 
Oral, nasogastric, or IV administration 
On days 1 and 2, administered 4 hours to 
30 minutes prior to carfilzomib.  See 
Section 22.1.2.1 for acceptable alternatives. 
Dexamethasone 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Less than 6 months of age:  1.3 mg/m2/dose TID 
(total daily dose = 3.9 mg/m2) 
Greater than or equal to 6 months of age:  
1.5 mg/m2/dose TID (total daily dose = 4.5 mg/m2) 
Oral, nasogastric, or IV administration. 
On days 8, 9, 15, and 16, administered  
4 hour to 30 minutes prior to carfilzomib.  Taper 
steroids to 0 mg over days 29 to 35.  See 
Section 22.1.2.1 for acceptable alternatives. 


Onyx Therapeutics, Inc. 
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Treatment Period  
(Induction Therapy Subjects Less Than 12 Months of Age) 
Comments 
Study Day 
1 2 3-7 
8 
9 10-11 12 13-14 15 16 17-21 22 23-27 
28 
29 
36-50  
PEG-asparaginase 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Less than 6 months of age:  1750 units/m2  
Greater than or equal to 6 months of age:  
2000 units/m2  
Administer IV over 1 to 2 hours or IM.  See 
Section 22.1.2.1 for acceptable alternatives. 
Daunorubicin 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Less than 6 months of age:  20 mg/m2  
Greater than or equal to 6 months of age:  
23 mg/m2  
Administer as IV push or as an infusion over 1 to 
15 minutes, or longer as per institutional practice.  
See Section 22.1.2.1 for acceptable alternatives.  
IT methotrexate 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
6 mg.  If a dose was received within 7 days of 
day 1 and was per protocol dosing, day 1 dose 
does not need to be repeated.  Day 29 dose is 
administered with IT hydrocortisone. 
IT cytarabine 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
15 mg, administer with hydrocortisone. 
IT hydrocortisone 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
12 mg.  See Section 22.1.4 for acceptable 
alternatives. 
IM = intramuscular; IT = intrathecal; IV = intravenous; PEG = polyethylene glycol; TID = three times a day 


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Table 18.  Phase 2 Schedule of Activities – Consolidation Therapy Subjects Greater Than or Equal to 12 Months of Age at 
Screening 
 
Treatment Period 
(Consolidation Therapy Subjects Greater Than or Equal to12 Months of 
Age) 
SFUa 
LTFU (every 
12 weeks)b 
Comments 
Study Day of 
Consolidation 
1 
2 
3 4 5 6 7 8 
9 
10 11 12 13 14 15 16 18 22 29-45c  
 
 
GENERAL AND 
SAFETY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital signs 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
Temperature, heart rate, respiratory 
rate, and systolic and diastolic blood 
pressures.  On days 29 to 45, 
assessment only required at time of 
bone marrow assessment. 
Karnofsky or 
Lansky 
Performance 
status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Lansky if less than 16 years of age; 
Karnofsky if greater than or equal to 
16 years of age 
Adverse events 
X 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collected from time of signing of the 
ICF.  Details regarding the reporting 
of adverse events are provided in 
Section 24.2.4. 
Serious adverse 
events 
X 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collected from time of signing of the 
ICF.  Details regarding the reporting 
of serious adverse events are 
provided in Section 24.2.4. 
Concomitant 
therapies review 
X 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collected from time of signing of the 
ICF.  Details regarding the reporting 
of concomitant therapies are 
provided in Section 22.7.2. 
LABORATORY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment Period 
(Consolidation Therapy Subjects Greater Than or Equal to12 Months of 
Age) 
SFUa 
LTFU (every 
12 weeks)b 
Comments 
Study Day of 
Consolidation 
1 
2 
3 4 5 6 7 8 
9 
10 11 12 13 14 15 16 18 22 29-45c  
 
 
Pregnancy test 
(females of 
childbearing 
potential only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine.  Additional 
on-treatment pregnancy testing may 
be performed at the investigator’s 
discretion if there is suspicion that a 
female subject is pregnant or per 
local laws and regulations. 
Hematology 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
See Table 28 for analytes.  On 
days 29 to 45, assessment to be 
performed weekly, at the time of 
bone marrow assessment, and on 
day 45 in subjects that have not yet 
proceeded to next therapy, samples 
obtained on day of bone marrow and 
within 1 week after the bone marrow 
will be assessed locally and a 
stained slide must be sent to central 
lab, unless subject has already 
started next therapy. 
Chemistry  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
See Table 28 for analytes.  In 
addition to chemistries in the 
complete metabolic panel, include 
adjusted calcium, ALP, magnesium, 
phosphorous, serum albumin, and 
total protein if not part of standard 
panel; direct bilirubin if total bilirubin 
is elevated; and uric acid until 
normalized for 2 consecutive 
measurements.   
On days 29 to 45, assessment only 
required at time of bone marrow 
assessment. 
Hepatitis B 
screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Only in subjects with positive 
hepatitis B serology at screening or 
past history of HBV infection.  
Testing performed locally. 


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Treatment Period 
(Consolidation Therapy Subjects Greater Than or Equal to12 Months of 
Age) 
SFUa 
LTFU (every 
12 weeks)b 
Comments 
Study Day of 
Consolidation 
1 
2 
3 4 5 6 7 8 
9 
10 11 12 13 14 15 16 18 22 29-45c  
 
 
STUDY-
SPECIFIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate/biopsy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
On days 29 to 45, perform 
assessment when peripheral blood 
counts recover (defined as ANC 
greater than or equal to 1000/L, 
platelets greater than or equal to 
100 000/L) or as clinically indicated, 
to assess for CR, by day 45, or as 
clinically indicated.  MRD BMA using 
NGS has priority over MRD BMA 
flow cytometry or PCR.  Bone 
marrow will be assessed locally and 
stained slides will be submitted to 
central laboratory for histological 
examination. 
Lumbar puncture 
with or without IT 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Lumbar puncture performed on 
days 15 and 22 only if CNS3 
(Table 3).  On days 29 to 45, 
assessment only required at time of 
bone marrow assessment. 
Testicular 
ultrasound/physic
al exam (males 
with testicular 
mass only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Remission is to be determined by the 
same technique used at screening 
Chest imaging (if 
mediastinal mass 
is present at 
screening only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
On days 29 to 45, assessment only 
required at time of bone marrow 
assessment. 
Other 
extramedullary 
disease 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Only if clinically indicated, response 
should be assessed using same 
method used at screening 
Vital Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 




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Table 19.  Phase 2 Dose Regimen for Consolidation Therapy – Subjects Greater Than or Equal to 12 Months of Age at 
Screening 
 
Treatment Period 
(Consolidation Therapy Subjects Greater Than or Equal to 12 Months of Age) 
Comments 
Study Day of Consolidation 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1
0 
1
1 
12 
1
3 
14 15 
1
6 
1
8 
22 
29-
45 
 
STUDY TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carfilzomib 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
56 mg/m2 for all doses.  Administer IV 
over 30  5 minutes. 
Prehydration and premedication 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
Greater than or equal to 
125 mL/m2/hour of IV fluid is required 
for 1 hour prior to carfilzomib 
administration.  Oral, nasogastric, or 
IV administration of dexamethasone 
3 mg/m2 4 hours to 30 minutes prior 
to carfilzomib. 
Cytarabine 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
75 mg/m2 daily.  Administer IV over 
1 to 30 min or SC.   
6-Mercaptopurine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
60 mg/m2 daily.  Administer orally  
Cyclophosphamide 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 g/m2 single dose.  Administer IV 
over 30 to 60 min. 
Vincristine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
1.5 mg/m2 per dose (maximum single 
dose 2 mg).  Administer as IV push 
over 1 min or infusion per institutional 
policy. 
PEG-asparaginase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
1000 U/m2 per dose.  Administer IV 
over 1 to 2 hours.  See 
Section 22.1.2.1 for acceptable 
alternatives. 
IT – CNS negative at screening 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
day 
29 
Methotrexate dose is age dependent 
(see Figure 4.).  IT therapy may be 
performed on day 29 per institutional 
standard practice.  See 
Section 22.1.4 for acceptable 
alternatives. 


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Treatment Period 
(Consolidation Therapy Subjects Greater Than or Equal to 12 Months of Age) 
Comments 
Study Day of Consolidation 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1
0 
1
1 
12 
1
3 
14 15 
1
6 
1
8 
22 
29-
45 
 
IT – CNS positive at screening 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
day 
29 
Methotrexate, cytarabine, and 
hydrocortisone doses are age 
dependent (see Figure 4).  IT therapy 
may be performed on day 29 per 
institutional standard practice.  See 
Section 22.1.4 for acceptable 
alternatives. 
CNS = central nervous system; IT = intrathecal therapy; IV = intravenous; PEG = polyethylene glycol; SC = subcutaneous  


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Table 20.  Phase 2 Schedule of Activities – Consolidation Therapy Subjects Less Than 12 Months of Age at Screening 
 
Treatment Period 
(Consolidation Therapy Subjects Less Than 12 Months of Age) 
SFUa 
LTFU (every 
12 weeks)b 
Comments 
Study Day of 
Consolidation 
1 
2 
3-6 7 8 
9 
10 11-13 14 15 16 17-20 24 25-27 29 36-50c 
 
 
 
GENERAL AND 
SAFETY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital signs 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Temperature, heart rate, 
respiratory rate, and systolic 
and diastolic blood pressures.  
On days 36 to 50, assessment 
only required at time of bone 
marrow assessment. 
Lansky 
Performance status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Only if subject is greater than 
12 months of age at start of 
consolidation 
Adverse events 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collected from time of signing 
of the ICF.  Details regarding 
the reporting of adverse events 
are provided in Section 24.2.4. 
Serious adverse 
events 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collected from time of signing 
of the ICF.  Details regarding 
the reporting of serious 
adverse events are provided in 
Section 24.2.4. 
Concomitant 
therapies review 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collected from time of signing 
of the ICF.  Details regarding 
the reporting of concomitant 
therapies are provided in 
Section 22.7.2. 


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Treatment Period 
(Consolidation Therapy Subjects Less Than 12 Months of Age) 
SFUa 
LTFU (every 
12 weeks)b 
Comments 
Study Day of 
Consolidation 
1 
2 
3-6 7 8 
9 
10 11-13 14 15 16 17-20 24 25-27 29 36-50c 
 
 
 
LABORATORY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
 
X 
 
 
 
 
X 
 
Day 
17 
X 
 
X 
X 
X 
 
See Table 28 for analytes.  On 
days 36 to 50, assessment to 
be performed weekly starting 
on day 36, at the time of bone 
marrow assessment, and on 
day 50 in subjects that have 
not yet proceeded to next 
therapy, samples obtained on 
day of bone marrow and within 
1 week after the bone marrow 
will be assessed locally and a 
stained slide must be sent to 
central lab, unless subject has 
already started next therapy. 
Chemistry 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
See Table 28 for analytes.  In 
addition to chemistries in the 
complete metabolic panel, 
include adjusted calcium, ALP, 
magnesium, phosphorous, 
serum albumin, and total 
protein if not part of standard 
panel; direct bilirubin if total 
bilirubin is elevated; and uric 
acid until normalized for 
2 consecutive measurements.   
On days 36 to 50, assessment 
to be performed weekly starting 
on day 36 and at time of bone 
marrow assessment. 
Hepatitis B 
screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Only in subjects with positive 
hepatitis B serology at 
screening or past history of 
HBV infection.  Testing 
performed locally. 


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Treatment Period 
(Consolidation Therapy Subjects Less Than 12 Months of Age) 
SFUa 
LTFU (every 
12 weeks)b 
Comments 
Study Day of 
Consolidation 
1 
2 
3-6 7 8 
9 
10 11-13 14 15 16 17-20 24 25-27 29 36-50c 
 
 
 
STUDY-SPECIFIC 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate/biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
On days 36 to 50, perform 
assessment when peripheral 
blood counts recover (defined 
as ANC greater than or equal 
to 1000/L and platelets 
greater than or equal 
to 100 000/L) or as clinically 
indicated, to assess for CR, by 
day 50, or as clinically 
indicated.  MRD BMA using 
NGS has priority over MRD 
BMA flow cytometry or PCR.  
Bone marrow will be assessed 
locally and stained slides will 
be submitted to central 
laboratory for histological 
examination. 
Lumbar puncture 
with or without IT 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
On days 36 to 50, assessment 
only required at time of bone 
marrow assessment. 
Testicular 
ultrasound/physical 
exam (males with 
testicular mass 
only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Remission is to be determined 
by the same technique used at 
screening 
Chest imaging (if 
mediastinal mass is 
present at 
screening only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
On days 36 to 50, assessment 
only required at time of bone 
marrow assessment. 
Other 
extramedullary 
disease 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Only if clinically indicated, 
response should be assessed 
using same method used at 
screening 
Vital status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 




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Table 21.  Phase 2 Dose Regimen for Consolidation Therapy – Subjects Less Than 12 Months of Age at Screening 
 
Treatment Period 
(Consolidation Therapy Subjects Less Than 12 Months of Age) 
Comments 
Study Day of 
Consolidation 
1 2 3-6 7 8 9 10 11-13 14 15 16 17-20 24 25-27 28b 
36-50  
STUDY TREATMENT 
Carfilzomib 
X X 
 
 
X X  
 
 
X 
X 
 
 
 
 
 
56 mg/m2 dose.  Administer IV over 30  5 minutes 
Prehydration and 
premedication 
X X 
 
 
X X  
 
 
X 
X 
 
 
 
 
 
Greater than or equal to 125 mL/m2/hour of IV fluid is required for 
1 hour prior to carfilzomib administration.  Oral, nasogastric, or IV 
administration of dexamethasone 3 mg/m2 4 hours to 30 minutes 
prior to carfilzomib. 
Cytarabinea 
 
 
X 
 
 
 X 
X 
 
 
 
X 
X 
X 
 
 
Less than 6 months of age:  50 mg/m2  
Greater than or equal to 6 months of age:  56 mg/m2 
Administer as IV push or SC, daily on days 3-6, 10-13, 17-20, and 
24-27. 
Subjects should have ANC greater than or equal to 300/L and 
platelets greater than or equal to 30 000/L to start each 4-day 
cytarabine block beginning on days 10, 17, and 24.  
6-Mercaptopurinea 
X X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 6 months of age:  40 mg/m2  
greater than or equal to 6 months of age:  45 mg/m2 
Administer orally, daily on days 1-28.  Administer on an empty 
stomach.  Actual dose per day should be varied, as needed, to 
yield a weekly dose as close to 280 mg/m2 if less than 6 months, 
or 315 mg/m2 if greater than or equal to 6 months, as possible. 
Cyclophosphamide 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Less than 6 months of age:  670 mg/m2  
greater than or equal to 6 months of age:  750 mg/m2 
Administer IV over 30 to 60 min. 
Mesna 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Less than 6 months of age:  134 mg/m2/dose  
Greater than or equal to 6 months of age:  150 mg/m2/dose 
Administer as IV over 15 minutes at 0, 4, and 8 hours from the 
start of cyclophosphamide 
IT methotrexate 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
6 mg.  Administer with hydrocortisone.   


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Treatment Period 
(Consolidation Therapy Subjects Less Than 12 Months of Age) 
Comments 
Study Day of 
Consolidation 
1 2 3-6 7 8 9 10 11-13 14 15 16 17-20 24 25-27 28b 
36-50  
IT cytarabine 
 
 
 
 
 
 X 
 
 
 
 
 
 
 
 
 
15 mg.  Administer with hydrocortisone.   
IT hydrocortisone 
 
 
 
 
 
 X 
 
 
 
 
 
X 
 
 
 
12 mg.  See Section 22.1.4 for acceptable alternatives. 
IT  intrathecal; IV  intravenous; SC  subcutaneous 
a For infants requiring make up doses of cytarabine or mercaptopurine, the time window for post consolidation bone marrow should be adjusted to start 1 week after 
completion of all chemotherapy and end 3 weeks after completion of chemotherapy. 
b Only applies to 6-Mercaptopurine, which is administered on days 1 to 28.  
 


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18. 
Phase 2:  Introduction 
18.1 
Phase 2 Study Rationale 
Approximately 20 of pediatric patients with T-cell ALL and 15 of patients with B-cell 
ALL will have a bone marrow relapse.  Treatment outcomes for children with relapsed 
ALL are poor, with intensive therapy and HSCT, overall survival ranges from 20 to 
40 for B-cell ALL and 0 to 25 for T-cell ALL using 1- to 10-year landmark analyses 
(Raetz and Teachey, 2016; Locatelli et al, 2012), and even lower in subjects with 
refractory or multiply relapsed ALL.  Recent advances in therapy for relapsed B-cell ALL, 
including CD19 targeting immune therapies and CD22 antibody drug conjugates (ADC), 
have improved response rates in relapsed/refractory B-cell ALL (Bhojwani et al, 2019; 
Gore et al, 2018; Maude et al, 2018; Kantarjian et al, 2016).  However, technical 
challenges for cell-based immunotherapies and relapse remain a significant problem.  
Many options are available for treatment of relapsed refractory ALL, but for patients with 
T-cell ALL or B-cell ALL that has relapsed after immune therapy, no treatment has been 
demonstrated to be preferred or effective and prognosis remains grim (Ruella and Maus, 
2016).  Effective treatment for patients who have failed conventional chemotherapy or 
newer immunotherapies requires tolerable regimens that induce deep durable responses 
that last long enough to permit subjects to undergo HSCT (Locatelli et al, 2012; Gaynon 
et al, 2005).   
Cooperative groups have worked toward the identification of novel agents that can 
partner with chemotherapy regimens that can be tolerated in these extensively treated 
patients (Wayne et al, 2017).  The COG AALL01P2 study was developed to provide a 
chemotherapy platform (VPLD) that was well tolerated in children with relapsed ALL for 
the purpose of combining with novel agents (Raetz et al, 2008, Wayne et al, 2017).  The 
COG AALL07P1 trial combined the proteasome inhibitor bortezomib with VPLD and 
demonstrated promising efficacy, especially in subjects with relapsed T-cell ALL (Horton 
et al, 2019).  The VXLD regimen in this study (Study 20140106) is similar to the VPLD 
regimen evaluated in the 01P2 and 07P1 studies by COG and uses the same 
chemotherapy agents evaluated in other VXLD-bortezomib trials (Messinger et al, 2012; 
Bertaina et al, 2017).   
Carfilzomib has the potential to improve upon the results seen with bortezomib-VPLD or 
-VXLD chemotherapy combinations due to a more favorable safety profile with less 
off-target side effects, enhanced efficacy given the potential to be active in 
bortezomib-resistant tumor cells (Franke et al, 2012), increased sensitivity of ex vivo ALL 


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cells to carfilzomib over bortezomib (Niewerth et al, 2013), and the superiority of 
carfilzomib over bortezomib observed in a head-to-head phase 3 study in relapsed 
multiple myeloma (ENDEAVOR), (Dimopoulos et al, 2016).   
The goal of this phase 2 part of the study is to investigate the clinical activity and safety 
of carfilzomib combined with VXLD (CFZ-VXLD) in pediatric subjects with relapsed and 
refractory ALL and to evaluate the effectiveness of the regimen as a means to bridge 
subjects to treatments with curative intent.  An observational study (Study 20180065) is 
being conducted by Amgen in collaboration with the TACL consortium to collect a robust 
set of data in children with relapsed/refractory ALL.  Subjects from this observational 
study that resemble the inclusion/exclusion criteria of the phase 2 part of the study will 
form an external control group that can be used to estimate the differences in CR rates 
of CFZ-VXLD versus standard of care regimens. 
18.2 
Background 
18.2.1 
Acute Lymphoblastic Leukemia 
See Section 3.1 for background information on ALL.  
18.2.2 
Treatment Outcomes in Pediatric Relapsed ALL 
Approximately 15 to 20 of pediatric patients with ALL will relapse.  Patients with 
relapsed disease can be risk stratified and treated based on the risk of treatment failure.  
Length of first CR and site of relapse are the 2 most important prognostic factors for 
successful outcome after relapse (Chessells, 1998).  With intensive therapy, that may 
include HSCT, overall survival after relapse ranges from 20 to 40 for B-cell ALL and 
0 to 25 for T-cell ALL (from 1- to 10-year landmark analyses) 
(Raetz and Teachey, 2016; Locatelli et al, 2012).  The goal of chemotherapy for 
relapsed ALL is to induce remission of sufficient depth and duration to allow the patient 
to receive potentially curative treatment with HSCT.  Depending upon clinical 
characteristics at time of relapse, 25 to 80 of patients fail to achieve remission.  Due 
to low quality remissions and toxicity of the salvage therapy, up to 50 of patients with 
relapsed ALL who do achieve a CR do not maintain the remission long enough to 
proceed to HSCT with currently available chemotherapy regimens (Gaynon et al, 2006; 
Gaynon, 2005).   
The development of immune therapy (eg, blinatumomab, chimeric antigen receptor 
T cell therapy [CAR-T], or inotuzumab) in the last 8 years has improved remission rates 
in subjects with relapsed or refractory B-cell ALL and may improve long-term survival in 
at least a subset of children with relapsed ALL (Bhojwani et al, 2019; Gore et al, 2018; 


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Maude et al, 2018; Kantarjian et al, 2016).  CAR-T therapy can induce CR in up to 
90 of patients with B-cell ALL even in advanced (second or greater relapse) and 
refractory relapse (Maude et al, 2018).  In addition, remissions induced with immune 
therapy are often very deep (MRD negative).  However, within this population, there 
remains a substantial failure rate with immune therapies and outcomes for these patients 
are generally very poor (Ruella and Maus, 2016).  In a clinical study of tisagenlecleucel, 
66 of subjects achieved a CR, with 1-year relapse-free survival rates of 39 overall 
and 59 for responders (Maude et al, 2018).  Similarly, the 1-year event-free survival 
rate for CAR-T therapy in advanced ALL is approximately 50 for treated patients and 
lower for blinatumomab (Gore et al, 2018; Maude et al, 2018).  A subset of these 
patients might be bridged to HSCT with an effective reinduction chemotherapy regimen.   
Most remissions for patients with relapsed T-cell ALL are short-lived suggesting high 
levels of residual disease and event-free survival is extremely poor ranging between 
0 and 16 (from 1- to 10-year landmark analyses) (Tallen et al, 2010; Raetz et al, 
2008; Gaynon et al, 2006; Giona et al, 1997).  In contrast to the advances in relapsed 
B-cell ALL, CR rates and survival of children with relapsed T-cell ALL have shown no 
significant change for more than 20 years. 
Despite the use of very intensive therapy in infants with ALL, long-term EFS is between 
28% and 45% and markedly inferior to older children (Biondi et al, 2006; Chessells et al, 
2002; Reaman et al, 1999; Silverman et al, 1997) due in part to a high incidence of 
mixed lineage leukemia rearrangements (Pieters et al, 2007).  The EFS for infants 
decreases with age: 0% to 29%, 26% to 50%, and 49% to 71% for infants < 3, 3 to < 6, 
and > 6 months, respectively (Salzer et al, 2012).  Attempts to intensify therapy in infants 
using a modification of VXLD therapy were associated with excessive induction toxicity 
(Salzer et al, 2012).  Of the first 68 infants enrolled, 25% died, including 58% of infants 
< 90 days of age; median time to death was 21 days into induction (15 days for infants 
< 90 days old).  Modifications to the dose regimen introduced in the Interfant-99 
(Pieters et al, 2007) and later Interfant-06 study (Salzer et al, 2015) have decreased the 
incidence of induction deaths to nearly the same as older children.  These modifications 
include additional supportive care recommendations regarding infection prevention 
(Salzer et al, 2015), a lower dose of daunorubicin, a pre-phase of prednisone (on days 1 
to 7) followed by dexamethasone (on days 8 to 28), use of L-asparaginase, and 
inclusion of cytarabine during induction (Pieters et al, 2007).  The proposed regimen for 
infants uses the COG AALL15P1 induction regimen, which was designed using the 


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amended Interfant-based AALL0631 induction regimen.  One notable change in 
AALL0631 was the substitution of L-asparaginase with pegaspargase, contributing to a 
lower cumulative dose.  This de-intensification, along with additional supportive care 
recommendations, increased complete remission rates and decreased induction deaths 
(Salzer et al, 2015).  Although the AALL15P1 study is for newly diagnosed ALL subjects, 
there are no published pediatric cooperative group studies for infants with relapsed ALL 
to reference for Study 20140106.   
18.2.2.1 
Rationale for Incorporating Proteasome Inhibitor with VXLD 
Several pediatric studies combining the first-generation proteasome inhibitor, 
bortezomib, with VXLD have demonstrated that the safety profile for the combination is 
similar to that of VXLD alone with the same bortezomib dose/schedule as that used in 
adults with multiple myeloma (Bertaina et al, 2017; Horton et al, 2013; Messinger et al, 
2012; Messinger et al, 2010).  The combination of bortezomib and VXLD/VPLD 
demonstrated very promising rates of CR and MRD response in several difficult-to-treat 
patient populations, including very early relapse, relapse after blinatumomab or stem cell 
transplant, or multiple relapses.  
Carfilzomib has the potential to improve upon the results seen with bortezomib plus 
chemotherapy combinations due to a more favorable safety profile with less off-target 
side effects, enhanced efficacy given the potential to be active in bortezomib-resistant 
tumor cells (Franke et al, 2012), increased sensitivity of ex vivo ALL cells to carfilzomib 
over bortezomib (Niewerth et al, 2013), and the superiority of carfilzomib over 
bortezomib observed in a head-to-head phase 3 study in relapsed multiple myeloma 
(ENDEAVOR), with significantly less neuropathy (Dimopoulos et al, 2017; Dimopoulos 
et al, 2016). 
18.2.3 
Therapeutic Needs in Relapsed or Refractory ALL 
Because outcomes remain poor for patients with relapsed or refractory T-cell ALL and 
relapsed or refractory B-cell ALL who have relapsed after targeted immune therapy, 
these patients represent a significant unmet need.  Thus, there is a clear need for novel 
agents to improve outcomes for these patients. 
Based on the efficacy observed with bortezomib therapies, carfilzomib in combination 
with conventional chemotherapy is expected to play an important role for addressing this 
unmet need.  While carfilzomib plus VXLD is not expected to be a curative therapy, 
carfilzomib offers the potential to increase the incidence and depth of remissions 
compared with existing therapies with acceptable safety, thereby acting as a bridge to 


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HSCT or other curative therapies in children and adolescents with relapsed or refractory 
ALL. 
In the phase 1b portion of Study 20140106, carfilzomib in combination with VXLD 
showed promising efficacy, with CR rates of 43 after induction and 55 overall in this 
population of pediatric patients with relapsed or refractory B- or T-cell ALL.  The phase 2 
part of this study will further evaluate the efficacy and safety of carfilzomib in 
combination with VXLD as a treatment in children with an otherwise dismal prognosis. 
18.2.4 
Justification of Treatment Effect 
After relapse the probability of achieving remission with salvage therapy varies based on 
several known risk factors including site of relapse, duration of first remission, number of 
relapses, and immune phenotype (T- vs B-cell) (Raetz and Bhatla, 2012).  In addition, 
subjects that are refractory to one or more salvage attempts have a markedly reduced 
chance of responding to subsequent salvage attempts.  Most studies of relapsed B- or 
T-cell ALL have tested salvage treatments in the setting of first untested (non-refractory) 
relapse.  In addition, because the usual endpoint in relapse studies is full CR, subjects 
that have received HSCT have typically been excluded due to reduced capacity for bone 
marrow recovery and greater toxicity observed in these subjects.  For example, the 
COG AALL01P2 study evaluated the VPLD and UKALLR3 trial the R3 regimens 
respectively, both studies limited enrollment to first untreated relapse and excluded 
subjects that had received prior HSCT (Raetz et al, 2008, Parker et al, 2010).  
Approximately 50% of subjects enrolled on the UKALLR3 study had late bone marrow 
relapse and another 22% isolated extramedullary relapse.  These patient populations 
have a much higher probability of responding to therapy than subjects enrolling in the 
current study.   
To establish a treatment effect for the VXLD-carfilzomib regimen it was hypothesized 
that the characteristics important for prediction of CR response enrolling in the phase 2 
can be predicted from the characteristics of the subjects that have enrolled in the 
phase 1 portion of the study.  The characteristics evaluated included number of 
relapses, refractory relapse, prior HSCT, duration of first remission, and immune 
phenotype.  The actual remission rate in the phase 1 portion of the study was then 
compared to the remission rate expected for subjects with these same characteristics.  
Although only a fraction of subjects with B-cell ALL that enrolled in phase 1 had relapsed 
after receiving immune therapy, it was anticipated that the observed differences in 
remission rates based on the evaluated characteristics would be similar. 


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A summary of the proportion of subjects stratified by immune phenotype, number of 
relapses, refractory relapses, early and very early first relapse, and prior HSCT is shown 
in Table 22.  The patient characteristics enrolled in Amgen’s now closed phase 1 study 
and anticipated to reflect the characteristics of subjects enrolling in the proposed phase 
2 part of the study, have a much higher risk of treatment failure compared to the 
COG AALL02P1 or UKALL-R3 study.  The more restrictive eligibility requirements for 
subjects with relapsed B-cell ALL will further reduce the comparability of the CR rates of 
the phase 2 population from that of either of these studies. 
 


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Table 22.  Covariate Distribution for Phase 1 Subjects  
Subject 
Covariates 
N = 22 
1st 
very early 
relapse 
1st 
early 
relapse 
1st 
refractory 
relapse 
1st relapse 
Prior 
HSCT 
1st 
refractory 
relapse 
prior 
HSCT 
2nd 
relapse 
2nd 
refractory 
relapse 
2nd 
relapse 
Prior 
HSCT 
2nd 
refractory 
relapse 
Prior 
HSCT 
3rd relapse 
 
 
 
 
 
 
 
 
 
 
 
T cell n = 10 
2a 
2 
1(3)a  
1 
3 a,a,a  
1 a  
 
 
 
 
B cell (>1st 
relapse) n = 6 
-- 
-- 
-- 
-- 
-- 
1 a  
2(4b,c,1) 
1 
1d 
1b 
B cell 1st relapse 
n = 6 
4a  
1a  
 
1a (d) 
 
 
 
 
 
 
Data as of 07 June 2020 
Very early relapse = first remission duration <18 months, early relapse = first remission 18-36 months, HSCT = hematopoietic stem cell transplant 
( ) number indicates number of refractory salvage regimens prior to study enrollment 
a 1 subject in each cell for each a had primary induction failure  
b Relapse after CAR-T 
c Relapse after blinatumomab 
d Relapse after inotuzumab, (d) Inotuzumab for primary induction failure 
 


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Trial data to estimate the probability of CR for subjects with these covariates were 
obtained from several data sources.  For subjects with T-cell ALL in first untreated 
relapse who did not previously receive a prior HSCT the CR rate after treatment with 
VPLD have been reported for the COG AALL02P1 study.  The regimen used in that 
study replaced dexamethasone with an equivalent dose of prednisone but was otherwise 
similar to the VXLD regimen for Study 20140106.  The CR rate was 29%, 2 of 7 subjects 
with T-cell achieved a full CR (Raetz, et al, 2008).  The CR rate for subjects with B-cell 
ALL who had a first untreated bone marrow relapse and received VXLD salvage therapy, 
was reported from 539 subjects who relapsed after being treated on the 1900 frontline 
series of COG studies (1997 to 2002).  The CR rate for VXLD was 38% and 80% for 
subjects with a first remission less than 18 months and 18 to 36 months, respectively 
(Harned and Gaynon, 2008).  The CR rate for subjects with multiple and/or refractory 
relapse were derived from a TACL study that evaluated all salvage attempts with intent 
to induce remission at 8 large academic centers over a 10-year time period (Ko et al, 
2010).  A second retrospective study was performed but did not include outcomes for 
patients with T-cell ALL (Sun et al, 2018).  Among 98 salvage procedures the CR rate for 
first, second, or greater than second refractory relapse were 20%, 24%, and 6% 
respectively, and among 116 salvage attempts for untested second and third relapse 
were 48% (45 of 93) and 30% (7 of 23) respectively.  In the TACL study, subjects with 
B-cell ALL represented 87% of the patient population and T-cell 13%.  The odds ratio for 
reinduction failure among subjects with relapsed T versus B-cell ALL was 2.0 
(Ko et al, 2010).  CR probabilities for T-cell subjects with refractory or multiple relapses 
were estimated by reducing the CR rate reported for the overall population by an odds 
ratio for failure of 2.0.  The CR estimates obtained from the TACL study represent 
approximations because the salvage regimens were not defined (only that they were 
considered to be intended to induce remission), the definition of CR required a lower 
neutrophil and platelet recovery than standard definition of CR, and CR without platelet 
recovery was included in the definition of CR.  These limitations are likely to have 
inflated the salvage CR rates; however, it is not possible to fully account for the impact of 
these variables on the CR estimates.   
To assess the potential impact of a prior HSCT on the probability of achieving CR 
following relapse, an Amgen external control database that was provided to FDA as part 
of the blinatumomab request for marketing authorization was evaluated 
(Study 20140228).  This real-world data set included 144 subjects from the European 
Union and 83 subjects from the United States.  The probability of achieving CR for 


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subjects who received a prior HSCT was 38.6% (58 of 150) and for those relapsing 
without a prior HSCT, it was 50.6% (39 of 77), an odds ratio of 1.63 favoring re-induction 
failure in subjects with a prior HSCT.  CR rates for subjects who relapsed after HSCT 
were first adjusted for other characteristics and then further decreased using an odds 
ratio of 1.63.  The final weighted CR rate based on the characteristics listed in Table 22.   
and methods of adjustments described yielded a CR rate for the control population of 
approximately 15% for T cell and 25% for B-cell.  Based on proposed mitigation 
procedures in the phase 2 part of the study that will allow for peripheral blood count 
recovery prior to bone marrow assessment the CR rate predicted from the phase 1 part 
of the study is 60% for B-cell ALL and 30% for T-cell ALL.   
18.2.5 
Amgen Investigational Product Background:  Carfilzomib 
Carfilzomib (formerly known as PR-171) is a tetrapeptide epoxyketone based inhibitor of 
the chymotrypsin like activity of the 20S proteasome.  The preclinical background for 
carfilzomib is summarized in Section 3.2.1, and the clinical background for carfilzomib is 
summarized in Section 3.2.2. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of carfilzomib 
is provided in the Carfilzomib Investigator’s Brochure. 
18.2.6 
Non-investigational Product Background:  VXLD, Modified BFM, and 
Intrathecal Chemotherapy 
Refer to the regional manufacturer package inserts for additional information. 
18.3 
Benefit/Risk Assessment 
The following benefit-risk assessment supports the conduct of this clinical study.  
Reference should be made to the Carfilzomib Investigator’s Brochure for further data on 
carfilzomib. 
18.3.1 
Therapeutic Context 
Outcomes for patients with relapsed or refractory ALL remain poor for subjects with 
T-cell ALL and those with B-cell ALL that have relapsed after targeted immune therapy, 
therefore these subjects represent a significant unmet need.  Thus, there is a clear need 
for novel agents to improve outcomes for these patients. 
18.3.2 
Key Benefits 
For patients with relapsed ALL, the first step toward cure is the achievement of complete 
remission.  As previously reviewed in Section 18.2.2.1, several studies in pediatric 
patients with relapsed/refractory ALL demonstrated promising efficacy when combining 


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bortezomib with VXLD (Bertaina et al, 2017; Horton et al, 2013; Messinger et al, 2012; 
Messinger et al, 2010).  In a recent update of COG AALL07P1 study 
(VPLD  bortezomib) outcomes, the CR rate for subjects with T-cell disease was 68 
(15/22 subjects) (Horton et al, 2019) compared to 29 (2/7) in subjects with relapsed 
T-cell ALL treated in COG AALL01P2 (VPLD) (Raetz et al, 2018).  For children with 
relapsed B-cell ALL, a direct comparison of the CR rates in subjects with very early 
relapse between AALL07P1 (VPLD-bortezomib) and AALL01P2 (VPLD) was 63 
(29/46) vs 56 (9/16).  In a much larger series, a CR rate of 38 was reported among 
children with very early first relapse treated with a single cycle of VXLD (Harned and 
Gaynon, 2008).  These results support the use of proteasome inhibition in the treatment 
of relapsed pediatric ALL.  As previously reviewed in Section 18.2.2.1, nonclinical data 
with ALL blast cells and clinical data in relapsed multiple myeloma indicate that 
carfilzomib is a more effective proteasome inhibitor than bortezomib.  As reviewed in 
Section 18.2.4, the results of VXLD-carfilzomib from the now closed phase 1 part of the 
study predict an approximate doubling of the CR rate, after accounting for covariates 
predictive for the probability of CR, 15 vs 30 for T-cell ALL and 25 vs 60 for multiply 
relapsed B-cell ALL. 
The potential benefits of the carfilzomib-VXLD regimen include improved disease 
response with an improved chance of achieving a remission that is deep and durable 
enough to permit subjects to undergo hematopoietic stem cell transplant or other 
potential curative treatments.  An improved CR rate and increased number of MRD 
negative responses may translate into a better chance for disease free and overall 
survival.   
18.3.3 
Key Risks 
The characterization of the risks associated with carfilzomib is based on clinical trial data 
evaluating the use of carfilzomib in combination with other drugs for the treatment of 
adult subjects with relapse/refractory multiple myeloma as well as post marketing 
experience in adult patients.  Thus, the incidence and nature of risks associated with 
carfilzomib may be different in the population of pediatric subjects with ALL in this study. 
For the phase 1 part of the 20140106 study, as of the cutoff date of 23 July 2020, a total 
of 22 subjects have been treated in the VXLD induction arm.  Out of 17 DLT-evaluable 
subjects, 1 DLT (grade 4 pulmonary hemorrhage) was observed at a dose 20 mg/m2.  All 
grade treatment-emergent adverse events reported in the induction phase with 
 30 incidence included events with the following PTs: hypertension (40.9), platelet 


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count decreased (36.4), anaemia (31.8), and pyrexia (31.8).  Serious adverse 
events with 2 or more events included events with the following PTs:  bacillus 
bacteraemia (n  2), posterior reversible encephalopathy syndrome (n  2), and 
pancreatitis acute (n  2).  The pancreatitis acute events were considered most likely 
associated with PEG-asparaginase.  The PTs for fatal treatment-emergent adverse 
events were:  acute lymphocytic leukaemia (n  1, in the setting of multiorganism sepsis) 
and pneumonia (n  1), both at the 56 mg/m2 dose. 
In the consolidation phase, a total of 11 subjects were treated.  The PTs for the all grade 
treatment-emergent adverse events with  30 incidence in the consolidation phase 
were: anaemia (72.7), nausea (63.6), febrile neutropenia (54.5), hypertension 
(54.5), platelet count decreased (54.5), alanine aminotransferase increased (45.5), 
abdominal pain (36.4), aspartate aminotransferase increased (36.4), headache 
(36.4), hypoalbuminaemia (36.4), hypokalaemia (36.4), pyrexia (36.4), and 
vomiting (36.4).  The PTs for the serious adverse events with 2 or more events 
included:  febrile neutropenia (n  6), drug hypersensitivity (n  2) and posterior 
reversible encephalopathy syndrome (n  2).  There were no fatal treatment-emergent 
adverse events reported. 
18.3.3.1 
Cardiac Toxicity 
New onset or worsening of pre-existing cardiac failure (eg, congestive heart failure, 
pulmonary edema, decreased ejection fraction), including fatalities, have occurred after 
administration of carfilzomib.  In clinical studies with carfilzomib, these events occurred 
throughout the course of carfilzomib therapy.   
ASPIRE evaluated carfilzomib at a dose of 27 mg/m2 twice weekly in combination with 
lenalidomide and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) 
in adult subjects with relapsed or refractory multiple myeloma.  Incidence of cardiac 
failure events reported in ASPIRE was as follows:  all grades: KRd: 7.1, Rd: 4.1; 
serious adverse events: KRd: 4.1, Rd: 2.1; grade  3 adverse events: KRd: 4.3, 
Rd: 2.1.  Most of the cardiac failure adverse events (all grades) were resolved (KRd: 
3.3, Rd: 1.5) or stabilized/not resolving (KRd: 2.6, Rd: 1.5) or resolved with 
sequelae (KRd: 0.5, Rd: 0).  Fatal outcomes were reported for 0.8 subjects from 
the KRd group and 1.0 from the Rd group.  Cardiac failure adverse events (all grades) 
leading to discontinuation of any investigational product were reported for 0.5 of 
subjects from the KRd group and 0.8 of subjects from the Rd group.   


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ENDEAVOR evaluated carfilzomib and low-dose dexamethasone (Kd) versus 
bortezomib plus low-dose dexamethasone (Vd) in adult subjects with relapsed or 
refractory multiple myeloma.  Incidence of cardiac failure events reported in ENDEAVOR 
was as follows:  all grades:  Kd: 10.8, Vd:  3.3; serious adverse events:  Kd:  3.9, 
Vd:  1.3;  grade  3 adverse events: Kd:  5.8, Vd:  2.0.  Most of the cardiac failure 
adverse events (all grades) were resolved (Kd:  3.7, Vd:  2.0) or stabilized/not 
resolving (Kd:  6.7, Vd:  0.9).  Fatal outcomes were reported for 0.2 subjects from 
the Kd group and 0.4 from the Vd group.  Cardiac failure adverse events (all grades) 
leading to discontinuation of any investigational product were reported for 3.7 of 
subjects from the Kd group and 0.9 of subjects from the Vd group.   
Subjects with New York Heart Association Class III and IV heart failure, recent 
myocardial infarction, and conduction abnormalities uncontrolled by medications were 
not eligible for the clinical study and may be at greater risk for cardiac complications.   
18.3.3.2 
Hypertension 
Hypertension has been reported as one of the common comorbidities in patients with 
multiple myeloma.  Based on the MarketScan claims database, the prevalence of 
hypertension as a comorbidity among multiple myeloma patients is 46.9 (Song et al, 
2016) and there was a 30 increase in the risk of hypertension in multiple myeloma 
versus non-multiple myeloma patients (Chari et al, 2016).  The incidence of hypertension 
adverse events in ASPIRE was as follows: all grades: KRd: 17.1, Rd: 8.7, serious 
adverse events: KRd: 0, Rd: 0.3; grade  3 adverse events: KRd: 6.4, Rd: 2.3.  
The incidence of hypertension (all grades) was higher in subjects with a history of 
hypertension: with history of hypertension: KRd: 20.5, Rd: 10.7; without history of 
hypertension: KRd: 13.7, Rd: 7.1.  No fatal outcomes for hypertension adverse 
events (all grades) were reported in ASPIRE.  Almost all the hypertension adverse 
events (all grades) were stabilized/not resolving (KRd: 8.7; Rd: 4.4) or resolved 
(KRd: 8.4, Rd: 4.1); resolved with sequelae was also reported (KRd: 0, Rd: 0.3).  
Hypertension adverse events (all grades) led to discontinuation of any investigational 
product in 0.3 subjects from the KRd and Rd groups each.  Hypertensive crisis 
occurred in  0.5 of subjects (KRd: 0.5, Rd: 0.3); all these adverse events were 
 grade 3. 
The incidence of hypertension adverse events in ENDEAVOR was as follows: all grades: 
Kd:  33.7, Vd:  10.5, serious adverse events: Kd:  0.9, Vd:  0.2; grade  3 


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adverse events: Kd:  15.6, Vd:  3.3.  The incidence of hypertension (all grades) was 
similar in subjects with a history of hypertension and subjects without a history of 
hypertension:  subjects with history of hypertension: Kd:  31.1, Vd:  10.8; subjects 
without history of hypertension: Kd:  36.4, Vd:  10.3.  No fatal outcomes for 
hypertension adverse events (all grades) were reported in ENDEAVOR.  The outcomes 
for hypertension adverse events reported in ENDEAVOR were stabilized/not resolving 
(Kd:  19.4, Vd:  4.2) and resolved (Kd:  14.0, Vd:  6.1).  Hypertension adverse 
events (all grades) led to discontinuation of any investigational product in 0.2 subjects 
from the Kd group and 0 of subjects from the Vd group.  Hypertensive crisis occurred 
in 0.2 of subjects in the Kd group and 0 of subjects in the Vd group, all of these 
adverse events were  grade 3. 
Blood pressure is monitored while on study and hypertension should be treated as 
needed.  If hypertension cannot be controlled, the carfilzomib dose should be held.  In 
case of hypertensive crisis, carfilzomib should be stopped until the hypertensive crisis 
resolved.  The investigator may consider restarting carfilzomib based on an individual 
benefit-risk assessment. 
18.3.3.3 
Acute Renal Failure 
Renal failure is a relatively common problem in patients with multiple myeloma 
(Dimopoulos et al, 2016; Bladé and Rosiñol, 2005).  Acute renal failure occurs most 
often in patients with multiple myeloma who have high rates of production and excretion 
of immunoglobulin (Ig)-free light chains, which may be toxic to the basement membranes 
of the glomeruli and/or the renal tubules and form obstructing tubular casts, particularly if 
the patient is dehydrated (Dimopoulos et al, 2016; Sanders and Booker, 1992). 
The incidence of acute renal failure in ASPIRE was as follows:  all grades: KRd: 9.2, 
Rd: 7.7; serious adverse events: KRd: 2.6, Rd: 1.8; grade  3 adverse events: 
KRd: 3.8, Rd: 3.3.  Most of the acute renal failure adverse events (all grades) were 
resolved (KRd: 6.1, Rd: 5.7) or stabilized/not resolving (KRd: 2.8, Rd: 1.8) or 
resolved with sequelae (KRd: 0.3, Rd: 0).  No fatal outcomes were reported for the 
KRd group; in the Rd group, fatal outcomes were reported for 0.3 of the subjects.  
Acute renal failure adverse events (all grades) leading to discontinuation of any 
investigational product were reported for 0.5 of subjects in the KRd group and 1.0 in 
the Rd group.   


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The incidence of acute renal failure in ENDEAVOR was as follows:  all grades:  
Kd:  10.4, Vd:  6.1; serious adverse events:  Kd:  3.9, Vd:  2.0; grade  3 adverse 
events: Kd:  5.6, Vd:  3.3.  Most of the acute renal failure adverse events (all grades) 
were resolved (Kd:  5.6, Vd:  3.1) or stabilized/not resolving (Kd:  4.5, Vd:  3.1).  
Fatal outcomes were reported for 0.2 of the subjects in the Kd group, in the Vd group 
no fatal outcomes were reported.  Acute renal failure adverse events (all grades) leading 
to discontinuation of any investigational product were reported for 1.3 of subjects in the 
Kd group and 0.4 in the Vd group. 
Acute renal failure was reported more frequently in patients with advanced relapsed or 
refractory multiple myeloma who received carfilzomib monotherapy.  The incidence was 
increased in patients with a decrease in estimated creatinine clearance, calculated using 
Cockcroft and Gault equation, prior to receiving carfilzomib.  Renal function should be 
monitored with regular measurement of the serum creatinine and/or estimated creatinine 
clearance.  Reduce or stop dose as described in the dose modification (Section 22.2).  
19. 
Phase 2:  Objectives and Endpoints 
All primary and secondary objectives will be analyzed for T-cell and B-cell ALL analysis 
sets separately, unless otherwise specified.  For definitions of CR, CRp, CRh, CRi, SD 
and PD see Table 26.  For the primary and secondary endpoint evaluation, response will 
be derived by the sponsor based upon local evaluation of bone marrow, peripheral 
blood, and extramedullary disease status.  Minimal residual disease status will be 
determined per central lab review of bone marrow MRD using NGS. 
Objectives 
Endpoints 
Primary 
 
Compare the rate of CR of CFZ-VXLD at 
the end of induction therapy to an 
appropriate external control.   
 
CR after induction therapy 
Primary Endpoint Estimand 
The OR for the PoCR for CFZ-VXLD versus external control. 
Secondary 
 
Evaluate the safety and tolerability of 
CFZ-VXLD  
 
Treatment-emergent and 
treatment-related adverse events and 
severe adverse events and laboratory 
abnormalities during the induction therapy 
and consolidation therapy 
 
Compare the rate of CR, CRp, CRh, and 
CRi of CFZ-VXLD at the end of induction 
therapy relative to an appropriate external 
control 
 
CR, CRp, CRh, and CRi at the end of 
induction therapy  


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 
Compare EFS for CFZ-VXLD to an 
appropriate external control 
 
EFS, defined as time from initiation of 
therapy until treatment failure (defined as 
failure to reach at least a CRi after 
consolidation or after induction in subjects 
that do not receive consolidation), 
relapse, or death from any cause 
 
Compare OS for CFZ-VXLD relative to an 
appropriate external control 
 
OS defined as time from initiation of 
therapy until death from any cause 
 
Estimate the DOR for CFZ-VXLD relative 
to an appropriate external control 
 
DOR, defined as time from earliest of CR, 
CRp, CRh, or CRi to relapse or death 
from any cause 
 
Estimate the rate of MRD[-] at the end of 
induction in subjects receiving CFZ-VXLD 
 
MRD status using NGS less than 10-4 
after induction therapy in subjects 
achieving CR 
 
Estimate the rate of MRD[-] bone marrow 
after induction and consolidation therapy 
in subjects with B-cell ALL or T-cell ALL 
receiving CFZ-VXLD 
 
MRD status using NGS less than 10-3 and 
less than 10-4 in subjects achieving CR, 
CRp, CRh, or CRi after induction and 
consolidation therapy, separately  
 
Estimate the proportion of subjects that 
bridge to stem cell transplant or CAR-T 
cell therapy in subjects receiving CFZ-
VXLD 
 
Occurrence of a stem cell transplant or 
CAR-T, without an intervening relapse 
after protocol specified therapy 
 
Estimate the rate of CR, CRp, CRh, and 
CRi of CFZ-VXLD at the end of 
consolidation therapy in subjects 
receiving CFZ-VXLD. 
 
CR, CRp, CRh, and CRi after 
consolidation  
 
Estimate the pharmacokinetics of 
carfilzomib when administered as part of 
VXLD regimen 
 
Carfilzomib pharmacokinetic parameters, 
including AUC, Cmax, and if feasible, t1/2 
 


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AUC = area under the concentration-time curve; CAR-T = chimeric antigen receptor T cell therapy; 
CFZ = carfilzomib; Cmax = maximum plasma concentration; CR = complete remission; CRh = complete 
remission with partial hematologic recovery; CRi = complete remission with incomplete hematologic 
recovery; CRp = complete remission with incomplete recovery of platelets; DOR = duration of response; 
EFS = event-free survival; MRD = minimal residual disease; MRD[-] = minimal residual disease negative 
bone marrow; NGS  next generation sequencing; OS = overall survival; t1/2 = half-life; VXLD = vincristine, 
dexamethasone, PEG asparaginase, daunorubicin  
20. 
Phase 2:  Study Design 
20.1 
Overall Design 
The phase 2 portion of the study is a multicenter, single-group, externally-controlled 
study of carfilzomib in combination with VXLD in a minimum of 100 subjects, unless 
futility is met.  Eligible subjects must be greater than or equal to 1 month to less than 
21 years old, with their original diagnosis at less than 18 years of age and must have 
ALL with bone marrow relapse (greater than or equal to 5 leukemia blasts in bone 
marrow) or refractory relapse with or without extramedullary disease of the T-cell 
phenotype or of the B-cell phenotype after having received a targeted B-cell immune 
therapy (eg, blinatumomab, inotuzumab, CAR-T, or therapy).  Infants enrolling on this 
study will receive a modified VXLD and optional consolidation based on the dose and 
schedule used in COG AALL15P1 study. 
The carfilzomib dose for phase 2 will be 20 mg/m2 on day 1 of induction, 56 mg/m2 on 
days 2, 8, 9, 15, and 16 of induction and days 1, 2, 8, 9, 15, and 16 of consolidation.  
Eligible subjects will be treated with VXLD plus carfilzomib for 1 cycle (induction), 
followed by assessment of treatment response.  All subjects who do not show 
progression during induction will undergo a bone marrow and extramedullary disease 
evaluation after completion of induction therapy between days 29 to 45 of induction 
(between days 36 to 50 for infants), based on blood count recovery but before the start 
of post-induction therapy, whichever comes first.  Response will be assessed per local 
and central laboratory review of bone marrow, peripheral blood and differential, and local 
assessment for sites of extramedullary disease.  Minimal residual disease will be 
assessed by NGS central laboratory review and local evaluation by flow cytometry 
and/or PCR or NGS when available. 
Subjects without disease progression as defined in Table 26 after induction may, at the 
investigator’s discretion, be treated with 1 cycle of consolidation chemotherapy plus 
carfilzomib.  Subjects who do not show disease progression during consolidation will be 
assessed for treatment response between day 29 to 45 of consolidation (between 


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day 36 to 50 for infants), based on blood count recovery or start of alternative therapy, 
whichever comes first. 
Treatment response after consolidation therapy will also be assessed per local and 
central laboratory review of bone marrow, peripheral blood and differential, and local 
assessment for sites of extramedullary disease.  When available, local laboratory 
assessments of MRD by flow cytometry and/or PCR or NGS will be collected.  The 
consolidation treatment will consist of one 28-day cycle of Children’s Oncology 
group-modified Berlin-Frankfurt-Munster (BFM) therapy; cyclophosphamide, cytarabine, 
6-mercaptopurine, PEG-asparaginase, vincristine, and IT therapy, or for  12 months of 
age a modified infant consolidation from COG AALL15P1; cyclophosphamide, 
cytarabine, 6-mercaptopurine, and IT therapy, combined with carfilzomib at a dose of 
56 mg/m2 (or lower if dose reduction was required during induction) at the same 
schedule as the induction therapy.  After completion of study therapy, subjects will be 
followed for subsequent treatment(s), event-free and overall survival.  
For selected objectives, the treatment response to induction of subjects receiving 
CFZ-VXLD will be compared to an external control arm of subjects from an observational 
study of relapsed pediatric ALL (Study 20180065) that received standard-of-care (SoC) 
chemotherapy, after appropriate adjustment.  More details will be included in the 
statistical analysis plan. 
The phase 2 part of the study design is described by a study schema in Section 17.11.1.  
The endpoints are defined in Section 19. 
20.2 
Number of Subjects 
A minimum of 100 subjects will be enrolled and receive at least one dose of carfilzomib 
in the phase 2 part of the study unless futility is met.  A minimum of 30 subjects with 
T-cell ALL and 50 subjects with B-cell ALL will be enrolled. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 25.2. 
20.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
20.3 
Justification for Investigational Product Dose 
Carfilzomib has been evaluated as a single agent and as part of a combination regimen 
for the treatment of adult subjects with multiple myeloma.  The MTD for single agent 
carfilzomib administered by IV infusion over 30 minutes on 2 consecutive days per week 
has been determined to be 56 mg/m2 (Study PX-171-007; data on file).  In combination 


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with melphalan and prednisone, the MTD of carfilzomib administered on this same 
schedule has been determined to be 36 mg/m2 in adults with relapsed or refractory 
multiple myeloma (Kolb et al, 2012).  Current practice is to start with 20 mg/m2 of 
carfilzomib before escalating to a higher dose.   
Carfilzomib was investigated in the phase 1b portion of this study administered alone 
and in combination with induction chemotherapy, for the treatment of relapsed or 
refractory ALL.  The recommended phase 2 dose, 56 mg/m2, was selected for 
combination with VXLD by the Cohort Safety Review Committee (CSRC) based on 
review of safety, efficacy, pharmacokinetic, and 
 data obtained from 
the phase 1b portion of the study described above. 
The selected dosing regimen of carfilzomib for the phase 2 portion of the study will 
consist of twice-weekly IV infusions (30  5 minutes) on days 1, 2, 8, 9, 15 and 16 of the 
induction cycle.  Subjects will receive 20 mg/m2 carfilzomib on day 1 of the induction 
cycle, and 56 mg/m2 on dosing days thereafter. 
Based on preliminary pharmacokinetic analyses in 14 pediatric subjects, carfilzomib 
exposure was approximately dose proportional between the dose range of 27 to 
56 mg/m2, when given in combination with the VXLD backbone.  Furthermore, 
dose-normalized exposures (Cmax and AUC) in subjects  6 years, between 6 to 
12 years, and  12 years of age were similar, suggesting little to no impact of age on 
carfilzomib pharmacokinetics in this population.  When compared to the adult multiple 
myeloma population (dose range 20 to 56 mg/m2), the geometric mean of 
dose-normalized exposures was similar; pharmacokinetic variability in pediatric subjects 
was high (%CV  49%), consistent with the observed variability in adult multiple 
myeloma subjects.  
Preliminary pharmacokinetic/pharmacodynamic analyses did not reveal any clear dose- 
or exposure-dependent relationships for efficacy.  Carfilzomib pharmacodynamics, as 
assessed by inhibition of proteasome activity (ie, chymotrypsin-like activity) in whole 
blood, were inhibited by over 90% following IV administration of 36 mg/m2 and higher, 
although proteasome activity of other subunits (ie, caspase-like and trypsin-like activity) 
were not maximally suppressed.  No clear trends in carfilzomib exposure were observed 
between responders and non-responders. 
Based on the observed efficacy in adult multiple myeloma subjects, similar 
dose-normalized exposures in children and adults, and observed pharmacodynamics, 


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these data suggest 36 to 56 mg/m2 may be an appropriate phase 2 dose, provided an 
acceptable safety and tolerability profile as determined by the CSRC.   
20.3.1 
Justification for Non-investigational Product Dose 
For induction, VXLD products are to be administered in accordance with the terms of 
marketing authorizations. 
For consolidation, if applicable, modified BFM products are to be administered in 
accordance with the terms of marketing authorizations. 
20.4 
End of Study 
The end of study date is defined as the date when the last surviving subject completes 
the safety follow-up, discontinues the study due to death, is lost to follow-up, withdraws 
full consent from the study, or the sponsor in consultation with regulatory authorities 
decides to close the study, whichever occurs first.   
The duration of the trial for an individual subject is estimated to be up to approximately 
29 months (including the screening, safety follow-up [30 days], and long-term follow-up 
[up to 2 years after safety follow-up]). 
21. 
Phase 2:  Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Response 
Technology (IRT). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 24.1.1). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
21.1 
Inclusion Criteria 
Subjects are eligible to be included in the phase 2 part of the study only if all of the 
following criteria apply: 
110 
Subject’s legally acceptable representative has provided informed consent when 
the subject is legally too young to provide informed consent and the subject has 
provided written assent based on local regulations and/or guidelines prior to any 
study-specific activities/procedures being initiated, except for standard of care 
local testing as permitted per Section 21.3. 


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111 
Age greater than or equal to 1 month to less than 21 years.  Subjects greater 
than or equal to 18 years must have had their original diagnosis at less than 
18 years of age. 
112 
Subjects must be diagnosed with relapsed or refractory relapsed ALL. 
113 
Subjects must have a documented first remission, less than 5% blasts in the 
bone marrow (M1 bone marrow) and no evidence of extramedullary disease.   
114 
T-cell ALL with bone marrow relapse (defined as greater than or equal to 
5% leukemia blasts in bone marrow) or refractory relapse with or without 
extramedullary disease. 
OR 
B-cell ALL with bone marrow relapse or refractory relapse (defined as greater 
than or equal to 5% leukemia blasts in bone marrow) after having received a 
targeted B-cell immune therapy (eg, blinatumomab, inotuzumab, or a CAR-T 
therapy) with or without extramedullary disease. 
115 
Adequate liver function:  bilirubin less than or equal to 1.5 x upper limit of normal 
(ULN), alanine aminotransferase (ALT) less than or equal to 5 x ULN. 
116 
Adequate renal function:  serum creatinine less than or equal to 1.5 x ULN or 
glomerular filtration rate (GFR) greater than or equal to 70 mL/min/1.73 m2; or for 
children less than 2 years of age, greater than or equal to 50 mL/min/1.73 m2. 
117 
Adequate cardiac function:  shortening fraction greater than or equal to 30% or 
ejection fraction greater than or equal to 50% 
118 
Karnofsky (subjects greater than or equal to 16 years of age) or Lansky (subjects 
12 months to less than 16 years of age) performance status greater than or equal 
to 50%. 
119 
Subjects must have fully recovered from the acute toxic effects of all previous 
chemotherapy, immunotherapy, or radiotherapy treatment before enrollment (for 
example: recovery from gastrointestinal toxicity may occur more rapidly than less 
reversible organ toxicities such as sinusoidal obstruction syndrome or 
non-infectious pneumonitis, for serious prior toxicities recommend discussion 
with Amgen medical monitor).  
120 
Life expectancy of greater than 6 weeks per investigator`s judgment at time of 
screening. 
21.2 
Exclusion Criteria 
Subjects are excluded from the phase 2 part of the study if any of the following criteria 
apply: 
211 
Prior treatment with carfilzomib.   
214 
Intolerance, hypersensitivity, or inability to receive any of the chemotherapy 
components of the VXLD regimen (or acceptable substitutes as listed in 
Section 22.1.2.1).  An exception is allowed for allergy to asparaginase products if 
Erwinia asparaginase is unable to be administered. 
215 
Autologous HSCT within 6 weeks prior to start of study treatment. 
216 
Allogeneic HSCT within 3 months prior to start of study treatment. 


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217 
Active GVHD requiring systemic immune suppression.  
218 
Less than 30 days from discontinuation of immune suppressive therapy 
administered for the treatment of acute or chronic GVHD. 
219 
Isolated extramedullary relapse. 
220 
Positive bacterial or fungal infection within 14 days of enrollment (except for 
documented line infection, line has been removed, and blood culture after line 
removal is negative for 5 days prior to first dose of induction therapy).  Antibiotics 
may be administered for prophylaxis as per institutional standards up to and after 
enrollment. 
221 
Subjects with less than 3 antibody half-lives since the last dose of monoclonal 
antibody (eg, 66 days for rituximab, 69 days for epratuzumab, inotuzumab for 
36 days), prior to first dose of investigational product must be discussed with the 
Amgen medical monitor and may be allowed to enroll based on extent of disease 
or evidence of rapidly rising peripheral or bone marrow blast counts.  
222 
Cell-based immunotherapy (eg, donor leucocyte infusion, CAR-T cells, tumor 
vaccines) within 42 days prior to first dose of investigational product.  If the 
Amgen medical monitor agrees, an exception may be granted to the 42-day 
requirement for subjects with rapidly rising peripheral or bone marrow blast 
counts.  
223 
Down’s syndrome. 
224 
Presence of another active cancer. 
225 
History of grade greater than or equal to 2 pancreatitis within 6 months to 
screening 
226 
Unresolved toxicities from prior anticancer therapy, defined as not having 
resolved to CTCAE version 4.03 grade 1 or to levels dictated in the eligibility 
criteria apart from alopecia or toxicities from prior anticancer therapy that are 
considered irreversible and do not trigger another exclusion criterion (defined as 
having been present and stable for greater than 4 weeks) 
227 
Antitumor therapy (chemotherapy, investigational agents, molecular-targeted 
therapy) within 7 days of day 1 of induction.  Exception: hydroxyurea to control 
peripheral blood leukemic cell counts is allowed until start of investigational 
product. 
228 
Active viral infection, including but not limited to cytomegalovirus (CMV), 
Hepatitis B infection with positive serum hepatitis surface antigen or hepatitis B 
DNA, HIV, Hepatitis C with detectable hepatitis C RNA.  Subjects who have 
previously received a stem cell transplant must be screened for CMV infection, 
unless both subject and donor are known to be CMV negative. 
229 
Currently receiving treatment in another investigational device or product study, 
or less than 14 days since ending treatment on another investigational device or 
product study. 
230 
Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of 
greater than 470 msec. 
231 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 


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232 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 6 months after the last dose of 
any study treatment or for 12 months after last dose of cyclophosphamide if 
administered during optional consolidation cycle. 
233 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception during treatment and for an additional 6 months after the 
last dose of any study treatment or for 12 months after last dose of 
cyclophosphamide if administered during optional consolidation cycle.  Refer to 
Section 29 for additional contraceptive information. 
234 
Female subjects of childbearing potential with a positive pregnancy test 
assessed at Screening by a serum or urine pregnancy test. 
235 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use a 
condom with spermicide during treatment and for an additional 6 months after the 
last dose of any study treatment, even if they have undergone a successful 
vasectomy. 
236 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom with spermicide during treatment, for duration of pregnancy, and 
for an additional 6 months after the last dose of any study treatment. 
237 
Male subjects unwilling to abstain from donating semen or sperm during 
treatment and for an additional 6 months after the last dose of any study 
treatment. 
238 
Known allergy to captisol (a cyclodextrin derivative used to solubilize carfilzomib; 
for a complete listing of Captisol-enabled drugs, see the Ligand Pharmaceuticals, 
Inc. website). 
21.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 27).  
Evaluations performed within 7 days of enrollment as part of routine medical care (eg, 
bone marrow aspirate/biopsy) may be used for screening assessments. 
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF), including the 
outcome of any required discussion with the Amgen medical monitor. 


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Each subject who enters into the screening period for the study (within 7 days prior to 
day 1) receives a unique subject identification number before any study-related 
activities/procedures are performed.  The subject identification number will be assigned 
by IRT.  This number will be used to identify the subject throughout the clinical study and 
must be used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.   
21.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened up to 3 times.  Refer to Section 24.1.1. 
22. 
Phase 2:  Treatments 
Study treatment is defined as any investigational product(s) or non-investigational 
product(s) intended to be administered to a study subject according to the study 
protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
A summary of the dosing and administration of each treatment is shown in Section 22.1. 


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22.1 
Treatment(s) Administered 
22.1.1 
Investigational Product:  Carfilzomib 
22.1.1.1 
Dosage Formulation 
Carfilzomib will be manufactured and packaged by Amgen and distributed using Amgen 
clinical study drug distribution procedures. 
Carfilzomib is supplied as a sterile, lyophilized, white to off-white powder ready for 
reconstitution.  It is supplied for single use in 50 mL Type 1 glass vials containing 60 mg 
of carfilzomib drug product with an elastomeric stopper and flip-off lid. 
22.1.1.2 
Dosage, Administration, and Schedule 
Carfilzomib will be administered twice-weekly IV over approximately 30 ( 5) minutes as 
indicated in Table 15, Table 17, Table 19, and Table 21.  The dose will be 20 mg/m2 on 
day 1 of induction therapy and at 56 mg/m2 for all subsequent doses during induction 
therapy and including all doses during consolidation therapy.   
Each subject’s first dose of carfilzomib will be calculated based upon baseline body 
surface area (BSA) using the Mosteller formula, including subjects less than 12 months 
of age.  In subjects with BSA greater than 2.2 m2, the dose should be capped based on 
a BSA of 2.2 m2.  The dose for each subject should not be revised unless the subject 
experiences a change in body weight of greater than 20 in which case the BSA and 
dose should be recalculated.  The carfilzomib dose must be adjusted for certain 
toxicities, see Section 22.2.1.1, Table 24, and Table 25 for a list of specific dose 
modifications.  
Carfilzomib will be administered as an IV infusion.  Mechanical infusion pumps are 
recommended, but gravity-dependent infusions are permitted if the infusion duration can 
be reliably maintained.   
The planned dose (mg/m2), quantity administered (mg), start date/time, stop date/time, 
reason for change in planned dose, reason for dose change/withheld, reason for dose 
delay, reason for dose interruption and package lot number of carfilzomib are to be 
recorded on each subject's eCRF. 
22.1.1.3 
Intravenous Prehydration 
Adequate hydration is required to mitigate the risks for TLS and pre-renal azotemia, 
which have been associated with carfilzomib.  Prehydration with at least 125 mL/m2/hour 
of IV fluid is required for 1 hour prior to carfilzomib administration; hydration 
management is otherwise at the investigator’s discretion and should be appropriate for 


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the clinical situation.  Pre-hydration for carfilzomib may be combined with pre-hydration 
for other study medications and is not in addition to any required hydration for other 
study medications.  
22.1.2 
Non-investigational Product:  VXLD 
22.1.2.1 
Dosage Formulation 
The components of VXLD (vincristine, daunorubicin, PEG-asparaginase, and 
dexamethasone) or protocol-approved alternative substitutes for these agents are 
commercially available.  The description, how supplied, and storage instructions for each 
drug product are available in the associated prescribing information.  The study staff is 
advised to refer to the prescribing information that is specific to the brand or formulation 
of the drug product being administered to subjects at their site.   
Induction Chemotherapy Backbone (VXLD) for children greater than or equal to 
12 months (see also Table 15).  For infants less than 12 months, see modifications to 
VXLD dose and schedule listed below and in Table 17. 
If carfilzomib window is adjusted, scheduled backbone therapy may be adjusted 
 3 days to align with carfilzomib at investigator’s discretion. 
 
Daunorubicin, 60 mg/m2 IV on day 2 
 
Administer into a large vein as an infusion over 15 to 60 minutes as required by 
institutional practice. 
 
Administration in conjunction with rapidly infusing D5W or normal saline is 
recommended. 
 
Protect from sunlight. 
 
Dexamethasone 6 mg/m2 per day - given orally BID (3 mg/m2 per dose given twice 
daily) on days 1 to 21 
 
IV administration is acceptable, if the subject is unable to tolerate oral 
administration. 
 
Round the calculated dosage up to the nearest one half tablet or 0.1 mL. 
 
PEG asparaginase 2500 U/m2 IV on days 4 and 18 
 
Infuse over 1 to 2 hours in D5W or normal saline. 
 
Rapid access to emergency medications (ie, epinephrine and 
methylprednisolone) during and for approximately 24 hours following dosage 
administration is strongly recommended. 
 
See Section 8.4.9 for information regarding the substitution of Erwinia for PEG 
asparaginase.   
 
Asparaginase erwinia chrysanthemi recombinant (RYLAZE) may be used in 
regions where approved and available as a replacement for PEG or Erwinia 
asparaginase.  RYLAZE is administered at a dose of 25 mg/m2 intramuscularly 


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on Monday, Wednesday, and Friday for 6 doses as a replacement of each single 
dose of pegaspargase.  Dose modifications are similar to those for asparaginase 
in Section 8.4.9 with specific instructions in the United States label and in 
Table 23. 
 
Alternate asparaginase formulations, or doses lower than the protocol specified 
dose, may be given per local standard of care after discussion with the Amgen 
medical monitor. 
Table 23.  Dose Modification for RYLAZE 
Adverse Reaction  Severity 
Action 
Hypersensitivity 
Reaction  
Grade 2  
Grade 3 to 4  
 
Treat the symptoms 
 
Discontinue RYLAZE permanently 
Pancreatitis 
Grade 2 to 4  
 
Hold RYLAZE for elevations in lipase or 
amylase greater than 2 times the ULN, 
or for symptomatic pancreatitis. 
 
Resume treatment when lipase and 
amylase are less than 1.5 times the 
ULN and symptoms are resolved.  
 
Discontinue RYLAZE permanently if 
clinical necrotizing or hemorrhagic 
pancreatitis is confirmed. 
Thrombosis 
Uncomplicated thrombosis 
 
Hold RYLAZE  
 
Treat with appropriate antithrombotic 
therapy  
 
Upon resolution of symptoms, consider 
resuming RYLAZE, while continuing 
antithrombotic therapy.  
Severe or life-threatening 
thrombosis 
 
Discontinue RYLAZE permanently.  
 
Treat with appropriate antithrombotic 
therapy. 
Hemorrhage 
Grade 3 to 4 
 
Hold RYLAZE 
 
Evaluate for coagulopathy and consider 
clotting factor replacement as needed.   
 
Resume RYLAZE with next scheduled 
dose if bleeding is controlled. 
Hepatotoxicity 
Total bilirubin greater than 
3 times to less than or 
equal to 10 times the ULN 
 
Hold RYLAZE until total bilirubin levels 
decrease to less than or equal to 1.5 
times the ULN. 
Total bilirubin greater than 
10 times the ULN 
 
Discontinue RYLAZE, do not make up 
missed doses.  
ULN  upper limit of normal. 
 
 
Vincristine 1.5 mg/m2 (maximum 2 mg dose) IV on days 1, 8, 15, and 22 
 
Administer as an IV push over 1 minute or as an infusion, in accordance with 
institutional practice. 


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CNS Treatment (According to age-based dosing presented in Table 6). 
Preservative free forms of cytarabine, hydrocortisone, and methotrexate should be used 
for IT administration.   
 
IT chemotherapy in accordance with institutional practice given within 7 days before 
enrollment or on day 1 
 
CNS negative subjects:  IT methotrexate given on day 8 
 
CNS positive subjects:  IT Triple Therapy (cytarabine, hydrocortisone, and 
methotrexate) given on days 8, 15, 22, and 29.  In regions where alternatives to 
hydrocortisone as the steroid component of triple IT therapy are used, sites may 
substitute according to local standard practice.  
In regions where the components of VXLD are not available, the following substitutions 
are permitted: 
 
Daunorubicin  
 
Doxorubicin (1 to 1 conversion from daunorubicin) 
 
Epirubicin (1.2 mg epirubicin for each 1 mg of daunorubicin) 
 
Idarubicin (1 mg idarubicin for each 6 mg of daunorubicin) 
 
Daunorubicin may be omitted, at the investigator’s discretion, for subjects 
enrolling less than 6 months from stem cell transplant or CAR-T therapy or 
subjects in third or higher relapse, or in refractory relapse if the subjects most 
recent salvage therapy included an anthracycline.   
 
PEG-asparaginase 
 
L-asparaginase 
 
Induction 
 
For subjects greater than or equal to 12 months during induction, 
administer 9000 U/m2 IM every Monday, Wednesday, Friday (M-W-F) for 
9 doses starting on day 1 or closest to day 1 matching M-W-F schedule.   
 
For infants greater than or equal to 6 to less than 12 months of age during 
induction, administer 6000 U/m2 IM every M-W-F for 6 doses starting on 
day 8 or closest to day 8 matching M-W-F schedule.   
 
For infants less than 6 months of age during induction, administer 
5000 U/m2 IM every M-W-F for 6 doses starting on day 8 or closest to 
day 8 matching M-W-F schedule. 
 
Consolidation 
 
For subjects greater than or equal to 12 months during consolidation, 
administer 6000 U/m2 IM every M-W-F for 3 doses starting on day 14 or 
closest to day 14 matching M-W-F. 
 
Infants do not receive asparaginase during consolidation. 
 
Subjects that are allergic to L-asparagine may substitute an appropriate dose of 
Erwinia asparaginase as described in Section 8.4.9. 


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 
If Erwinia asparaginase is not available, sites may elect to delete asparaginase 
treatment or may conduct desensitization procedure prior to administration of 
either PEG- or L-asparaginase, using a desensitization procedure acceptable to 
their site.   
 
Dexamethasone 
 
Prednisone (20 mg/m2 converts to 3 mg/m2 dexamethasone) 
 
Prednisolone (20 mg/m2 for each 3 mg/m2 dexamethasone) 
 
Methylprednisolone (15 mg/m2 for each 3 mg/m2 dexamethasone) 
22.1.2.1.1 
Rationale for Change in VXLD Chemotherapy 
Changes in the VXLD backbone compared with the phase 1 portion of the study is 
intended to reduce toxicity of the VXLD backbone as a result of changes to the patient 
population.  Changes in the eligibility criteria for the phase 2 portion of the study require 
subjects with B-cell ALL to be more heavily treated prior to enrollment compared with the 
phase 1 portion of the study.  In addition, the overall level of prior therapy for subjects 
who enrolled in the phase 1 portion of the study increased over time.   
Treatment-related mortality with a 4-drug induction therapy such as VXLD in relapsed 
ALL with recent prior transplant, CAR-T therapy, or in subjects with refractory relapse is 
known to range from 12 to greater than 20 and is likely higher for subjects with 
combinations of these risk factors.  For example, overall induction mortality was 1.4 for 
primary treatment, 6.3 for first relapse, and 20.8 for second relapse 
(Saarinen-Pihkala et al, 2006); treatment mortality was 12 (6 of 51 pediatric subjects) 
for refractory first relapse (von Stackelberg et al, 2011) and 20 for relapse within 
6 months of stem cell transplant compared to 7.7 for relapses  6 months from 
transplant (Willasch et al, 2017).   
In the phase 1 portion of the study, 10 subjects were treated with VXLD and carfilzomib 
at the RP2D of 56 mg/m2.  Two subjects who received recent stem cell transplant had 
early death during induction as a result of toxicity attributable to VXLD.  In addition, 
subjects with refractory relapse, multiply relapsed, or recent stem cell transplant or 
CAR-T therapy rarely recover bone marrow function at the end of 4-drug induction such 
as VXLD.   
Based on the review of phase 1 safety data, investigators have the option to eliminate 
anthracycline for certain groups of subjects based on elevated risk of unacceptable 
toxicity, including subjects within 6 months of a CAR-T or stem cell transplant, multiple 


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relapsed (greater than first relapse), or subjects with refractory relapse who received an 
anthracycline based therapy in their most recent treatment.  
22.1.2.2 
Dosage, Administration, and Schedule 
During induction therapy VXLD will be administered as indicated in Table 15 and 
Table 17. 
22.1.3 
Non-investigational Product:  Modified BFM  
22.1.3.1 
Dosage Formulation 
The components of the modified BFM regimen (cytarabine, 6-mercaptopurine, 
cyclophosphamide, vincristine, and PEG-asparaginase) or approved alternative 
substitutes for these agents are commercially available.  The description, how supplied, 
and storage instructions for each drug product are available in the associated 
prescribing information.  The study staff is advised to refer to the prescribing information 
that is specific to the brand or formulation of the drug product being administered to 
subjects at their site. 
Protocol-approved alternatives are provided in Section 22.1.2.1. 
22.1.3.2 
Dosage, Administration, and Schedule 
For children greater than 12 months of age, the modified BFM consolidation is identical 
to that in the phase 1b portion of the study, see Section 8.1.3 for details.  During 
consolidation therapy modified BFM will be administered as indicated in Table 19 and 
Table 21 for children greater than or equal to 12 months or less than 12 months of age, 
respectively. 
22.1.4 
Non-investigational Product:  Intrathecal Chemotherapy 
22.1.4.1 
Dosage Formulation 
Intrathecal therapy is considered SOC and the components (methotrexate, cytarabine, 
and hydrocortisone [or for regions where hydrocortisone is not used, steroid acceptable 
to the site]) are commercially available.  The description, how supplied, and storage 
instructions for each drug product are available in the associated prescribing information.  
The study staff is advised to refer to the prescribing information that is specific to the 
brand or formulation of the drug product being administered to subjects at their site. 
22.1.4.2 
Dosage, Administration, and Schedule 
During induction therapy and consolidation therapy age dependent doses of IT 
chemotherapy (and for regions where hydrocortisone is not used, steroid acceptable to 
the site) will be administered as indicated in Table 15, Table 17, Table 19, and Table 21.  


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For regions where the SOC for IT medication does not include steroid, that component 
may be omitted.  Use of alternate IT regimens per local practice may be allowed after 
discussion with medical monitor. 
22.1.5 
Medical Devices 
No investigational medical devices will be used.   
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices.   
22.1.6 
Other Protocol-required Therapies 
The investigator will be responsible for obtaining supplies of the protocol-required 
therapies. 
22.1.6.1 
Tumor Lysis Syndrome 
Subjects at high risk of tumor lysis should be assessed rapidly for evidence of 
symptomatic hyperleukocytosis, TLS, and coagulopathy.  
 
Relevant laboratory tests from the screening period include: 
 
Complete blood count (CBC) 
 
Serum electrolytes, including calcium and phosphorus 
 
Creatinine 
 
Blood urea nitrogen (BUN) 
 
Uric acid 
Continued monitoring of these laboratory values at intervals suitable to the clinical 
condition is required, until abnormalities have resolved or the risk has abated.  The risk 
for serious acute TLS usually subsides within the first 72 hours after initiation of therapy. 
 
If coagulopathy is suspected, monitoring of the following additional laboratory tests is 
strongly recommended: 
 
Prothrombin and activated partial thromboplastin times 
 
Fibrinogen 
 
D-dimer 
 
To manage hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia, 
the following is required: 


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 
Begin allopurinol 
 
Institutional guidelines for dosing and administration should be followed. 
 
Continue until peripheral blasts and extramedullary disease have been reduced.  
 
Treatment with Rasburicase should be considered for subjects with severe 
hyperuricemia, oliguria, or severe renal dysfunction. 
 
Screening for glucose-6-phosphate dehydrogenase deficiency prior to 
Rasburicase administration is strongly recommended. 
 
Institutional guidelines for dosing and administration should be followed. 
 
Hydrate at least 100 125 mL/m²/h to maintain urine output at least 3 mL/kg/h 
 
Continue until peripheral blasts and extramedullary disease have been 
reduced. 
 
Institutional guidelines for administration should be followed. 
 
If institutional practice includes alkalinization, alkalinize urine to maintain urine 
pH 6.5 to 7.5. 
 
The regimen for alkalinizing urine is at the investigator’s discretion. 
 
Institutional guidelines for dosing and administration should be followed. 
 
Alkalinization is not recommended when treating with Rasburicase. 
22.1.6.2 
Blood Products 
 
Blood products are provided at the discretion of the investigator. 
 
Institutional guidelines for administration should be followed. 
22.1.6.3 
Pneumocystis Jiroveci Prophylaxis 
 
Pneumocystis prophylaxis (PCP) must be provided throughout the study period. 
 
Oral administration of TMP SMX is preferred and is recommended to be 
administered twice weekly on consecutive days or per local standard of care.  
Alternative agents, such as dapsone, atovaquone, or aerosolized or IV pentamidine 
may be used if there is a documented contraindication to TMP SMX or significant 
concern for bone marrow suppression.  The rationale for use of an alternative agent 
should be specified in the eCRF. 
 
Institutional guidelines for dosing and administration should be followed. 
 
For subjects with delayed recovery of peripheral blood counts investigators should 
consider replacing TMP-SMX after day 22 of induction with alternative therapy until 
recovery of bone marrow function, Atovoquone, aerosolized or IV pentamidine, 
dapsone, or other agent per institutional standards may be considered as short-term 
alternative to TMP-SMX. 
22.1.6.4 
Fungal Prophylaxis 
 
Fungal prophylaxis must be provided during periods of neutropenia (ANC less 
than 500/L) from the Induction Cycle through the end of study treatment. 


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 
Echinocandin (ie, caspofungin, micafungin, or anidulafungin) or amphotericin agents 
are acceptable. 
 
Institutional guidelines for dosing and administration should be followed. 
 
Provide treatment level doses, rather than prophylactic doses. 
 
Azole antifungal agents (ie, fluconazole, itraconazole, voriconazole, or 
posaconazole) given concurrently with vincristine may increase risk of neurotoxicity 
and their use as prophylaxis is not permitted. 
22.1.6.5 
Herpes Virus Prophylaxis 
 
Herpes simplex virus (HSV) prophylaxis must be provided throughout the study 
period for subjects with a history of documented or suspected HSV or varicella zoster 
virus infection. 
 
Acyclovir or valacyclovir are acceptable. 
 
Institutional guidelines for dosing and administration should be followed. 
22.1.6.6 
Bacterial Prophylaxis 
 
Bacterial prophylaxis during periods of neutropenia is strongly recommended, due to 
the high risk for serious bacterial infections in this population.  Prophylaxis should 
continue until post-nadir myelorecovery and include appropriate coverage for 
gram-negative species and expanded gram-positive coverage. 
 
Institutional guidelines for dosing and administration should be followed. 
22.1.6.7 
Intravenous Immunoglobulin Supplementation 
 
Intravenous immunoglobulin (IVIg) supplementation for subjects with 
hypogammaglobulinemia (less than 500 mg/dL) is recommended, due to the high 
risk for infections in this population.  IV Ig infusions should use concentrations no 
greater than 5 g/dL to avoid renal toxicity. 
 
Institutional guidelines for dosing and administration should be followed. 
22.1.6.8 
Central Line Care 
 
Measures to minimize the risk for catheter associated serious bacterial infections 
must be taken throughout the study period. 
 
The specific regimen for central line care should be consistent with institutional 
guidelines. 
22.1.6.9 
Fever and Neutropenia 
22.1.6.9.1 
Definition 
 
Fever and neutropenia is defined as a temperature greater than or equal 38.5C on a 
single occasion, or greater than 38C on 2 occasions within 2 hours, and an ANC 
less than 0.50 x 109/L. 
22.1.6.9.2 
Evaluation 
 
Blood cultures should be obtained from all lumens. 
 
Additional cultures (urine, cerebral spinal fluid [CSF], respiratory, etc) are obtained at 
the investigator’s discretion and should be based on the specific clinical presentation. 


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 
Chest radiographs and other imaging studies are obtained at the investigator’s 
discretion and should be based on the specific clinical presentation. 
22.1.6.9.3 
Treatment 
 
Prompt empiric broad spectrum coverage for both gram-negative and gram-positive 
bacterial infection must be provided IV as soon as possible. 
 
Additional gram-negative coverage and glycopeptide agents are at the investigator’s 
discretion and should be based on the specific clinical presentation. 
 
Antifungal, antiviral, and other additional agents are at the investigator’s discretion 
and should be based on the specific clinical presentation. 
 
Institutional guidelines for dosing and administration should be followed. 
22.1.6.9.4 
Persistent or Recurrent Symptoms 
 
If fever persists for greater than 96 hours or recurs after 3 days of treatment, 
surveillance for fungal infections or other occult infections is strongly recommended. 
 
Studies to consider include, but are not limited to: 
 
Computed tomography (chest, sinuses, abdomen/pelvis, etc) 
 
Bronchoalveolar lavage 
 
Viral PCR (adenovirus, Epstein Barr virus, cytomegalovirus, COVID 19, etc) 
 
If not already part of the treatment regimen, treatment dose antifungal therapy should 
be initiated. 
 
Although prohibited for prophylaxis, azoles may be provided at the investigator’s 
discretion. 
 
Institutional guidelines for dosing and administration should be followed. 
 
The addition of other antimicrobial agents should be seriously considered and is at 
the investigator’s discretion. 
 
Institutional guidelines for dosing and administration should be followed. 
22.1.6.10 
Myeloid Growth Factors 
Investigators are strongly encouraged to administer prophylactic systemic antibiotics 
during periods of neutropenia (ANC less than 500/L).  
 
Granulocyte colony stimulating factors may be administered starting 24 hours after 
the last dose of cytotoxic chemotherapy per investigators discretion and are 
recommended for subjects that are likely to have delayed neutrophil recovery, such 
as multiply relapsed, a history of prior stem cell transplant, or a history of delayed 
neutrophil recovery after cytotoxic chemotherapy based on observations from 
subjects in the phase 1 portion of this study.  Institutional guidelines for dosing and 
administration should be followed. 
 
Administration of myeloid growth factors in response to severe infection or fever and 
neutropenia is at the investigator’s discretion 


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22.1.6.11 
Gastritis Prophylaxis 
 
Prophylaxis with either a histamine 2 (H2) blocker or proton pump inhibitor is 
required during the Induction Cycle. 
 
Continued administration of gastritis prophylaxis during the optional cycle of 
consolidation therapy is at the investigator’s discretion. 
22.1.6.12 
Prevention and Management of Nausea and Vomiting 
 
Prophylactic antiemetic administration is strongly recommended when emetogenic 
chemotherapy, including IT therapy, is administered. 
 
The precise antiemetic regimen is at the investigator’s discretion. 
 
Corticosteroid administration as part of the antiemetic regimen is prohibited. 
 
Institutional guidelines for dosing and administration should be followed. 
 
Intravenous fluids and/or nutrition support should be provided, if nausea or vomiting 
prevent adequate intake of fluids or nutrients. 
22.1.6.13 
Constipation Prophylaxis 
 
Administration of stool softeners and/or laxatives to prevent constipation is strongly 
recommended. 
 
The precise bowel regimen is at the investigator’s discretion. 
 
Institutional guidelines for dosing and administration should be followed. 
22.1.6.14 
Mucositis 
 
Mucositis should be managed with IV hydration, hyperalimentation, and analgesia, 
as indicated.  In addition, consider coverage with broad spectrum gram-positive and 
gram-negative empiric antibiotic therapy and empiric antiviral and antifungal therapy, 
as indicated. 
22.1.6.15 
Contraception 
Contraception requirements are provided in Section 29. 
22.1.6.15.1 
Female of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered of childbearing potential: 
1. Premenopausal female with 1 of the following: 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
Note:  Site personnel documentation from the following sources is 
acceptable:  1) review of subject medical records, 2) subject medical 
examination, or 3) subject medical history interview. 


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2. Premenarchal female 
3. Postmenopausal female 
a. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state 
in women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
b. Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they 
wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
22.1.6.15.2 
Female Subjects  
Female subjects of childbearing potential must agree to use one highly effective method 
of contraception (as described in the table below) during treatment and for an additional 
12 months after the last dose of protocol-required therapies.  Contraception must be in 
place at least 2 weeks prior to the first study treatment. 
Highly Effective Contraceptive Methods for Female Subjects 
Failure rate of less than 1% per year when used consistently and correctly. 
 
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the 
female subject of childbearing potential and that the vasectomized partner has 
received medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments.  The reliability of sexual 
abstinence must be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject.) 
If a female subject is suspected of being pregnant, the protocol-required therapies must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed. 


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22.1.6.15.3 
Male Subjects 
If the male’s sole sexual partner is of non-childbearing potential or has had a bilateral 
tubal ligation/occlusion, he is not required to use additional forms of contraception during 
the study.  The definition of non-childbearing potential is provided above. 
Male subjects with a partner of childbearing potential must agree to not father a child 
during treatment and for an additional 6 months after the last dose of protocol-required 
therapies. 
Contraceptive options for male subjects include: 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies).  The reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject or 
 
Use a condom during treatment and for an additional 6 months after the last dose of 
protocol-required therapies.  
The female partner is to use an acceptable method of effective contraception such as:  
hormonal, IUD, IUS, female barrier method (diaphragm, cervical cap, contraceptive 
sponge [a female condom is not an option because there is a risk of tearing when both 
partners use a condom]).  Male subjects must not donate sperm during treatment and for 
an additional 6 months after the last dose of protocol-required therapies. 
Male subjects with a pregnant partner must practice sexual abstinence or wear a 
condom to prevent exposure of the unborn child to study drugs through semen. 
22.1.6.15.4 
Unacceptable Methods of Birth Control for Male and Female 
Subjects 
Birth control methods that are considered unacceptable in clinical trials include:  periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method. 
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to fetus if they become pregnant or father a child 
during treatment and for 6 months after the last dose of protocol-required therapies.  
22.1.7 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device(s) after it is released for 
distribution to market or clinic by either (1) Amgen or (2) distributors or partners for 


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whom Amgen manufactures the material.  This includes all components distributed with 
the drug, such as packaging drug containers, delivery systems, labeling, and inserts.  
This includes any investigational product provisioned and/or repackaged/modified by 
Amgen including carfilzomib. 
Any product complaint(s) associated with an investigational product supplied by Amgen 
are to be reported. 
22.1.8 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
 
The following treatments are excluded: 
 
Marketed or investigational anticancer therapeutics that are not a component of 
this treatment regimen 
 
Radiotherapy, except as clinically indicated for control of life-threatening 
symptoms related to CNS or mediastinal mass 
 
Investigational agents for non-neoplastic conditions 
 
See Section 22.1.6.4 and Section 22.1.6.9.4, and Section 22.1.6.10 for 
instructions about azole antifungal agents and myeloid growth factors, 
respectively, as their administration is restricted to certain circumstances.  
22.2 
Dose Modification 
22.2.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Carfilzomib may be discontinued, temporarily delayed, or dosage temporarily reduced, in 
the event of a treatment-related toxicity that, in the opinion of the investigator, warrants 
discontinuation, temporary delay or dose reduction.  Carfilzomib must be temporarily 
interrupted and/or reduced or discontinued based on toxicities indicated in Table 25.  
Dose levels for decreasing carfilzomib are in Table 24.  Subjects requiring a temporary 
dose interruption due to infection related adverse events may resume treatment at the 
same dose once the subject is stable and the infection is under control.  Subjects that 
require dose reduction due to toxicities listed in Table 25 should remain at that reduced 
dose level (unless a subsequent dose reduction is required) until the end of the cycle.   
Subjects continuing on to the optional consolidation therapy may be rechallenged with 
same dose carfilzomib at the investigator’s discretion.  If the toxicity recurs after the 
subject is rechallenged, omit until improved to grade indicated in Table 25 and then 
resume at 1 dose level lower as shown in Table 25.  For the phase 2 part of the study, 
the guidance provided in the dose modification table (Table 25) supersedes guidance for 
carfilzomib dose reductions provided in Sections 8.2 and 8.4.1. 


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Dose modification guidelines for chemotherapy agents that are part of the VXLD 
regimen are provided in Sections 8.4.2 through 8.4.10. 
Table 24.  Example Dose Decrements for Carfilzomib 
Nominal Dose 
(mg/m2) 
Reduced Carfilzomib Doses (mg/m2) 
Dose -1 
Dose -2 
Dose -3 
56 
45 
36 
27 
Table 25.  Dose Modification Table for Carfilzomib 
Symptom/Sign/Investigation 
Recommended Action 
Carfilzomib 
Tumor lysis syndrome 
Therapy is not interrupted for tumor lysis 
syndrome unless there are life-threatening 
clinical or laboratory findings 
 
 grade 3 
 
grade 4 life-threatening sequelae 
See Section 22.1.6.1 for management recommendations 
 
 
 
No adjustment 
 
Withhold carfilzomib until resolution to  grade 4 then 
resume at full dose 
Thrombotic microangiopathy (TMA) 
Fever, microangiopathic hemolytic 
anemia, thrombocytopenia, renal failure, 
neurologic changes 
If the diagnosis is suspected, withhold carfilzomib and 
manage per standard of care including plasma exchange as 
clinically appropriate.  If TMA is confirmed, permanently 
discontinue.  If the diagnosis of TMA is excluded, carfilzomib 
dosing may be resumed. 
Cardiovascular and pulmonary 
Congestive heart failure (CHF): 
New onset or worsening CHF 
 
 
 
 grade 3 
 
 
 grade 3 
Regardless of the attribution to study drug, hold the 
carfilzomib until resolution of CHF or return to baseline.   
Appropriate medical management should be initiated.  If no 
resolution or return to baseline after 4 weeks, permanently 
discontinue carfilzomib. 
 
Once congestive heart failure resolves or returns to 
baseline, resume at full dose. 
 
Once CHF resolves or returns to baseline, reinstate 
carfilzomib at 1 dose level reduction.   
Pulmonary Toxicities: 
Noninfectious interstitial lung disease, 
acute respiratory failure, ARDS 
(grade  3) 
Withhold carfilzomib until resolved to grade 1 or baseline.  
Resume at 1 level dose reduction 


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Hypertension (defined based on blood pressure measurements adjusted for children per standard 
pediatric practice, mean of 3 resting measurements). 
General guidelines for management of hypertension per American Association of Pediatrics (AAP) are 
provided in Flynn et al, 2017.  Management of hypertension should be according to AAP guidelines or per 
institutions standard practice.  
grade  3 
 
 
grade  3 
Continue at same dose if initiation of appropriate treatment 
controls hypertension per institutional practice  
 
Withhold carfilzomib until blood pressure returns to normal 
or baseline.  Initiate appropriate anti-hypertensive therapy 
prior to resuming therapy at 1 dose level reduction 
Pulmonary hypertension (grade  2) 
Withhold carfilzomib until resolution to grade 1 or baseline 
and restart at 1 dose decrement. 
Venous thrombosis/embolism grade  3 
Withhold dose and adjust anticoagulation regimen; resume 
at full dose once anticoagulation has been optimized per 
treating investigators discretion. 
Infections and infestations 
Infection grade 4 
 Withhold carfilzomib until the infection is controlled and 
signs of cardiopulmonary instability have resolved.   
 If subject has competed day 22 chemotherapy 
recommend initiation of granulocyte colony stimulating 
factor (GCSF) 24 hours after last dose of cytotoxic 
chemotherapy 
  If subject has not competed day 22 chemotherapy 
consider omitting day 22 therapy and initiating GCSF 
based on risk benefit assessment 
Hepatitis B reactivation 
 Withhold carfilzomib until infection is adequately 
controlled 
 Resumption of carfilzomib may be considered in subjects 
whose hepatitis B reactivation is controlled and where 
the benefits of study therapy outweigh the risks 
Hepatic dysfunction and related investigations 
grade  3 elevation in bilirubin 
( 3 x ULN), ALT and/or AST  
( 5 x ULN) 
 
 
 
 
 
 Drug induced hepatotoxicity attributable 
to carfilzomib 
 If attributed to carfilzomib withhold until resolution to 
baseline and monitor twice weekly.  Resume carfilzomib 
with 1 dose level reduction for remainder of cycle, if 
drug-induced hepatoxicity is excluded.   
 If reduced dose is tolerated for the remainder of the cycle, 
the dose may be re-escalated to full dose in next cycle 
(consolidation) if applicable and if drug induced 
hepatotoxicity is excluded. 
 
 
Discontinue carfilzomib 
Peripheral neuropathy 
Grade 3 or grade 2 with pain 
If attributed to carfilzomib, withhold until resolved to 
 grade 2 without pain, then resume carfilzomib at 1 dose 
level reduction. 
Grade 4 
Discontinue 


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Posterior reversible encephalopathy (PRES) 
Variable combination of altered mental 
status, vision changes, seizure, 
hypertension, headaches 
If PRES is suspected, withhold carfilzomib.  Evaluate with 
neuroradiological assessment for radiographic evidence of 
PRES.  If diagnosis is confirmed, permanently discontinue 
carfilzomib.  If diagnosis excluded and clinically appropriate, 
may resume at previous dose. 
Dyspnea 
Dyspnea (grade  2) 
Withhold carfilzomib until resolution to grade 1 or baseline, 
then resume at 1 dose decrement. If caused by another 
adverse event listed in this table, follow recommendations 
for that adverse event. 
Renal dysfunction 
CrCl 15 mL/min/1.73 m2  
Full dose, unless the reduction is to  50 of baseline 
clearance then withhold dose and monitor renal function 
until recovery, resume at same dose 
CrCl  15 mL/min/1.73m2 (grade 4) not 
requiring dialysis 
Withhold dose and monitor.  If toxicity is due to carfilzomib, 
reduce dose by 1 dose level when renal function recovers to 
25 of baseline.  If renal toxicity is not related to carfilzomib, 
resume dose at the discretion of the investigator. 
CrCl  15 mL/min/1.73m2 (grade 4) 
requiring dialysis 
Withhold dose until CrCl returns to  15 mL/minute then 
resume same dose.  If dialysis required use the maximal 
dose of 20 mg/m2 and administer carfilzomib after dialysis. 
Other non-hematologic toxicity 
 
Any drug-related grade  3 
non-hematologic toxicity not previously 
listed 
For carfilzomib attribution, withhold carfilzomib until toxicity 
resolves to  grade 1 or baseline, resume at 1 dose level 
lower and complete cycle 
Progressive multifocal leukoencephalopathy (PML) 
New or worsening neurologic, cognitive or 
behavioral signs or symptoms that may be 
suggestive of PML 
If PML is suspected, withhold administration of carfilzomib; 
patients should be promptly referred to a specialist and 
appropriate diagnostic testing should be initiated.  
Discontinue carfilzomib if PML diagnosis is confirmed. 
22.2.1.1 
Amgen Investigational Product:  Carfilzomib 
The reason for dose change of carfilzomib is to be recorded on each subject’s eCRF. 
22.2.1.2 
Amgen/Non-Amgen Non-Investigational Product:  VXLD, Modified 
BFM, and Intrathecal Chemotherapy 
The reason for dose change of any non-investigational product(s) is to be recorded on 
each subject’s eCRF(s). 
22.2.1.3 
Dose Modifications for Modified Infant Consolidation 
Follow guidance in Sections 8.4.2 to 8.4.10 with the following exceptions: 
Cyclophosphamide  
In presence of macroscopic hematuria, omit.  If there is a history of previous significant 
hematuria, hydrate before cyclophosphamide until specific gravity is less than 1.010 and 
hydrate at 125 mL/m2/hr for 24 hours after dose.  Monitor for adequate urine output as 
per institution guidelines.  Give IV mesna at a total dose that is 60% of the 
cyclophosphamide dose divided to 3 doses (eg, if the cyclophosphamide dose is 


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1000 mg/m2, the total mesna dose is 600 mg/m2 or 200 mg/m2/dose).  Give the first 
mesna dose 15 minutes before or at the same time as the cyclophosphamide dose and 
repeat 4 and 8 hours after the start of cyclophosphamide.  This total daily dose of mesna 
can also be administered as IV continuous infusion.  The continuous infusion should be 
started 15 to 30 minutes before or at the same time as cyclophosphamide and finished 
no sooner than 8 hours after the end of cyclophosphamide infusion. 
Cytarabine (IV or SC) 
Subjects should have ANC greater than or equal to 300/L and platelets greater than or 
equal to 30 000/L to start each 4-day cytarabine block.  Once a 4-day block has 
started, do not interrupt for uncomplicated myelosuppression. 
Do not withhold cytarabine for fever if it is likely to have been caused by the cytarabine.  
Obtain blood cultures if a central line is present.  For rash or conjunctivitis, withhold for 
grade 3 to 4 toxicity until resolved.  Make up missed doses and consider concurrent 
treatment with hydrocortisone or dexamethasone, and/or with dexamethasone 
ophthalmic drops for conjunctivitis. 
Mercaptopurine 
If possible, mercaptopurine therapy should not be interrupted.  If a cytarabine block has 
to be postponed or interrupted, then mercaptopurine should also be interrupted.  Omitted 
mercaptopurine doses should be made up until the planned cumulative total dose 
1680 mg/m2 (60 mg/m2 x 28 doses) for subjects greater than or equal to 12 months, 
1260 mg/m2 (45 mg/m2 x 28 doses) for infants 6 to less than 12 months, 1120 mg/m2 
(40 mg/m2 x 28 doses) for infants less than 6 months.   
IT Methotrexate 
Systemic toxicity:  the dosage for IT methotrexate will not be reduced for systemic 
toxicity (myelosuppression, mucositis, etc).  Instead, leucovorin may be used at a dose 
of 5 mg/m2/dose every 12 hours x 2 doses, beginning 48 hours after the IT therapy has 
been delivered.  This may reduce the risk of worsening already existent 
myelosuppression (ANC less than 500/L) or mucositis.  Do not administer leucovorin 
solely to prevent myelosuppression. 
22.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided separately. 


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22.4 
Measures to Minimize Bias:  Randomization and Blinding 
22.4.1 
Method of Treatment Assignment 
Subjects who meet eligibility criteria will be assigned to treatment with CFZ-VXLD. 
22.4.2 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
22.5 
Treatment Compliance 
Administration of IV or SC medicinal products will occur at the study center.  Oral 
medication may be administered at the center or dispensed for self-administration at 
home.  Subjects/subject’s legal representatives are to document all administered doses 
and missed doses in a medication diary for all study-required medication taken at home.  
22.6 
Treatment of Overdose 
There is no specific antidote for carfilzomib.  Therapy for overdose involves monitoring 
and management of acute side effects until the subject is stable. 
22.7 
Prior and Concomitant Treatment 
22.7.1 
Prior Treatment 
Prior therapies for ALL that were being taken/used from time of diagnosis through the 
signing of the informed consent will be collected. 
22.7.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 22.1.8. 
Concomitant therapies are to be collected from time of informed consent through the 
safety follow-up visit. 
23. 
Phase 2:  Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 23.1 and 23.2. 


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23.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see Table 14) 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
and must document this decision in the subject’s medical records.  Subjects who have 
discontinued investigational product and/or other protocol-required therapies or 
procedures should not be automatically removed from the study.  Whenever safe and 
feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with Section 27. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments (during induction and/or consolidation) may include any of the 
following: 
 
Decision by sponsor 
 
Lost to follow-up 
 
Adverse Event 
 
Subject Request 
 
Subject or their legally acceptable representative withdraws consent for study 
treatment 
 
Requirement for alternative therapy 
 
Noncompliance with study procedures, including administration of prohibited 
medications 
 
Pregnancy  
 
Death 
 
Ineligibility determined 
 
Protocol Deviation 
 
Disease Progression 


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23.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject, or legal guardian, does not 
wish for the subject to receive further protocol-required therapies or procedures, and the 
subject does not wish to or is unable to continue further study participation.  Subject data 
up to withdrawal of consent will be included in the analysis of the study, and where 
permitted, publicly available data can be included after withdrawal of consent.  The 
investigator is to discuss with the subject, or legal guardian, appropriate procedures for 
withdrawal from the study, and must document the subject’s decision to withdraw in the 
subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 30 for further details).  Refer to the Schedule of Activities (Table 14) for data to 
be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
23.2.1 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
23.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  


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 
For subjects who are lost to follow-up, the investigator can search publicly available 
records where permitted to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 
24. 
Phase 2:  Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Section 17.11.2).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
24.1 
General Study Periods 
24.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject/legal 
representative has signed the informed consent form, the site will register the subject in 
the IRT and screen the subject in order to assess eligibility for participation.  The 
screening window is up to 7 days before day 1.  
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 21.4) as applicable.  Bone marrow aspirate must be 
obtained and a morphologic diagnosis of relapsed or refractory ALL must be determined 
prior to study enrollment.  In the event that aspirate cannot be obtained, diagnosis may 
be made by biopsy.  It is not necessary for the results of immunophenotyping or 
cytogenetic studies to be available prior to enrollment or the initiation of study treatment. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening up to 3 times.  
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 
7 day/week screening window will begin.  Subjects will retain the same subject 
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more than 7 days after the original signing of the informed consent form, all screening 
procedures, including informed consent, must be repeated. 
24.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Section 17.11.2).  The date of the first 
dose of carfilzomib is defined as day 1.  All subsequent doses and study visits will be 
scheduled based on the day 1 date.  Investigational products are to be administered 
after all other assessments have been completed, unless otherwise specified, during 
each visit that it is required. 
24.1.3 
Safety Follow-up 
The safety follow-up visit is to be performed 30 days after the last dose of protocol 
specified systemic anti-leukemia therapy in induction or consolidation whichever is later, 
or prior to next therapy following induction if not proceeding to optional consolidation, or 
prior to next therapy after consolidation. 
24.1.4 
Long-term Follow-up 
After discontinuation from study treatment, subjects are to continue follow-up every 
12 weeks for up to 2 years after the safety follow-up, death, subject is lost to follow-up, 
or the sponsor decides to close the study, or the last living subject completes the safety 
follow-up, whichever comes first.  The information collected in this phase includes 
relapse date (if applicable), date of subsequent treatment with stem cell transplant (if 
applicable), date of treatment start with subsequent immune therapy, if applicable 
(blinatumomab, inotuzumab, or CAR-T), and vital status. 
Disease response assessments, including subsequent ALL therapies, and survival 
information will be collected as indicated in the Schedule of Activities. 
24.1.5 
End of Study for Individual Subjects 
The end of study for each subject is defined as the date of whichever of the following 
occurs first:  subject completes the safety follow-up or long-term follow-up (whichever is 
later), subject discontinues the study due to death, subject is lost to follow-up, subject 
withdraws full consent from the study, last surviving subject enrolled in the study 
completes the safety follow-up triggering the end of the study, or the sponsor decides to 
close the study.  
24.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 


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24.2.1 
General Assessments  
24.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC and Amgen approved informed consent before any study-specific procedures 
are performed. 
24.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected to 
study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on 
 
and PK of the protocol-required therapies.  
24.2.1.3 
Medical History 
Medical history will include collecting information on the subject's significant medical 
conditions, prior surgeries, and neuropathy history, dating back to the original diagnosis.  
Record all findings on the medical history eCRF.  The current toxicity grade will be 
collected for each condition that has not resolved.  Cardiovascular risk factors, which 
include family history of cardiovascular disease and smoking history, will also be 
collected.   
In addition to the medical history above, ALL history must date back to the original 
diagnosis. 
24.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
24.2.1.5 
Physical Measurements 
Height (in centimeters) should be measured without shoes.  Weight (in kilograms) should 
be measured without shoes.  
Body surface area should be calculated using the Mosteller Formula (Mosteller, 1987):   
BSA (m²) = ([Height(cm) × Weight(kg)]/3600) ½. 
24.2.1.6 
Substance Abuse History 
Obtain a detailed history of prior and/or concurrent use of tobacco. 
24.2.1.7 
Karnofsky and Lansky Performance Status  
Performance status will be assessed by the Karnofsky and Lansky scales (Appendix F).  
Performance status will be included in the physical examination (Section 24.2.1.4). 


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24.2.2 
Efficacy Assessments 
24.2.2.1 
Response Assessment 
Response assessments will be performed by the investigator at the timepoints indicated 
in the Schedule of Activities (Table 14, Table 16, Table 18, and Table 20).  Bone marrow 
aspiration, lumbar puncture, extramedullary disease assessment, and CBC with 
differential and platelets will be performed to assess the disease status.  Lumbar 
puncture to assess disease status will not be required after the second lumbar puncture 
for subjects who are CNS-negative.  Subjects who are CNS-positive must have 
2 consecutive lumbar punctures without evidence of leukemia, before lumbar puncture is 
no longer required for assessment of disease status. 
During the recovery window from day 29 through day 45 (day 36 to 50 for infants) after 
induction or consolidation if applicable, peripheral blood counts with differential should 
be obtained weekly and on the day of the bone marrow assessment.  If clinically feasible 
subjects should be allowed to recover marrow function and peripheral blood counts prior 
to performing the bone marrow.  Count recovery within 7 days of the bone marrow may 
be used to assign response status, assuming all other requirements for response are 
met.  In subjects that do not proceed to consolidation or next therapy before day 45 
(day 50 for infants), peripheral blood counts with differential should be obtained on 
day 45 (day 50 for infants).  In the event that multiple bone marrow assessments are 
performed during the day 29 to 45 (or day 36 to 50 for infants) window and multiple 
assessments of M1 (less than 5% blasts) or NE, the investigator should report the best 
response level with the order from best to worst being CR, CRp, complete remission with 
partial hematologic recovery (CRh), CRi, NE.  Subjects whose response at any time 
during the response window is SD or PD should retain that response. 
A portion of the bone marrow collected at the time of these response assessments will 
be submitted to a central laboratory, for determination of MRD.  Additional stained slides 
of bone marrow aspirate (or biopsy if aspirate is not available) and peripheral blood will 
be submitted to central laboratory for histological examination, full instructions for 
collection and submission are provided separately. 
The criteria for determining treatment response are defined in Table 26.   


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Table 26.  Treatment Response Definitions 
Complete remission 
(CR) 
- Attainment of M1 bone marrow status (less than 5% blasts in a bone marrow 
aspirate and at least 200 cells counted) with no evidence of circulating blasts 
or extramedullary disease 
- Recovery of peripheral counts:  
 
ANC greater than or equal to 1000/L 
 
Platelets greater than or equal to 100 000/L 
Complete remission 
without platelet recovery 
(CRp) 
- Attainment of M1 bone marrow status with no evidence of circulating blasts 
or extramedullary disease 
- Recovery of peripheral counts:  
 
ANC greater than or equal to 1000/L 
 
Platelet count less than 100 000/L 
Complete remission 
with partial hematologic 
recovery (CRh) 
- Attainment of M1 bone marrow status with no evidence of circulating blasts 
or extramedullary disease 
- Recovery of peripheral counts:  
 
ANC greater than or equal to 500/L but less than 1000/L 
 
Platelet count greater than or equal to 50 000/L but less than 
100 000/L 
Complete remission 
with incomplete 
hematologic recovery 
(CRi) 
- Attainment of M1 bone marrow status with no evidence of circulating blasts 
or extramedullary disease 
- ANC and platelet counts not fulfilling criteria for CRh, CRp, or CR  
Stable disease (SD) 
Subject has an evaluable bone marrow and does not satisfy the criterion for 
PD, fails to qualify for CR, CRp, CRh, or CRi 
Non-evaluable 
Subject does not qualify for PD based on peripheral blood blasts or 
extramedullary disease progression, and neither bone marrow aspirate or 
biopsy are adequate for pathological evaluation  
Progressive disease 
(PD) 
An increase from baseline (or nadir) of greater than or equal to 25% in bone 
marrow blasts, an absolute increase in the number of circulating leukemia 
cells of at least 5000 cells/L, development of new sites of extramedullary 
disease, or a greater than or equal to 50% increase in size of previously 
involved sites from nadir 
ANC = absolute neutrophil count; CR = complete remission; CRh = complete remission with partial 
hematologic recovery; CRi = complete remission with incomplete hematologic recovery; CRp = complete 
remission with incomplete recovery of platelets; PD = progressive disease; SD = stable disease 
Note:  When criteria are met for more than 1 response level the response level to report is the one indicating 
the highest bone marrow recovery with the order of recovery being CR > CRp > CRh > CRi.  When criteria 
are met for both CRi and blast-free marrow, CRi should be reported. 
Reference:  NCCN, 2022; Shallis et al, 2021 


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24.2.2.1.1 
Bone Marrow Aspirate 
Bone marrow aspirates will be obtained for morphologic diagnosis of relapsed or 
refractory ALL.  Stained aspirate slides from the same pull used by the local laboratory 
to determine response will be submitted for central laboratory histological review to 
evaluate response. 
Bone marrow aspirate must be obtained and a morphologic diagnosis of relapsed or 
refractory ALL must be determined prior to study enrollment.  In the event that aspirate 
cannot be obtained, diagnosis may be made by biopsy.  It is not necessary for the 
results of immunophenotyping or cytogenetic studies to be available prior to enrollment 
or the initiation of study treatment.  Bone marrow status definitions are provided in 
Table 2.  The results of the local laboratory are applicable for inclusion into the study and 
to start study treatment if the results of the central laboratory are not yet available at the 
time these decisions are made.   
The priority order of collection for the screening bone marrow aspirate sample, based on 
the volume and quality of sample obtained: 
 
Morphological diagnosis  
 
MRD by NGS centrally 
 
MRD by flow cytometry/PCR locally 
24.2.2.1.2 
Minimal Residual Disease Assessment 
MRD assessment will be conducted in a central laboratory using next generation 
sequencing (NGS) by Adaptive.  MRD testing as needed for clinical care may be done 
by a local laboratory using PCR or NGS and/or flow cytometry. 
Bone marrow obtained during screening will be submitted to a central laboratory to 
facilitate the analysis of MRD by NGS.  If adequate bone marrow aspirate for MRD 
cannot be collected, peripheral blood will be obtained prior to treatment and stored for 
Bone marrows 
performed as part of routine medical care may be used for central lab MRD assessment. 
Sites that perform local assessment for MRD at end of induction and/or consolidation are 
asked to report the result and method of assessment on the appropriate CRF.  These 
data will be used for 
 (additional details will be provided in the 
statistical analysis plan [SAP]). 


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24.2.2.1.3 
Lumbar Puncture 
Cerebrospinal fluid must be obtained prior to the initiation of study treatment and 
examination must include: 
 
Red blood cell (RBC) count 
 
White blood cell (WBC) count 
 
Differential 
 
Cytology 
It is not necessary for central nervous system (CNS) status to be declared prior to the 
initiation of study treatment.  CNS status must be declared prior to the second scheduled 
lumbar puncture, however, as this informs the treatment regimen from that day on.  CNS 
status definitions are provided in Table 3. 
Subjects with CNS 3 leukemia at baseline will be considered to be CNS-positive and 
treated accordingly.  Subjects with CNS2 status are to be determined to be either CNS 
positive (CNS3) or negative (CNS1) according to local institutional practice.  The 
schedule of IT therapy will be determined by the status declared by the site. 
The first dose of IT chemotherapy may be given with the lumbar puncture obtained 
during screening or at the time relapse is determined if it occurs within 7 days of 
induction day 1, in accordance with institutional practice, and is considered to be part of 
day 1 study treatment, provided that study enrollment and the remainder of day 1 study 
treatment occur within the required timeframe. 
24.2.2.1.4 
Testicular Ultrasound 
Ultrasound or physical exam.  Institutions may substitute alternative methods based on 
standard of practice.  Capture as positive or negative/resolved on the eCRF. 
24.2.2.1.5 
Chest Imaging 
Chest X-ray or institutional standard.  Positive or negative/ resolved on the eCRF. 
24.2.3 
Safety Assessments 
Planned timepoints for all safety assessments are listed in the Schedule of Activities see 
(Table 14, Table 16, Table 18, and Table 20). 
24.2.3.1 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.   


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Subject must be in a supine position in a rested and calm state for at least 5 minutes 
before blood pressure assessments are conducted.  If the subject is unable to be in the 
supine position, the subject should be in most recumbent position as possible.  The 
position selected for a subject should be the same that is used throughout the study and 
documented on the vital signs eCRF.  The temperature location selected for a subject 
should be the same that is used throughout the study and documented on the vital signs 
eCRF. 
24.2.3.2 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The ECG must 
include the following measurements: heart rate, QRS, QT, QTc, and PR intervals.  The 
principal investigator (or eg, designated site physician, central reader) will review all 
ECGs.  Once signed, the original ECG tracing will be retained with the subject's source 
documents.  At the request of the sponsor, a copy of the original ECG will be made 
available to Amgen.   
24.2.3.3 
Echocardiograms (ECHOs) 
All subjects will have a baseline ECHO, including assessments of systolic and diastolic 
left ventricular function and right ventricular function. 
Subjects with clinical symptoms of congestive heart failure during or after induction 
should have an echocardiogram to evaluate cardiac function prior to initiation of the 
optional consolidation. 
24.2.3.4 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
24.2.4 
Adverse Events and Serious Adverse Events  
24.2.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
24.2.4.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 and is described in 
Section 28. 


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The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after signing of the informed 
consent/assent through the safety follow-up visit or 30 days after the last dose of 
investigational product/protocol-required therapies, whichever is later, are reported using 
the Events CRF. 
24.2.4.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent/assent through the safety follow-up visit or 30 days after the last dose of 
investigational product/protocol-required therapies, whichever is later, are reported using 
the Events CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee immediately and no later than 24 hours of the investigator’s awareness of the 
event, as indicated in Section 28.  The investigator will submit any updated serious 
adverse event data to the sponsor immediately and no later than 24 hours of it being 
available. 
Since the criteria for the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events, if adverse events correspond to grade 4 CTCAE toxicity grading 
scale criteria (eg, laboratory abnormality reported as grade 4 without manifestation of life 
threatening status), it will be left to the investigator’s judgment to also report these 
abnormalities as serious adverse events.  For any adverse event that applies to this 
situation, comprehensive documentation of the event’s severity must be recorded in the 
subject medical records. 
24.2.4.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
During the long-term follow-up period, if the investigator becomes aware of serious 
adverse events suspected to be related to investigational product after the 
protocol-required reporting period (as defined in Section 24.2.4.1.2) is complete, then 
these serious adverse events will be reported to Amgen.  The investigator will report 
serious adverse events to Amgen immediately and no later than 24 hours following the 
investigator’s awareness of the event on the Events CRF.   
There is no requirement to actively monitor study subjects after the study has ended with 
regards to study subjects treated by the investigator.  However, if the investigator 
becomes aware of serious adverse events suspected to be related to investigational 


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product, then these serious adverse events will be reported to Amgen immediately and 
no later than 24 hours following the investigator’s awareness of the event.  
Serious adverse events reported after the end of the study will be captured within the 
safety database as clinical trial cases and handled accordingly based on relationship to 
investigational product.  
If further safety related data are needed to fulfill any regulatory reporting requirements 
for a reportable event, then additional information may need to be collected from the 
subject’s records after the subject ends the study.  
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 28. 
24.2.4.1.4 
Safety Endpoints that are Study Endpoints 
Safety endpoints (eg, mortality) that are study endpoints are reported on the Events 
CRF.  All endpoints that also meet the criteria of serious adverse events must also be 
transmitted to safety immediately and no later than 24 hours of the investigator’s 
awareness of the event (refer to Section 28).  
24.2.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
24.2.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 23.3).  
Further information on follow-up procedures is given in Section 28. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following awareness of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Events CRF. 


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24.2.4.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
24.2.4.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
24.2.4.5.1 
Adverse Events of Special Interest 
The events of special interest for this protocol include the following: 
 
cardiac toxicity (cardiac failure, myocardial ischemia, myocardial infarction, 
and cardiac arrest) 
 
pulmonary toxicities (acute respiratory distress syndrome, acute respiratory 
failure, acute diffuse infiltrative pulmonary disease such as pneumonitis and 
interstitial lung disease) 
 
pulmonary hypertension 
 
dyspnea 
 
hypertension including hypertensive crises 
 
acute renal failure 
 
hemorrhage and thrombocytopenia 
 
tumor lysis syndrome (TLS) 
 
infusion reactions 


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 
hepatic toxicity 
 
venous thromboembolism 
 
hepatitis B virus (HBV) reactivation 
 
thrombotic microangiopathy 
 
posterior reversible encephalopathy syndrome (PRES) 
 
progressive multifocal leukoencephalopathy 
Investigators should monitor subjects for signs and symptoms of these risks.  
These risks are monitored by the procedures and laboratory tests described in the 
schedule of activities (eg, vital signs, hematology and chemistry laboratories, 
ECG, echocardiogram, or other clinically indicated tests) and should be reported 
by the Investigator to Amgen as adverse events or serious adverse events as per 
requirements described above (Refer to the Schedule of Activities [Table 14, 
Table 16, Table 18, and Table 20]).  The management of these risks is described in 
Table 25.  For additional information on these adverse events of special interest 
and other potential adverse reactions of carfilzomib, please refer to the 
Carfilzomib Investigator’s Brochure. 
24.2.4.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of 
male subjects will be collected after the start of study treatment and until 6 months after 
the last dose of any study treatment or for up to 12 months if subject received 
cyclophosphamide in optional consolidation cycle. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in Section 29.   
Amgen Global Patient Safety will follow-up with the investigator regarding additional 
information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 29. 
24.2.5 
Clinical Laboratory Assessments 
Refer to Section 26 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 14, Table 16, Table 18, and Table 20.) for the timing and 
frequency.  


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The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values.  In general, abnormal 
laboratory findings without clinical significance (based on the investigator's judgment) 
are not to be recorded as adverse events.  However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events.  
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event. 
Pregnancy Testing 
A high sensitivity (urine or serum) pregnancy test should be completed at screening for 
females of childbearing potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, see Figure 7).  Refer to Section 29 for contraceptive requirements.  
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
Hepatitis B Testing 
All hepatitis testing will be performed locally.  All subjects will be tested at screening for 
hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and 
hepatitis B core antibody (anti-HBc), unless performed within 6 months of screening and 
there was no change in the subject’s risk factors within these 6 months.  Subjects with 
positive testing or a history of prior HBV infection should have consultation with a 
specialist and must have HBV-DNA testing at screening and again at safety follow up.  
Subjects that have received Hepatitis B vaccination with only anti-HBs positivity and no 
clinical signs of hepatitis do not require HBV-DNA monitoring.  A repeat HBV-DNA 
should be obtained at SFU only in subjects that required HBV-DNA at screening. 
24.2.6 
Pharmacokinetic Assessments 
All subjects will have pharmacokinetic samples assessed. 
Blood samples will be collected for measurement of plasma concentrations of carfilzomib 
as specified in the Schedule of Activities (Table 14, Table 16, Table 18, and Table 20).  


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25. 
Phase 2:  Statistical Considerations 
25.1 
Statistical Hypotheses 
The primary hypothesis is that CFZ-VXLD is superior to standard-of-care with regards to 
CR rate.  This corresponds to evaluating whether the 95% CI for adjusted odds ratio 
(OR) between CR rate of CFZ-VXLD subjects versus external control subjects excludes 
1 for each phenotype (B-cell/T-cell) independently. 
25.2 
Sample Size Determination 
The sample size was determined based on practical considerations and limited phase 1 
data available as specified in Section 18.2.4.  Due to the rarity of the patient population, 
a minimum of 50 B-cell subjects and a minimum of 30 T-cell ALL subjects are planned to 
be enrolled, in order to reach more than 70 power for testing the primary hypothesis for 
at least one phenotype at 2-sided alpha of 0.05, with an interim futility analysis. 
The external control arm is expected to include approximately 74 B-cell ALL subjects 
and approximately 60 T-cell ALL subjects as per the primary analysis sets 
(B-PAS/T-PAS) included in Study 20180065.  More details will be presented in the 
Study 20180065 protocol which will provide the data for the external control arm. 
For selected objectives, the response and disease status for each subject will be derived 
by the sponsor based upon the local assessments and following the definitions included 
in Table 26. 
Additionally, after appropriate propensity score adjustment, CR rate is expected to be 
25 for B-cell and 15 for T-cell subjects from the external control arm, and 
approximately 60 for B-cell and 30 for T-cell subjects from CFZ-VXLD arm.  As these 
estimates are based on data available so far, additional scenarios proposed for the 
experimental arm CR rates and sample sizes and the power/external control sample 
sizes expected in these cases are included in Table 27.   


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Table 27.  Power Estimates Based on Various Scenarios for Sample Size and 
Hypothesized Relative Effect 
Phenotype 
Control 
Arm 
CRR 
CFZ-VXLD 
Arm CRR 
Control 
Arm 
Sample 
Size 
CFZ-VXLD 
Arm 
Sample 
Size 
Powera 
B-cell  
0.25 
0.5 
74 
50 
0.70 
B-cell  
0.25 
0.55 
74 
50 
0.85 
B-cell  
0.25 
0.6 
74 
50 
0.94 
B-cell  
0.25 
0.5 
66 
56 
0.72 
B-cell  
0.25 
0.55 
66 
56 
0.86 
B-cell  
0.25 
0.6 
66 
56 
0.94 
B-cell  
0.25 
0.5 
62 
60 
0.71 
B-cell  
0.25 
0.55 
62 
60 
0.87 
B-cell  
0.25 
0.6 
62 
60 
0.95 
T-cell  
0.15 
0.3 
60 
30 
0.24 
T-cell  
0.15 
0.3 
60 
40 
0.27 
CFZ-VXLD  carfilzomib combined with VXLD; CRR  complete remission rate; VXLD  vincristine, 
dexamethasone, PEG-asparaginase, daunorubicin 
a The power was adjusted with a factor of 0.99 due to interim analysis for futility. 
The hypothesized treatment effect size was determined based on the covariates 
predictive of CR observed in the phase 1 portion of the trial and the CR rates reported in 
the literature for those characteristics.  More details are presented in Section 18.2.4. 
For each phenotype separately (B-cell/T-cell), H0 will be rejected at the primary analysis 
if the adjusted OR 95 CI from the propensity adjusted model is above 1.  The power 
was estimated assuming that both treatment arms will be balanced with respect to 
baseline prognostic factors after propensity score adjustment, the control arm probability 
of CR (PoCR) will be consistent at the time of futility and primary analysis, the odds ratio 
of PoCR is 1 under H0, and the power loss is at most 0.01 under H1.  The power was 
adjusted by a factor of 0.99 due to futility check. 
Since the variance of the log odds ratio will be inflated with the IPTW-ATT method 
compared to a non-weighted model, the estimates were adjusted by a variance inflation 
factor of 1.4 obtained via simulation using data from the blinatumomab B-cell ALL 
pediatric US Study 20140228 and European Study 20120299.  The inflation factor was 
selected as the empirical 95 CI upper limit using the sandwich estimator of the log 
odds ratio standard error.  A grid search approach was used to estimate the sample size 


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needed for the test.  For each candidate number of subjects for the test arm, the lower 
bound of the 95 CI of the odds ratio (incorporating variance inflation factor) for each 
possible pair of outcomes was calculated and compared with 1.  Power was derived as 
the summation of the joint probabilities of those pairs of outcomes with a lower bound 
greater than 1.  The R-script for power calculation is presented in SAP. 
25.3 
Analysis Sets, Subgroups, and Covariates 
25.3.1 
Analysis Sets 
All analysis sets below will be analyzed for B-cell and T-cell phenotypes separately. 
Additional details will be provided in the SAP. 
25.3.1.1 
Primary Analysis Set 
The primary analysis set (PAS) will include subjects enrolled in the experimental 
CFZ-VXLD arm who received at least 1 dose of carfilzomib and all external control 
subjects included in the B-PAS/T-PAS defined in the Study 20180065 protocol.  If 
external control subjects have multiple qualifying therapies, the last qualifying therapy 
will be chosen. 
25.3.1.2 
Safety Analysis Set 
This analysis set will include subjects enrolled to the experimental CFZ-VXLD arm who 
received at least 1 dose of carfilzomib. 
25.3.1.3 
Per Protocol Analysis Set 
This analysis set will include subjects enrolled to the experimental CFZ-VXLD arm who 
received at least 1 dose of carfilzomib and have no important protocol deviations as 
described in the SAP. 
25.3.1.4 
Interim Futility Analysis Set 
The interim futility analysis set will include approximately 60 subjects (60 of the 
planned number of subjects) from the experimental CFZ-VXLD arm who have received 
at least one dose of carfilzomib and have had the opportunity to complete a post 
induction response evaluation and all available subjects from the external control 
arm by the time of interim analysis (as defined in Interim Analysis Set 
[T-IAS/B-IAS] of Study 20180065 protocol). 
25.3.2 
Covariates 
Details of the covariates used in the propensity score modeling will be specified in the 
SAP. 


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25.3.3 
Subgroups 
Primary (CR) and selected secondary endpoints (CRh, CRp, and CRi), occurrence of a 
stem cell transplant or CAR-T therapy, EFS, and OS endpoints will be explored in the 
following subgroups of interest using the PAS; analyses will be performed separately for 
B-cell and T-cell ALL populations, unless otherwise specified.  When there is not a 
sufficient number of subjects in the subgroup (ie, less than 20 of subjects in a 
treatment arm), relevant subgroups may be combined.  In these subgroup analyses, all 
treatment arm subjects will receive a weight of 1 while control arm subjects will be 
IPTW-ATT weighted, with the same weights used for the primary analysis of the primary 
endpoint.  Odds ratio and 95 CI will be produced for CR, CRh, CRp, and CRi.  Hazard 
ratio (HR) and 95 CI will be produced for EFS and OS.   
 
History of prior HSCT  
 
History of primary induction failure 
 
Relapse time from HSCT 
 
Early T cell precursor phenotype (for T-cell phenotype only) 
 
Number of prior relapses 
 
Refractory qualifying relapse  
 
Cytogenetic risk (high risk  t(9:22), MLL translocation, hypodiploidy 
[ 44 chromosomes]) 
 
Duration of first remission 
 
Age at diagnosis  
 
Sex  
 
Isolated BM at relapse  
 
Blast percent in marrow prior to the qualifying treatment 
 
Geographical region  
The additional secondary endpoints:  occurrence of a SCT or CAR-T, and MRD[-] status 
will be estimated in the same subgroups listed above, using the Safety Analysis set with 
no adjustment. 
Additional details will be provided in the SAP. 
25.3.4 
Handling of Missing and Incomplete Data 
Incomplete adverse event start dates, concomitant medications start or stop dates, 
death date, and missing baseline covariates will be imputed, and the details of missing 
data analysis and imputation rules will be described in SAP. 


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25.4 
Statistical Analyses 
The SAP will be developed and finalized before database lock.  Below is a summary of 
the timing and methods for the planned statistical analyses.  To preserve study integrity, 
the final analysis will be conducted and reported following the end of study, as defined in 
Section 24.1.5. 
25.4.1 
Planned Analyses 
25.4.1.1 
Interim Futility Analysis 
An interim analysis for futility will be conducted independently for each phenotype T-cell 
and B-cell, respectively.  The analysis will occur after at least 60 subjects from the 
experimental arm have received at least one dose of carfilzomib and had the 
opportunity to complete a post induction response evaluation.   
The futility criterion will be derived such that the probability of futility is at least 70 
under H0 and the power loss is at most 0.01 under H1, using a Bayesian predictive 
probability approach.  Additional details are provided in the SAP. 
25.4.1.2 
Primary Analysis 
The primary analysis for each phenotype will occur when the external control subjects 
from B-PAS/T-PAS have been selected and at least 100 enrolled subjects in the 
experimental arm have received at least one dose of carfilzomib and had the opportunity 
to complete a post induction response evaluation.  All the available data on primary, 
secondary, and exploratory endpoints will be summarized at this time. 
25.4.1.3 
Final Analysis 
The final analysis will occur after the end of the study for all subjects. 
For each planned analysis, data will be subject to ongoing checks for integrity, 
completeness, and accuracy in accordance with the Data Management Plan with the 
expectation that all outstanding data issues are resolved ahead of the snapshot.  The 
data will be locked to prevent further changes, and a snapshot of the locked database 
will be used in the analysis. 
25.4.2 
Methods of Analyses 
25.4.2.1 
General Considerations 
Unless otherwise specified, the data will be presented for the Safety Analysis Set for 
B-cell and T-cell phenotypes analyzed separately. 
Summary statistics will be provided for selected endpoints.  For continuous variables, 
the number of subjects with non-missing data (n), mean, standard deviation, median, 


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minimum, and maximum will be presented.  For discrete data, the frequency and percent 
distribution will be presented.  Unless otherwise indicated, percentages will be calculated 
with respect to the number of subjects in the analysis set.  Confidence intervals, when 
presented, will be constructed at the 2-sided 95% level.  For binomial variables, exact 
distribution methods will be employed.  The distribution of time-to-event endpoints will be 
summarized by Kaplan-Meier method when applicable.   
Individual subject listings will be produced for selected endpoints using data recorded on 
the eCRFs or derived data. 
25.4.2.2 
Efficacy Analyses 
Unless otherwise specified, all efficacy endpoints will be analyzed for B-cell and T-cell 
phenotype independently.  The comparison analyses for CR, CRh, CRp, CRi, EFS, and 
OS endpoints will use the PAS, while for all the other efficacy endpoints, the Safety 
Analysis Set will be used.  DOR will be analyzed only on responders from PAS (ie, 
subjects who reached a response of CR, CRp, CRh, or CRi). 
Analyses of Primary Efficacy Endpoint 
To evaluate the treatment effect with respect to the outcome of CR rate among pediatric 
relapsed or refractory ALL subjects, an external control arm representing pediatric ALL 
subjects receiving SoC without carfilzomib will be selected from the observational 
Study 20180065 according to the study protocol.  For the primary analysis, the 
20140106 study will be analyzed as a virtual randomized controlled trial comparing 
enrolled subjects treated with the CFZ-VXLD regimen versus the external control arm.  
The OR for the PoCR for CFZ-VXLD versus control will be estimated from a logistic 
regression model with inverse probability treatment weights for the average treatment 
effect of the treated (IPTW-ATT).  These weights are derived for each CFZ-VXLD and 
control subject based on the propensity score for receiving CFZ-VXLD.  Outlier weights 
will be trimmed if identified.  Covariates that remain imbalanced after propensity score 
(PS) adjustment will be added in the analysis model as a sensitivity analysis.  The 
95% CI of the OR will be calculated using a robust sandwich covariance estimator and 
the lower bound of the 95% CI will be compared to 1.  The CR rate and 95% CI by arm 
will also be estimated using the same logistic regression model. 
Details of the PS analysis using IPTW-ATT approach will be specified in the SAP. 
Estimated CR rate and 95% CI by arm along with OR (95% CI) of CR between 
CFX-VXLD and appropriated weighted external control using PS will be calculated via 


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the weighted logistic regression for the subgroups listed in Section 25.3.3.  The same 
weights as those included in the primary analysis will be used for subgroup analyses.  A 
forest plot will be produced for the estimated ORs (95% CIs). 
The CFZ-VXLD subjects reaching CR at the end of Induction will also be summarized 
along with their Clopper Pearson 95% CI. 
The sensitivity analyses will be considered and specified in the SAP.  
Analyses of Additional Secondary Efficacy Endpoints 
The proportion of safety analysis subjects and corresponding Clopper Pearson 95% CI 
will be estimated for the below secondary endpoints:   
 
MRD status using NGS less than 10-4 after induction therapy in subjects achieving 
CR 
 
Occurrence of a stem cell transplant or CAR-T, without an intervening relapse after 
protocol specified therapy 
 
CR, CRp, CRh, and CRi after induction therapy 
 
CR, CRp, CRh, and CRi after consolidation therapy  
 
MRD status using NGS less than 10-3 and less than 10-4 in subjects achieving CR, 
CRp, CRh, or CRi after induction and consolidation therapy, separately 
The rate of CRp, CRh, and CRi at the end of induction per arm and the OR for 
CFZ-VXLD versus control will be estimated from a logistic regression model with 
IPTW-ATT adjustment along with their 95% CIs.  This analysis will be performed 
following a similar approach and sensitivity analyses as for primary endpoint analysis. 
EFS, OS, and DOR will be summarized by Kaplan-Meier method.  The distribution of 
EFS/OS/DOR time including median and other quartiles will be summarized descriptively 
using the KM method (Klein and Moeschberger, 1997).  The corresponding 95% CI for 
the median and other quartiles will be constructed using KM method with log-log 
transformation.  Survival rates at 6, 12, 18, and 24 months will be estimated, and the 
corresponding 95% CIs will be calculated using the method of Kalbfleisch and Prentice 
(1980).  The duration of the follow-up for OS/EFS will be estimated by reverse 
Kaplan-Meier method (Schemper and Smith 1996).  KM curves will also be presented for 
OS and EFS.  The HR for CFZ-VXLD vs external control arm will be derived for OS/EFS 
using Cox regression.  This analysis will be adjusted following a similar approach and 
weights as for primary endpoint analysis.  If the number of responders is small, the KM 
method may not provide reliable estimates for DOR; in this case, only descriptive 
statistics or listings will be provided. 


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Similar sensitivity analyses as for primary endpoint analysis will be considered for 
EFS/OS and are described in more detail in the SAP.  
 
Details will be specified in the SAP amendment. 
25.4.2.3 
Safety Analyses 
25.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
The safety analysis will include all data specified in Sections 25.4.2.3.2 through 
25.4.2.3.10 and will be based on the safety analysis set analyzed for B-cell and T-cell 
separately. 
Additionally, the safety data will be summarized by age categories. 
25.4.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product or other 
protocol-required therapies, and significant treatment-emergent adverse events will also 
be provided.  
25.4.2.3.3 
Laboratory Test Results 
Actual values and change from baseline for laboratory measurements will be 
summarized and presented in subject listings.  Additionally, the type, incidence, and 
severity of laboratory abnormalities will also be analyzed. 
25.4.2.3.4 
Vital Signs 
Actual value and change from baseline for vital sign results including systolic/diastolic 
blood pressure, heart rate, respiratory rate, and temperature will be summarized. 
25.4.2.3.5 
Physical Measurements 
Actual value and change from baseline for the physical measurements including height, 
weight, and BSA will be summarized. 
25.4.2.3.6 
Electrocardiogram 
The ECG measurements from this clinical study were performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.   


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25.4.2.3.7 
Echocardiogram 
Echocardiogram, including assessments of systolic and diastolic left ventricular function 
and right ventricular function, will be summarized at baseline using descriptive statistics 
based on the Safety Analysis Set.  Additionally, the unscheduled ECHO assessments 
(as clinically indicated, such as congestive heart failure) will be summarized using 
descriptive statistics, based on the number of adverse events that trigger the 
unscheduled ECHO assessments. 
25.4.2.3.8 
Exposure to Investigational Product 
Descriptive statistics in terms of treatment duration (days), number of actual treatment 
days, total dose received, number of doses administered, average dose per 
administration, actual dose intensity, and relative dose intensity will be produced to 
describe the exposure to carfilzomib.  Number (%) of subjects with carfilzomib dose 
modifications (missed doses, dose delays, dose reductions, and dose interruptions) will 
be summarized. 
Descriptive statistics will be produced to describe the exposure to investigational 
product.  
25.4.2.3.9 
Exposure to Non-investigational Product 
All the analyses planned for investigational product will be carried over for each drug 
in any chemotherapy combination and CNS treatment combination, as specified in the 
SAP.  For CNS combination drugs (methotrexate cytarabine, and hydrocortisone), 
exposure will be summarized for CNS positive and negative separately. 
25.4.2.3.10 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving therapies of interest will be 
summarized by preferred term or category as coded by the World Health Organization 
Drug (WHO DRUG) dictionary. 
26. 
Phase 2:  Clinical Laboratory Tests 
The tests detailed in Table 28 will be performed by the local laboratory unless otherwise 
indicated.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 21.1 to 21.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 


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Table 28.  Phase 2 Analyte Listing 
Chemistry 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT) 
Creatinine clearance (calculated) 
or GFR 
RBC 
Nucleated RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Platelets 
WBC 
Differential 
• Bands/stabs 
• Segmented neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
• Myeloblasts 
• Promyelocytes 
• Myelocytes 
• Metamyelocytes 
• Atypical lymphocytes 
 
Coagulation tests: 
INR 
aPTT 
Pancreatic function tests: 
Amylase 
Lipase 
Viral studies: 
HBsAg 
anti-HBc 
anti-HBs 
Hepatitis C antibody 
CMV PCRa 
HIVb 
Serum or Urine pregnancy 
MRD (flow cytometry and/or PCR) 
 
Central Laboratory: 
Bone marrow aspirate for MRD by 
NGS 
Pharmacokinetics 
 
Stained bone marrow aspirate 
slides for histology  
Stained slides of peripheral blood 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; anti-HBc = hepatitis B core antibody; 
anti-HBs = hepatitis B surface antibody; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CMV = cytomegalovirus; GFR = glomerular filtration rate; 
HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; HLA = human leukocyte 
antigen; INR = international normalized ratio; LDH = lactate dehydrogenase; MCH = mean corpuscular 
hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; 
MRD = minimal residual disease; NGS = next generation sequencing; RBC = red blood cell count; 
RDW = red cell distribution width; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum 
glutamic-pyruvic transaminase; WBC = white blood cell count 
a required at screening for subjects with a history of prior stem cell transplant or known to be CMV positive. 
b HIV assessment is recommended. 
27. 
Phase 2:  Study Governance Considerations 
An independent Data Monitoring Committee (DMC) will review every 6 months all 
available safety and efficacy data for the safety analysis set.  Additionally, the DMC will 
evaluate interim futility analysis.  The DMC will communicate major safety concerns and 
recommendations regarding study modification or termination based on the safety and 
efficacy parameters to Amgen in accordance with the DMC charter.  An Independent 
Biostatistics Group (IBG) will generate and provide regular reports to the DMC.   
Records related to the closed-session meetings will be maintained by the IBG for the 
duration of the study.  Amgen will be responsible for maintaining records concerning the 


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DMC open-session meeting and the DMC’s recommendation.  Records related to the 
closed-session meetings will be transferred and stored in the trial master file (TMF) at 
the conclusion of the study, and those related to the open-session will be filed on an 
ongoing basis in TMF.  Further details are provided in the DMC charter. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC.  A copy of 
the written approval of the protocol and informed consent form must be received by 
Amgen before recruitment of subjects into the study and shipment of Amgen 
investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 


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Recruitment Procedures 
Site staff will identify potential subjects from their existing patient population or may seek 
referral patients through existing professional networks or other community sources such 
as patient advocacy groups.  All patient-facing materials must be reviewed/approved by 
the sponsor and the local IRB/IEC.   
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and 
the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 


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physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 23. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 7 days from the previous informed consent form signature 
date. 


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Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
The subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the CRF demographics page, in addition to the unique subject identification number, 
include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
Subject data should be kept in a secure location.  Access to subject data will be limited 
to authorized individuals, as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Amgen complies with all relevant and applicable laws and regulations that protect 
personal information in order to ensure subject confidentiality and privacy.  Subjects are 
designated by a unique subject identification number in the Sponsor’s systems.  The 
Sponsor uses access-controlled systems to house, review and analyze subject data.  
These systems are backed-up regularly to minimize the risk of loss of subject data; 
procedures are also defined for data recovery in the event of data loss.  The Sponsor 
has standard operating procedures in place that restrict access to subject data to those 
who require access to this data based on their role and have also completed the 


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required training.  These procedures also outline the process for revoking access to 
such data when it is no longer needed.  In the event of a security breach, the Sponsor 
has procedures in place for notification of privacy incidents and to address these 
incidents, via its Business Conduct Hotline. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance, and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.  Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 


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Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An Investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 


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In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities (eg, 
pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Case report forms must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the IRT 
system (if used, such as subject ID and randomization number) and CRF entries if the 
CRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as paper questionnaires for a clinical outcome assessment or certain 
demographic information). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 






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The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 








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Figure 6.  Phase 2 Sample Electronic Serious Adverse Event Contingency Report 
Form (paper-based form) 
 


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29. 
Phase 2:  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information 
Study-specific contraception requirements for males and females of childbearing 
potential are outlined in Section 21.  Contraceptive use and methods should be 
consistent with local regulations for subjects participating in clinical studies. 
Male and female subjects of childbearing potential should be advised of the pregnancy 
prevention requirements and the potential risk to the fetus if they become pregnant or 
father a child during treatment and for 6 months after the last dose of any study 
treatment or for 12 months after last dose of cyclophosphamide if administered during 
optional consolidation cycle for female subjects of child-bearing potential. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include documented 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  Females with 
documented permanent infertility due to an alternate medical cause (eg, Mullerian 
agenesis, androgen insensitivity, gonadal dysgenesis), can be considered not of 
childbearing potential. 
Note: Bilateral tubal ligation/occlusion is not considered a permanent sterilization 
method. 
Note:  Documentation from the following sources is acceptable to provide confirmation of 
each sterilization method:  1) review of subject’s medical records; 2) subject’s medical 
examination; or 3) subject’s medical history interview. 
A postmenopausal female is defined as: 
 
A woman of  55 years with no menses for 12 months without an alternative medical 
cause OR   
 
A woman age < 55 years with no menses for at least 12 months and with a 
follicle-stimulating hormone (FSH) level within the definition of “postmenopausal 
range” for the laboratory involved.  In the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required.  
Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal); because an 
indirect interaction between oral contraceptives and PEG-asparaginase (or Erwinia) 


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cannot be ruled out, oral hormonal contraception is not recommended for female 
subjects during PEG- or Erwinia-asparaginase treatment 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Contraception Methods for Male Subjects  
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject)  
 
Use a condom with spermicide during treatment and for an additional 6 months after 
the last dose of any study treatment 
The female partner of a male subject should consider using a highly effective method of 
contraception as stated above, or an acceptable method of contraception such as: 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system 
 
Hormonal birth control method: pill, shots/injections, implants (placed under the skin 
by a healthcare provider), skin patches  
 
Female barrier method: diaphragm, cervical cap, contraceptive sponge for female 
subjects stated above (a female condom should not be used because there is a risk 
of tearing when both partners use a condom) 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 6 months after last dose of 
any study treatment or up to 12 months if the female subject received 
cyclophosphamide in optional consolidation therapy. 


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 
Information will be recorded on the Pregnancy Notification Form (see Figure 7).  The 
form must be submitted to Amgen Global Patient Safety within 24 hours of the site’s 
awareness of a subject’s pregnancy.  (Note: Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions 
local privacy laws). 
 
After obtaining the female subject’s signed consent for release of pregnancy and 
infant health information, the investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 6 months after 
last dose of any study treatment or up to 12 months if the female subject received 
cyclophosphamide in optional consolidation therapy.  This information will be 
forwarded to Amgen Global Patient Safety.  Generally, infant follow-up will be 
conducted up to 12 months after the birth of the child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an adverse event or serious adverse event.  Abnormal 
pregnancy outcomes (eg, spontaneous abortions, stillbirth, fetal death, congenital 
anomalies) will be reported as an adverse event or serious adverse event.  Note that 
an elective termination with no information on a fetal congenital malformation or 
maternal complication is generally not considered an adverse event, but still must be 
reported to Amgen as a pregnancy exposure case. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 28.  While the 
investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of a serious adverse event through spontaneous reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment while pregnant (see Section 23.1 for details). 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 
In the event a male subject fathers a child during treatment, and for an additional 
6 months after last dose of any study treatment after discontinuing protocol-required 
therapies, the information will be recorded on the Pregnancy Notification Form.  The 
form (see Figure 7) must be submitted to Amgen Global Patient Safety within 
24 hours of the site’s awareness of the pregnancy.  (Note: Sites are not required to 
provide any information on the Pregnancy Notification Form that violates the country 
or regions local privacy laws). 
 
Males with pregnant partners or whose partners become pregnant during treatment 
and for an additional 6 months after last dose of any study treatment must practice 
sexual abstinence or use a condom through 6 months after last dose of any study 
treatment. 


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 
The investigator will attempt to obtain a signed consent for release of pregnancy and 
infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed consent for release of pregnancy and 
infant health information, the investigator will collect pregnancy outcome and infant 
health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 6 months after last dose of any 
study treatment or up to 12 months if the female subject received cyclophosphamide 
in optional consolidation therapy. 
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
awareness of the event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 232. 
 
With the female subjects signed consent for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 6 months after last dose of any study 
treatment or up to 12 months if the female subject received cyclophosphamide in 
optional consolidation therapy. 


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Figure 7.  Phase 2 Pregnancy and Lactation Notification Forms 
 


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30. 
Sample Storage and Destruction 
Any blood 
pharmacokinetics) sample collected according to the 
Schedule of Activities (Table 14, Table 16, Table 18, and Table 20) can be analyzed for 
any of the tests outlined in the protocol and for any tests necessary to minimize risks to 
study subjects.  This includes testing to ensure analytical methods produce reliable and 
valid data throughout the course of the study.  This can also include, but is not limited to, 
investigation of unexpected results, incurred sample reanalysis, and analyses for 
method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand ALL, 
the dose response and/or prediction of response to carfilzomib, and characterize 
aspects of the molecule (eg, mechanism of action/target, metabolites).  Results from this 
analysis are to be documented and maintained but are not necessarily reported as part 
of this study.  Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, 
 
 
 
 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood or bone marrow samples and any other components from the cells can be located 
and destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140106 
Carfilzomib for Injection 
Page 243 of 243 
CONFIDENTIAL 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 27 for subject confidentiality. 


Product:  Carfilzomib for Injection 
Protocol Number:  20140106 
Date:  28 August 2023 
Page 1 of 13 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 12 
Protocol Title:  Phase 1b/2 Study of Carfilzomib in Combination With Induction 
Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic 
Leukemia 
 
Amgen Protocol Number:  Carfilzomib 20140106 
EudraCT Number:  2014-001633-84 
NCT Number:  02303821 
 
Amendment Date: 
28 August 2023 
 
Rationale: 
This protocol (dated 28 August 2023) is primarily being amended in the phase 2 portion 
only (Sections 1, 2, and 17.11 through 25) to update the interim analysis and primary 
analysis external control arm datasets, including updates to the number of subjects and 
impact on the statistical power.  In addition, safety monitoring language was added in 
subsection 24.2.4.5.1, ‘Adverse Events of Special Interest’.  These changes were made 
to be consistent with Amendment 4 of the United States Food and Drug Administration 
(FDA) Written Request dated 01 August 2023.  Changes including, but not limited to, the 
following were incorporated into the protocol: 
 
The approximate sizes of the external control arm datasets (Study 20180065) for 
the B-cell and T-cell primary analysis sets (B-PAS/T-PAS) were updated to 
approximately 74 B-cell acute lymphoblastic leukemia (ALL) subjects and 
approximately 60 T-cell ALL subjects from 90 and 70 subjects, respectively.  
Previous versions of the protocol included external control sample sizes that 
were larger than required to support the analysis. 
 
Language was added to the methods of interim analysis for futility to specify that 
the interim analysis will be done with the external control datasets that are 
available at time of interim.  Previous versions of the protocol required the 
complete external control arm dataset to be available for interim analysis. 
 
“Full” Analysis was revised to “Final” Analysis.  Definition of Final Analysis Sets 
(T-FAS/B-FAS) was removed, as not required.  A definition of a Final Analysis 


Product:  Carfilzomib for Injection 
Protocol Number:  20140106 
Date:  28 August 2023 
Page 2 of 13 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Set is not required due to the revisions to Interim and Primary Analyses.  As 
revised, all external control data, as well as all 20140106 subjects, will be 
included in the Primary Analysis (and in the Final Analysis). 
 
Language was updated in the Primary and Interim Futility Analyses sections to 
align with the new approximate size of the external control arm datasets from 
Study 20180065. 
 
Power estimates were adjusted based on the expected approximate number of 
external control arm datasets provided above. 
 
Safety monitoring language was added in subsection 24.2.4.5.1, ‘Adverse Events 
of Special Interest’. 
 
Additional changes were made for consistency and alignment throughout the 
protocol including, but not limited to, administrative, typographical, formatting, 
numbering, and abbreviation changes. 


Product:  Carfilzomib for Injection 
Protocol Number:  20140106 
Date:  04 November 2022 
Page 1 of 92 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 11 
Protocol Title:  Phase 1b/2 Study of Carfilzomib in Combination With Induction 
Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic 
Leukemia 
 
Amgen Protocol Number 20140106 (formerly CFZ008) 
EudraCT number 2014-001633-84 
NCT number NCT 02303821 
 
Amendment Date: 
04 November 2022 
 
Rationale: 
The primary reasons for this protocol amendment are to: 
 
Allow the use of routine care procedures obtained within 7 days before enrollment to 
satisfy screening requirements.  This is added due to a lack of clinical justification for 
repeating procedures that have no clinical benefit to the subject but expose the 
subject to potential risk.  This flexibility is expected to reduce post-enrollment 
eligibility deviations and facilitate enrollment.   
 
Update minimum enrollment numbers of subjects with relapsed T-cell acute 
lymphoblastic leukemia (ALL) and with relapsed B-cell ALL based on current 
enrollment and health authority expectations.  The minimum numbers of patients in 
the external control arm with relapsed B-cell ALL were also updated based on the 
status of incoming control arm data.  The respective sample size estimates and 
expected power have been adjusted accordingly. 
Additional changes are made to:  
 
Respond to site feedback regarding confusion between phase 1 and phase 2 
sections of the protocol.  The synopsis is revised to remove phase 1 information and 
expand phase 2 information.  Revisions to bring focus to phase 2 of the protocol 
result in a re-numbering of Sections 17 and beyond (eg, former Section 17 is now 
Section 18).  Section and table names are revised to include “Phase 2” for clarity 
(throughout protocol).   
 
Add details to define analytes used in the derivation of remission status for 
evaluation of the primary and secondary endpoints, and clarify that hematology and 
bone marrow aspirate/biopsy samples must be assessed locally 
 
Revise the description of the primary endpoint to clarify that there is a single 
endpoint of complete remission (CR).  The previous amendment language included 
time window definitions for infants and children that could have been misinterpreted 
to suggest a CR endpoint for infants and a separate CR endpoint for children.  The 
same clarification is made to the secondary endpoint for CR, complete remission 


Product:  Carfilzomib for Injection 
Protocol Number:  20140106 
Date:  04 November 2022 
Page 2 of 92 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
without platelet recovery (CRp), complete remission with partial hematologic 
recovery (CRh), and complete remission with incomplete hematologic recovery (CRi) 
after consolidation therapy. 
 
Allow bone marrow to be assessed by aspirate or biopsy or flow if morphology is not 
available, and permit bone marrows that are performed as part of routine medical 
care to be used for central laboratory minimal residual disease (MRD) assessment  
 
In the schedule of activities, replace the line for adverse events, serious adverse 
events, and concomitant therapies review with “X” to prevent any confusion that 
these will be collected, at a minimum, from screening through safety follow up.  No 
change is made to the timing of these activities. 
 
Corrections to schedule of activities tables:  added row for “other extramedullary 
disease assessment” and removed day 10 hematology, which was listed in error, 
from Table 20 (consolidation therapy for subjects less than 12 months of age) 
 
Remove exclusion criteria 212 and 213.  These required a 3-month window after 
previous proteasome inhibitor therapy, and a 2-month window after previous VXLD 
(or similar).  These exclusions were not present in the phase 1 portion of the 
protocol, their removal was requested by investigators, and is consistent with 
guidance to remove time-based washout periods from clinical trials eligibility (Harvey 
et al, 2021). 
 
Correct inclusion criterion 113 so eligibility requires less than 5 blasts 
 
Extend window allowed to make up missed doses from 1 day to 3 days  
 
Allow alternate dosing or formulation of L-asparaginase in accordance with local 
standard of care  
 
Allow substitution of intrathecal regimens based on local practice  
 
Recommendation to collect medical history and surgical history 30 days prior to 
signing the ICF is removed to allow collection of full ALL medical history  
 
Update treatment response definition in alignment with National Comprehensive 
Cancer Network guidelines (2022) and Shallis et al, 2021, consistency with 
Study 20180065, and Amgen endpoint guide for leukemia 
 
Clarify details of the independent Data Monitoring Committee and independent 
Biostatistics Group, and remove requirement for every 3-month Steering Committee 
meetings 
 
Update the covariates for subgroup analyses, and specify the categories into the 
SAP 
 
To reduce confusion, the phase 1 pregnancy and lactation notification forms are 
removed with references to the respective forms to use for phase 2 
 
Safety reporting language updated per new Amgen protocol template updates 
 
Revisions made for internal consistency of document (eg, number of allowed screen 
fails in Section 24.1.1 revised to align with Section 20.4; male contraception time 
revised in Section 22.1.6.15.3, Male Subjects to align with exclusion criteria) 
 
Update investigator list on the cover page  
 
Typographical and formatting issues were corrected throughout the document. 


Product:  Carfilzomib for Injection 
Protocol Number:  20140106 
Date:  04 November 2022 
Page 3 of 92 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
References 
Harvey RD, Mileham KF, Vishal Bhatnagar V, et al.  Modernizing clinical trial eligibility 
criteria:  recommendations of the ASCO-Friends of Cancer Research washout period 
and concomitant medication work group.  Clin Cancer Res.  2021;27:2400-2407. 
National Comprehensive Cancer Network.  Acute Lymphoblastic Leukemia v1.2022.  
April 4, 2022. 
Shallis RM, Pollyea DA, Zeidan AM.  The complete story of less than complete 
responses:  The evolution and application of acute myeloid leukemia clinical responses.  
Blood Reviews.  2021;48:1-10. 


Product:  Carfilzomib for Injection 
Protocol Number:  20140106 
Date:  03 August 2021 
 
Page 1 of 20 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020, Version: 6.0 
Amendment 10 
Protocol Title:  Phase 1b/2 Study of Carfilzomib in Combination With Induction 
Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic 
Leukemia 
Amgen Protocol Number (Carfilzomib for Injection) 20140106 
EudraCT Number 2014-001633-84 
NCT Number:  02303821 
Amendment Date: 
03 August 2021 
Rationale: 
This protocol is being amended to: 
 
Remove the pharmacogenetic biomarkers from the exploratory objectives in 
phase 2. 
 
Update inclusion criterion 114 to allow subjects who received blinatumomab for 
treatment of MRD positive disease during first remission or for primary induction 
failure to achieve a first remission.  
 
Update exclusion criterion 221 to require discussion with Amgen medical 
monitor for subjects with less than 3 antibody half-lives since the last dose of 
monoclonal antibody. 
 
Add exclusion criterion for known allergy to captisol in phase 2 of the study. 
 
Add assessments for pancreatic function tests in the Schedule of Activities for 
phase 2. 
 
Add assessments for echocardiograms in the Schedule of Activities for phase 2. 
 
Update treatment of central nervous system-positive subjects to allow 
alternatives to hydrocortisone substitutions per local standard practice.  
 
Clarify instructions for lumbar puncture. 
 
Clarify information collected during long-term follow-up. 
 
Change day 29 to day 28 in the Schedule of Activities for dose regimen for 
consolidation therapy in subjects aged less than 12 months at screening. 
 
Update the reasons for early removal for protocol-required investigational 
product(s) or procedural assessments. 
 
Update allowance for rescreening from 1 time to 3 times.  
 
Add the use of asparaginase erwinia chrysanthemi recombinant (RYLAZE) as a 
replacement for polyethylene glycol asparaginase or Erwinia asparaginase in 
regions where approved and available for subjects less than 12 months of age at 
screening receiving Berlin-Frankfurt-Munster consolidation therapy.  
 
Administrative, typographical, and formatting changes were made throughout the 
protocol. 
This amendment only applies to the ongoing phase 2 part of the study.  


Product:  Carfilzomib 
Protocol Number:  20140106 
Date:  04 February 2021 
Page 1 of 4 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 9 
Protocol Title:  Phase 1b/2 Study of Carfilzomib in Combination With Induction 
Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic 
Leukemia 
 
Amgen Protocol Number 20140106 (formerly CFZ008) 
 
Amendment Date: 
04 February 2021 
 
Rationale: 
The 20140106 study protocol has been amended as follows: 
 
The recommended phase 2 dose of 20/56 mg/m2 carfilzomib identified from phase 1 
by the Cohort Safety Review Committee was added. 
 
Protocol-approved substitutions with dose equivalents were specified for 
components of VXLD or intrathecal chemotherapy for regions where these 
components are not available to allow enrollment globally while ensuring 
comparability of backbone therapy. 
 
The omission of components of VXLD treatment (eg, anthracycline) under certain 
conditions or steroid from intrathecal chemotherapy is allowed to be consistent with 
current clinical practice or local standard of care. 
 
For subjects  12 months, the dose of daunorubicin during induction was changed 
from 25 mg/m2 for 4 doses to 60 mg/m2 and the dosing frequency was decreased 
from 4 times to once per cycle (reduced total dose from 100 to 60 mg/m2).  This 
change is intended to reduce toxicity of the VXLD backbone by both reducing the 
total daunorubicin dose and to move it earlier in regimen to allow bone marrow 
function more time to recover.  The change matches the design for daunorubicin 
used with the VPLD backbone in similar patients in COG Study AALL01P2 and 
Study AALL07P1 (VPLD  bortezomib). 
 
The rationale for changes to the VXLD regimen in the phase 2 versus phase 1 
portions of the study was added. 
 
Vindesine was removed as an acceptable replacement for vincristine because no 
planned country/region is expected to require this substitution.  
 
The discontinuation of asparaginase is allowed if Erwinia asparaginase is not 
available or desensitization procedure for asparaginase. 
 
Details on non-investigational products and other protocol-required therapies were 
added to the phase 2 portion of the study for clarity. 
 
The recommended dosing of trimethoprim sulfamethoxazole was added along with 
suggested alternatives for contraindication or significant concerns of bone marrow 
suppression, with a requirement to include the rationale for the use of an alternative 
agent in the case report form.  


Product:  Carfilzomib 
Protocol Number:  20140106 
Date:  04 February 2021 
Page 2 of 4 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Clarification was added that adjustment of the carfilzomib dose is required for certain 
toxicities. 
 
Dose modification guidelines, including adding guidance for progressive multifocal 
leukoencephalopathy and resuming carfilzomib with controlled hepatitis B 
reactivation, were aligned with those of the carfilzomib program for consistency 
across studies. 
 
Supportive care requirements and guidelines were updated and guidelines for 
mucositis was added based on the recommendations of the steering committee. 
 
The most impactful difference in patient population between phase 1 and phase 2 
was clarified. 
 
A correction was made to the inclusion criterion that adequate cardiac function is 
defined as shortening fraction of  30 not  30. 
 
A correction was made to the inclusion criterion that life expectancy must be 
 6 weeks not  6 weeks. 
 
Clarification was added to the exclusion criterion that subjects should be excluded for 
intolerance, hypersensitivity, or inability to receive any of the chemotherapy 
components of the VXLD regimen (or acceptable substitutes as defined in the 
protocol). 
 
Corrections were made to the exclusion criteria that subjects should refrain from 
becoming pregnant or breastfeeding and must use contraception for 6 months after 
the last dose of any study treatment or for 12 months after the last dose of 
cyclophosphamide if used. 
 
A recommendation was added that oral hormonal contraception not be used during 
PEG- or Erwinia asparaginase treatment due to a potential interaction. 
 
Collection of serious adverse events was extended through long-term follow-up for 
compliance with clinical trial guidance. 
 
A requirement for cytomegalovirus (CMV) polymerase chain reaction (PCR) testing 
at screening was added for subjects with prior transplant. CMV PCR testing at 
screening was added to the schedule of assessments and analyte listing to clarify 
the required testing for these subjects and those who are CMV positive, and to 
further clarify that CMV testing is recommended for all subjects. 
 
Clarification was added to the schedule of assessments that subjects with symptoms 
of congestive heart failure during or after completion of induction therapy should 
have an echocardiogram before optional consolidation. 
 
The timing of hematology collection in induction and consolidation for infants was 
corrected to day 36 (not day 35). 
 
Clarification was added to the schedule of assessments the clinical chemistry 
parameters that are required beyond a standard metabolic panel. 
 
A correction was made to remove cholesterol, HDL, LDL, and triglycerides from the 
analyte listing because they are not required for any exclusion criteria or monitoring. 
 
Clarification was added that calculated creatinine clearance or glomerular filtration 
rate is required at screening. 
 
Segmented neutrophils was added to the analyte listing to allow for calculation of 
total neutrophils. 


Product:  Carfilzomib 
Protocol Number:  20140106 
Date:  04 February 2021 
Page 3 of 4 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
The requirement for unstained slides of bone marrow aspirate and peripheral blood 
were removed. 
 
Clarification was added that chest imaging is only required for subjects with a mass 
present at screening. 
 
 blood sample collection was added at 60 minutes after the end of 
carfilzomib infusion on day 1 of induction to better monitor proteasome inhibition. 
 
 pharmacokinetic blood sample collection were added during 
consolidation to allow comparison between induction and consolidation 
 
The dosing schedule of study treatments was separated from the schedule of 
assessments for consistency with phase 1 and other cooperative protocols. 
 
Clarification was added that subjects may be discontinued from study treatment due 
to death and for those determined to be ineligible for the study. 
 
The objectives, endpoints, and analysis sets of the phase 2 portion were aligned with 
the statistical analysis plan (SAP). 
 
Phase 2 endpoints were clarified (eg, removal of ‘full’ from complete response 
because it has no meaning).  None of the edits change the endpoints themselves. 
 
The treatment response definitions were updated per more recent United States 
Food and Drug Administration (US FDA) requirements and a definition for 
non-evaluable was added. 
 
The definition of induction death was clarified with respect to the timing of response 
evaluation. 
 
Clarification was added that assessment of response is central review of stained 
slides of bone marrow aspirate, peripheral blood, and minimal residual disease 
(MRD) by next generation sequencing (NGS) and local assessment of sites of 
extramedullary disease and MRD by flow cytometry and/or PCR or NGS if available 
 
The missing baseline covariates imputation, sample size determination, and 
statistical analysis sections were updated to be consistent with SAP version 2.0, 
dated 19 November 2020 which was amended based on the feedback from the US 
FDA. 
 
Statistical comparison between experimental arm and external control arm of 
duration of response was removed and only descriptive statistics will be summarized 
because it will be analyzed only on responders in the Primary Analysis Set. 
 
Subgroup analyses for subjects who had anthracycline omitted from VXLD induction 
were added.  Relapse time from prior transplant, number of prior relapses, and 
duration of most immediate prior remission subgroups were aligned with SAP. 
 
Clarification was added that a sensitivity analysis will include any covariates still 
imbalanced after propensity score analysis. 
 
The planned analyses for echocardiograms were added. 
 
Details about the role of the independent biostatisticians who will support the futility 
efficacy analysis for Data Monitoring Committee (DMC) were added. 
 
The investigators on the cover page were updated to reflect the anticipated 
involvement in the phase 2 portion of the study. 
 
The anticipated number of sites participating in phase 2 was added. 


Product:  Carfilzomib 
Protocol Number:  20140106 
Date:  04 February 2021 
Page 4 of 4 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
A reference was added in the DMC section of the phase 1 protocol to the 
corresponding section for phase 2 to clarify the different roles of the DMC across 
phases. 
 
Typographical and formatting issues were corrected throughout the document. 


Product:  Carfilzomib 
Protocol Number:  20140106 
Date:  13 August 2020 
Page 1 of 1 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 8 
Protocol Title:  Phase 1b/2 Study of Carfilzomib in Combination With Induction 
Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic 
Leukemia 
 
Amgen Protocol Number 20140106 
 
 
Amendment Date: 
13 August 2020 
 
Rationale: 
The 20140106 study protocol has been amended as follows: 
 
Addition of the phase 2 part to the existing phase 1 study to allow currently 
participating sites to seamlessly continue to enroll subjects without a break in 
availability of this therapy for subjects that may benefit from carfilzomib combined 
with vincristine, dexamethasone, PEG-asparaginase, and daunorubicin (VXLD).   
 
The primary objective of the phase 1 part of the study has been amended to 
clarify that in addition to determining the maximum tolerated dose, the objective 
is also to recommend a phase 2 dose of carfilzomib with induction therapy. 
 
Typographical and formatting changes have been made throughout the 
document. 
 


Product:  Carfilzomib for Injection 
Protocol Number:  20140106 
Date:  19 September 2019 
Page 1 of 11 
CONFIDENTIAL 
 
 
Amendment 7 
Protocol Title:  Phase 1b Study of Carfilzomib in Combination With Induction 
Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic 
Leukemia 
 
Amgen Protocol Number carfilzomib 20160104 (formerly CFZ008) 
 
Amendment Date: 
19 September 2019 
Rationale: 
The protocol is amended to: 
 
To add hepatitis B testing at screening for all subjects and at the safety follow up 
for subjects with positive hepatitis B serology at screening or past history of HBV 
infection.  Subjects with hepatitis B infection with positive hepatitis B DNA are 
excluded from the study.  In addition, guidance was provided for the monitoring and 
management of HBV infections. 
 
To allow enrollment of subjects with first refractory bone marrow relapse 
occurring any time after original diagnosis after achieving a CR (ie,  1 failed attempt 
to induce a second remission) in the study. 
 
To indicate that prior therapy with inotuzumab within 36 days (3 antibody 
half-lives), rather than 30 days, is exclusionary.  
 
To indicate that next generation sequencing will be used to assess MRD status 
and lymphoblasts at the end of the Induction Cycle. 
 
To indicate that the degree of proteasome inhibition will only be assayed in whole 
blood. 
 
To clarify that subjects should be in a rested and clam state before blood 
pressure measurements but are not required to be supine. 
 
To clarify the reporting requirements for AEs that are laboratory findings that do 
not result in a clinical action or alter treatment. 
 
To clarify that for the Cohort Safety Review Committee and the Data Monitoring 
Committee as-is snapshots will be used for the analyses. 
 
To clarify that for the final analyses the database will be cleaned, processed and 
a locked database used in the analysis. 
 
Editorial changes (including typographical, grammatical, and formatting) have 
been made throughout the document. 


Onyx Therapeutics, Inc.
Clinical Study Protocol No. 20140106
Carfilzomib for Injection
Page 135 of 148
CONFIDENTIAL
APPENDIX K
SUMMARY OF CHANGES
Amendment 6
Protocol Title:  Phase 1b Study of Carfilzomib in Combination With Induction 
Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
Amgen Protocol Number 20140106 (formerly CFZ008)
Amendment Date:
24 October 2018
Rationale:
The protocol is amended to:

Modify the stopping criteria for the Bayesian algorithm
Rationale:  Changes to language on how the Bayesian output will be used to 
determine the maximum tolerated dose in order to trigger the end of the study.

Update the cohort safety review committee language.
Rationale:  Update increases the discretion of the cohort safety review committee to 
recommend the maximum tolerated dose.

Add 2 additional dose levels in dose escalation 2
Rationale:  Accumulating pharmacokinetic data in children indicates drug exposure 
was approximately 40% lower than that of adults at the same dose and schedule; 
therefore, current dose escalation plan updated to include 2 higher dose levels.

Minor modifications to the definition of dose limiting toxicities that are based on 
biochemical adverse events without clinical manifestations

Administrative updates, editorial changes, and style and formatting revisions have 
been made to improve clarity and consistency throughout the document.  Significant 
changes are described in the table below.  Detailed, changed text is displayed for first 
major occurrence only.  Changes in sections of the protocol body were also made in 
the protocol synopsis and elsewhere in the document, as applicable.  Added text is 
presented in bold format.
Approved 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140106 
Carfilzomib for Injection 
Page 129 of 131 
APPENDIX K 
SUMMARY OF CHANGES 
Amendment 5 
Protocol Title:  Phase 1b Study of Carfilzomib in Combination With Induction 
Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia 
Amgen Protocol Number 20140106 (formerly CFZ008) 
Amendment Date: 
11 September 2017 
Rationale: 
The protocol is amended to: 
• Modify the language for dexamethasone dose instruction in the VXLD regimen from 
6 mg/m2 twice daily to 6 mg/m2 per day BID – given orally (3 mg/m2 per dose given 
twice daily). 
Rationale:  Update the language describing required dexamethasone dosing 
instructions to ensure clarity and remove ambiguity. 
• Update the posterior reversible encephalopathy syndrome (PRES) language.  
Rationale:  Update PRES language to ensure alignment between study protocol and 
the carfilzomib Investigator Brochure v17.1. 
• Update PRES management recommendation with a no “re-challenge requirement”. 
Rationale:  Prohibit reintroduction of carfilzomib if PRES is identified in a subject at 
the request of the Global Safety Team (GST). 
• Administrative updates, editorial changes, and style and formatting revisions have 
been made to improve clarity and consistency throughout the document.  Significant 
changes are described in the table below.  Detailed, changed text is displayed for first 
major occurrence only.  Changes in sections of the protocol body were also made in 
the protocol synopsis and elsewhere in the document, as applicable.  Added text is 
presented in bold format.
CONFIDENTIAL 
Approved 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140106 
Carfilzomib for Injection 
Page 129 of 135 
APPENDIX K 
SUMMARY OF CHANGES 
 
Amendment 4 
Protocol Title:  Phase 1b Study of Carfilzomib in Combination with Induction 
Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia 
 
Amgen Protocol Number 20140106 (formerly CFZ008) 
 
Amendment Date: 
22 February 2017 
Rationale: 
The protocol is amended to: 
• Revise inclusion criteria regarding hepatic function 
Rationale:  Provide clarity that subjects with hyperbilirubinemia due to Gilbert 
syndrome are only eligible if they have a direct bilirubin ≤ 1.5 x institutional upper 
limit of normal. 
• Modify carfilzomib infusion time from "approximately 30 minutes" to 
"30 ± 5  minutes" 
Rationale:  Provide clarity on the infusion time ensuring all subjects are exposed to 
the same range of IV infusion time. 
• Add language within the Induction Cycle describing the dose level lists with the 
carfilzomib dose for each dose escalation and specify that during Dose Escalation 2, 
subjects will receive 20 mg/m2 of carfilzomib on Day 1 of the Induction Cycle.  
Rationale:  This language was erroneously omitted during Amendment 3. 
• Update Study 20140106 Induction Cycle Dose Escalation 2 (VXLD) road map with 
actual dose administered placeholders to match the VXLD backbone. 
Rationale:  Dexamethasone, vincristine, and PEG-asparaginase administration 
placeholders were not correctly placed within the appropriate study day. 
CONFIDENTIAL 
Approved 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140106 
Carfilzomib for Injection 
Page 130 of 135 
• Administrative updates, editorial changes, and style and formatting revisions have 
been made to improve clarity and consistency throughout the document.  Significant 
changes are described in the table below.  Detailed, changed text is displayed for first 
major occurrence only.  Changes in sections of the protocol body were also made in 
the protocol synopsis and elsewhere in the document, as applicable.  Deletions of text 
are presented in strikethrough format.  Added text is presented in bold format.
CONFIDENTIAL 
Approved 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140106 
Carfilzomib for Injection 
Page 129 of 228 
CONFIDENTIAL 
APPENDIX K 
SUMMARY OF CHANGES 
 
Amendment 3 
Protocol Title:  Phase 1b Study of Carfilzomib in Combination with Induction 
Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia 
 
 
Amgen Protocol Number Carfilzomib for Injection 20140106 (formerly CFZ008) 
 
Amendment Date: 
20 October 2016 
Rationale: 
The protocol is amended to: 
• Add a second dose escalation portion to evaluate carfilzomib with a different 
chemotherapy backbone (VXLD) of vincristine, dexamethasone, 
PEG-asparaginase, and daunorubicin 
Rationale: Toxicity related to the R3 induction chemotherapy backbone of 
dexamethasone, mitoxantrone, PEG-asparaginase, and vincristine is suspected to 
have limited the ability to dose escalate carfilzomib.  A second dose escalation 
using the less toxic VXLD backbone is being added to the protocol to ensure the 
optimal dose of carfilzomib is selected before moving on to a Phase 2 study.  
• Remove the Phase 2 portion of the study 
Rationale: The Phase 2 portion of the study will instead be conducted with a 
stand-alone protocol treating subjects at the defined MTD. 
• Revise eligibility criteria to  
o Include enrollment of subjects aged 21 years or younger at the time of 
initial ALL diagnosis and limiting enrollment to those aged > 1 year at the 
time of study treatment initiation 
o Include the enrollment of subjects with any first relapse of T-ALL, 
removing the limitation to those with an early relapse 
Approved 
 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140106 
Carfilzomib for Injection 
Page 130 of 228 
CONFIDENTIAL 
o Modify definition of adequate liver function 
o Specify grade of pancreatitis as an exclusion criterion 
o Clarify evidence for bacteria or fungal infection 
o Clarify antineoplastic agents that are included in prior therapy restrictions 
• Clarify the target number of subjects to be enrolled in each age group 
• Change requirement for medical monitor approval with requirement to contact 
medical monitor 
• Remove the requirement for bone marrow biopsy during screening 
• Revise Section 8.4 (Dose Modification Guidelines) to  
o Add text clarifying that the carfilzomib dose modification guidelines also 
apply to the Optional Consolidation Cycle 
o Add dose modification guidelines for daunorubicin 
• Add Section 8.6 (Product Complaints) 
• Revise Section 9 (Supportive Care Requirements and Guidelines) to 
o Clarify that fungal prophylaxis must be provided during periods of 
neutropenia 
o Correct definition for fever and neutropenia 
o Update Section 9.14 (Contraception) 
• Update Section 12.6 (Pregnancy and Lactation Reporting) 
• Add guidelines for taking temperature and blood pressure of subjects 
• Add Section 15.7 (Publication Policy)  
• Update Section 3 (Background Information) 
• Make minor text clarifications, additions, and edits throughout the protocol 
Approved 
 
 


Approved 
 
 
Onyx Therapeutics, Inc.
Clinical Study Protocol No. CFZ008
Carfilzomib for Injection
Page 116 of 126
CONFIDENTIAL
APPENDIX H
SUMMARY OF CHANGES
Administrative updates, editorial changes, and style and formatting revisions have been made 
to improve clarity and consistency throughout the document.  Significant changes are
described in the table below.
Significant changes from the Protocol Amendment 1 to Amendment 2 are:

Added details of MRD specimen collection, including the type of specimen to be 
submitted or the timing of the specimen collection

Added detailed information regarding timing of 
 specimen 
collection

Corrected inconsistencies within the protocol and between the protocol and the 
laboratory manual regarding the proper day for collection of blood or saliva to serve 
as a source of normal (non-tumor) DNA from subjects who have consented to the 
optional genomic studies

Removed ≥ Grade 3 peripheral neuropathy or neuropathic pain from the definition of 
dose limiting toxicity, due to its strong association with vincristine and rare 
association with carfilzomib

Corrected the dose modification of vincristine in the setting of constipation, ileus, or 
typhlitus to reflect modification at ≥  Grade 3, rather than > Grade 3

Added information about PRES and the required dose modification of carfilzomib 
when PRES is suspected

Updated the options for pregnancy testing during screening to include a urine 
pregnancy test, to include a urine pregnancy test, which is less invasive and more 
readily available at pediatric facilities


Approved 
 
 
Onyx Therapeutics, Inc.
Clinical Study Protocol No. CFZ008
Carfilzomib for Injection
Page 117 of 126
CONFIDENTIAL

Increased the duration of required contraception to incorporate the best practices for 
all drugs in the treatment regimen

Modified the definition of permanent sterilization and revised the list of highly 
effective methods of contraception, to be consistent with recent guidance

Added language to allow for higher total bilirubin level at screening, for subjects with 
a diagnosis of Gilbert syndrome

Added language to clarify that the restricted use of antineoplastic agents prior to 
enrollment only applies to the use of agents with therapeutic intent
Administrative updates, editorial changes, and style and formatting revisions have been made 
to improve clarity and consistency throughout the document.  Significant changes are 
described in the table below.  Detailed, changed text is displayed for first major occurrence 
only.  Changes in sections of the protocol body were also made in the protocol synopsis and 
elsewhere in the document, as applicable.  Deletions of text are presented in strikethrough 
format.  Added text is presented in bold format.


Onyx Therapeutics, Inc.
Clinical Study Protocol No. CFZ008
Carfilzomib for Injection
Page 114 of 117
CONFIDENTIAL
APPENDIX H:
SUMMARY OF CHANGES
Administrative updates, editorial changes, and style and formatting revisions have been made 
to improve clarity and consistency throughout the document.  Significant changes are
described in the table below.
Significant changes from the Original Protocol to Amendment 1 are:

Added PK sample collection times of 2 and 4 hours after the end of carfilzomib 
infusion

Germline DNA collection time moved to the end of Induction


SAP_001.pdf: 
Product:  AMG 981 (Carfilzomib) 
Protocol Number:  20140106 
Date:  29 August 2023 
Page 1 of 86 
CONFIDENTIAL 
 
 
Statistical Analysis Plan 
Protocol Title: 
Phase 1b/2 Study of Carfilzomib in Combination With 
Induction Chemotherapy in Children With Relapsed 
or Refractory Acute Lymphoblastic Leukemia 
Short Protocol Title: 
A Phase 1b/2 study of Carfilzomib in Pediatric ALL 
Protocol Number: 
20140106 (formerly CFZ008) 
NCT Number: 
NCT02303821 
Authors: 
, Ph.D., MS 
Biostatistics Senior Manager, Amgen Inc 
 
, Ph.D. 
Biostatistician, PAREXEL International  
 
, Ph.D. 
Biostatistics Director, Amgen Inc 
 
Sponsor: 
Onyx Therapeutics, Inc., an Amgen Inc. subsidiary 
One Amgen Center Drive 
Thousand Oaks, California 91320 
United States 
Phone: 1-805-447-1000 
Fax: 1-805-480-4978 
SAP Date:  
Document Version 
Date 
Original (v [1.0]) 
Amendment 1 (v [2.0]) 
Amendment 1 (v [2.0]) 
Amendment 2 (v [3.0]) 
09 January 2019  
21 August 2020 
15 March 2021 
29 August 2023 
 


Product:  AMG 981 (Carfilzomib) 
Protocol Number:  20140106 
Date:  29 August 2023 
Page 2 of 86 
CONFIDENTIAL 
 
 
Version Number 
Date 
(DDMMMYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
09 January 2019 
Original Version 
Amendment 1 (v2.0) 
21 August 2020 
Rationale: 
The purpose of this SAP amendment is for: 
The protocol amendment of adding a phase 2. 
The phase 2 externally-controlled study is a 
multicenter, single-group study of carfilzomib 
in combination with VXLD in pediatric 
subjects. 
 
Changes: 
List of Abbreviations and Definitions of Terms 
1.Introduction 
 
Added: 
phase 1b and 2 protocol for study 20140106, 
AMG 981/Carfilzomib dated 07August2020. 
This SAP also provides details of utilizing an 
external control arm from the observational 
study 20180065 to be used for the analysis of 
phase 2 in study 20140106 after propensity 
score adjustment.  The details are included in 
Appendix B. The scope of this document 
includes the interim analysis, the primary 
analysis and the final analysis that are 
planned and will be executed by the Amgen 
Global Biostatistical Science department 
unless otherwise specified, e.g., standard PK 
analysis may be provided by Clinical 
Pharmacology, Modeling and Simulation 
(CPMS). 
Appendix B: 
Added: 
Phase 2 Statistical Analysis Plan 
 
19 Nov 2020 
Per FDA’s feedback 
Updated: 
 
Table 23.1, Number of prior lines of salvage 
therapy is treated as categorical variable 
 
 
Added: 
 
Handling of missing data for covariates in 
Section 20.2 


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Protocol Number:  20140106 
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CONFIDENTIAL 
 
 
Version Number 
Date 
(DDMMMYYY) 
Summary of Changes,  
including rationale for changes 
 
Section 15.2 additional detail of sample size 
calculation 
 
 
 
Supportive analysis for primary endpoint of 
CR to descriptively compare with the best 
available therapy via literature search in 
Section 21.5.1 
  
15 Mar 2021 
Per protocol amendment V9.0 
Removed: 
In Section 21.5, Statistical comparison 
between experimental arm and external 
control arm of duration of response was 
removed and only descriptive statistics will be 
summarized. 
 
Updated: 
Details about the role of the independent 
biostatisticians who will support the futility 
efficacy analysis for Data Monitoring 
Committee (DMC) in Section 21.1. 
 
Handling of missing data for adverse events, 
concomitant medications, death, and anti-
cancer therapy are replaced by Amgen 
standard imputation rules in Appendix F. 
 
Per FDA request, the number of pre-specified 
covariates for the primary analysis was 
reduced.   
 
Some definitions were updated for 
administrative reasons. 
 
Added: 
Added 3 additional subgroups per protocol 
amendment V9.0: chemotherapy versus 
immunotherapy as last therapy prior to 
enrollment, anthracycline omitted from VXLD 
in induction (yes vs no), geographical region 
(EU vs Not EU) in Section 16.2. 
 


Product:  AMG 981 (Carfilzomib) 
Protocol Number:  20140106 
Date:  29 August 2023 
Page 4 of 86 
CONFIDENTIAL 
 
 
Version Number 
Date 
(DDMMMYYY) 
Summary of Changes,  
including rationale for changes 
Model selection algorithm has been removed 
from the primary analysis and added as a 
sensitivity analysis. 
 
The planned analyses for echocardiograms 
were added in Section 21.6.8. 
 
Added COVID-19 related analysis in Section 
21.2, 21.3 and 21.6.10 
Amendment 2 (v3.0) 
29 Aug 2023 
Major changes to align with protocol 
amendment 10/11 and 12: 
1. Section 16. Objectives and Endpoints: 
 
added “treatment response will be 
derived by the sponsor based upon 
local evaluation of bone marrow, 
peripheral blood, and 
extramedullary disease status.” 
 
reworded primary endpoint as “CR 
after induction therapy” 
 
reworded the secondary endpoint 
of response after consolidation 
therapy to “CR, CRp, CRh, and CRi 
after consolidation therapy”    
 
2. Section 17.2. Sample Size: 
 
changed sample size for CFZ-VXLD 
from “approximately 40 B-cell and 
60 T-cell ALL subjects” to “a 
minimum of 50 B-cell ALL subjects 
and a minimum of 30 T-cell ALL 
subjects” 
 
changed sample size for external 
control from “150 B-cell ALL 
subjects and 70 T-cell ALL 
subjects” to “approximately 74 B-
cell ALL subjects and 
approximately 60 T-cell ALL” 
subjects” 
 
updated the numbers in the table 
for sample size and power 
estimates accordingly 
 
changed the number of subjects in 
experimental arm at interim 
analysis (IA) from 50 to 60  
3. Section 18.2. Subgroup: 
 
added subgroup “History of 
primary induction failure” 


Product:  AMG 981 (Carfilzomib) 
Protocol Number:  20140106 
Date:  29 August 2023 
Page 5 of 86 
CONFIDENTIAL 
 
 
Version Number 
Date 
(DDMMMYYY) 
Summary of Changes,  
including rationale for changes 
 
changed the category of “Relapse 
time from prior allogeneic HSCT” 
to <12 months, ≥12 months, 
Unknown  
 
clarified age subgroup to Age at 
diagnosis and changed the 
categories to <1 year, 1 to <2 years, 
2 to <10 years, ≥10 years 
 
added subgroup Sex, Isolated bone 
marrow at relapse, Blast percent in 
bone marrow prior to the qualifying 
treatment 
 
changed geographical region 
category 
4. Section 19. Definitions: 
 
added a table to list all the study 
treatments 
 
changed the calculation of Actual 
Dose Intensity and Relative Dose 
Intensity by using treatment days 
instead of duration of treatment 
(days)  
 
changed the term ‘Disease 
response’ to ‘Treatment response’, 
and changed ‘complete response’ 
to ‘complete remission’; also 
changed the central lab for 
response evaluation to sponsor 
derived response per local 
evaluation 
 
updated the description of 
definition for EFS 
 
added the definition for CR rate, 
rate of CRi or better, last known 
alive date, history of primary 
induction failure 
 
updated the Study Day 1 definition 
to keep consistent with protocol 
 
added definition for MRD 
endpoints 
 
updated the definition of treatment 
response 
5. Section 20. Analysis Sets: 
 
removed “Full Analysis Set”  
 
added Induction Safety Analysis 
Set and Consolidation Safety 
Analysis Set 
 
added the IPDs that will be 
excluded from Per Protocol Set 
 
updated the Interim Futility 
Analysis Set 


Product:  AMG 981 (Carfilzomib) 
Protocol Number:  20140106 
Date:  29 August 2023 
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CONFIDENTIAL 
 
 
Version Number 
Date 
(DDMMMYYY) 
Summary of Changes,  
including rationale for changes 
 
removed Earliest Relapse Analysis 
Set 
6. Section 21. Planned Analyses: 
 
reorganized the paragraphs and 
updated the language for Interim 
Analysis section 
 
changed the sample size required 
in experimental arm at interim 
analysis from “approximately first 
50% (20 with B-cell and 30 with T-
cell)” to “at least 60 subjects” 
 
changed that the interim analysis 
will be performed by the IBG 
 
added “at least 100 enrolled” 
subjects in the experimental arm 
“have received at least one dose of 
carfilzomib” to Primary Analysis 
7. Section 22.3. Handling of Missing and 
Incomplete Data 
 
added initial ALL diagnosis, prior 
ALL therapy medication, prior 
HSCT, remission to prior ALL 
therapy, and relapse to prior ALL 
therapy 
8. Section 23.3. Subject Accountability 
 
added MRD sample disposition 
9. Section 23.5. Demographic and Baseline 
Characteristics 
 
added additional age groups 
 
added an additional demographics 
summary presenting side-by-side 
for phase 1 total, phase 2 total, and 
total of phase 1 and phase 2 to 
better characterize the 
demographics 
10. Section 23.6. Efficacy Analysis: 
updates in the efficacy endpoint 
summary tables and in the text:  
(a) specified that the descriptive 
summary of CR and CRi or better at 
the end of Induction, EFS, OS, and 
DOR will also be performed based on 
Safety Analysis Set and Per Protocol 
Set  
(b) removed sIPTW from the sensitivity 
analysis since the treatment effect is 
estimated based on the average 
treatment effect for treated (ATT) 


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Protocol Number:  20140106 
Date:  29 August 2023 
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Version Number 
Date 
(DDMMMYYY) 
Summary of Changes,  
including rationale for changes 
subjects per protocol, whereas sIPTW 
is based on the average treatment 
effect (ATE) for the entire population 
(c) removed the PS matching from the 
sensitivity analysis due to small 
sample size of B-cell and T-cell in each 
arm and an expected smaller sample 
size after PS matching  
(d) removed the Earliest Relapse 
Analysis Set from the sensitivity 
analysis due to small sample size for 
external control 
(e) added investigator assessed 
treatment response, and sponsor 
derived treatment response using 
central lab data for the sensitivity 
analysis 
11. Section 23.7. Safety Analysis:  
 
specified TEAEs definition for 
induction treatment period and 
consolidation treatment period 
 
added EOI (event of interest) and 
treatment related SAEs to the 
analysis 
 
removed lab analyte LDH and the 
table for the list of all lab tests 
 
added hydrocortisone to the list of 
CNS combination drugs 
 
specified (1) exposure summary 
will be separated for induction 
treatment period and consolidation 
treatment period; (2) exposure 
summary for IT chemotherapy, 
only includes number of doses 
administered, and ratio of number 
of actual doses to number of the 
protocol specified doses; (3) the 
number and percentage of subjects 
receiving VXLD or an approved 
alternate agent in induction 
chemotherapy will be summarized 
for each agent; (4) specified that 
the summary of total dose 
received, average dose per 
administration, actual dose 
intensity and relative dose 




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Protocol Number:  20140106 
Date:  29 August 2023 
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Version Number 
Date 
(DDMMMYYY) 
Summary of Changes,  
including rationale for changes 
and Date of Relapse to Prior ALL 
Therapy  
16. Appendix G. Treatment Response 
Definitions 
 
added this section to specify the 
definitions/derivations for 
treatment response of CR, CRp, 
CRh, CRi, and for PD, SD and NE 
17. The terminology complete response 
was changed to complete remission 
throughout the SAP. 


Product:  AMG 981 (Carfilzomib) 
Protocol Number:  20140106 
Date:  29 August 2023 
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CONFIDENTIAL 
 
 
1. 
Table of Contents 
1. 
Table of Contents ................................................................................................. 10 
2. 
Introduction ........................................................................................................... 17 
3. 
Phase 1 Objectives, Endpoints and Hypotheses ................................................... 17 
4. 
Objectives and Endpoints ..................................................................................... 17 
4.1 
Hypotheses and/or Estimations ................................................................. 18 
5. 
Phase 1 Study Overview....................................................................................... 18 
5.1 
Study Design ............................................................................................. 18 
5.2 
Sample Size .............................................................................................. 20 
5.3 
Adaptive Design ........................................................................................ 21 
6. 
Covariates and Subgroups ................................................................................... 21 
6.1 
Planned Covariates ................................................................................... 21 
6.2 
Subgroups ................................................................................................. 21 
7. 
Definitions ............................................................................................................. 21 
8. 
Analysis Sets ........................................................................................................ 25 
8.1 
Safety Analysis Set ................................................................................... 25 
8.2 
Response-Evaluable Analysis Set ............................................................. 25 
8.3 
Interim Analyses Set(s) ............................................................................. 25 
9. 
Planned Analyses ................................................................................................. 25 
9.1 
Interim Analysis and Early Stopping Guidelines ........................................ 25 
9.2 
Primary Analysis ....................................................................................... 25 
9.3 
Final Analysis ............................................................................................ 25 
10. 
Data Screening and Acceptance ........................................................................... 26 
10.1 
General Principles ..................................................................................... 26 
10.2 
Data Handling and Electronic Transfer of Data ......................................... 26 
10.3 
Handling of Missing and Incomplete Data ................................................. 26 
10.4 
Detection of Bias ....................................................................................... 26 
10.5 
Outliers ..................................................................................................... 26 
10.6 
Distributional Characteristics ..................................................................... 26 
10.7 
Validation of Statistical Analyses ............................................................... 26 
11. 
Statistical Methods of Analysis.............................................................................. 27 
11.1 
General Considerations ............................................................................. 27 
11.2 
Subject Accountability ............................................................................... 27 
11.3 
Important Protocol Deviations ................................................................... 27 
11.4 
Demographic and Baseline Characteristics ............................................... 28 
11.4.1 
Demographics ........................................................................... 28 
11.4.2 
Medical History .......................................................................... 28 


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Protocol Number:  20140106 
Date:  29 August 2023 
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11.4.3 
Disease Characteristics ............................................................. 28 
11.5 
Efficacy Analyses ...................................................................................... 29 
11.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 30 
11.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 30 
11.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 31 
11.6 
Safety Analyses ........................................................................................ 31 
11.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 31 
11.6.2 
Analyses of Exploratory Safety Endpoints ................................. 32 
11.6.3 
Adverse Events ......................................................................... 32 
11.6.4 
Laboratory Test Results ............................................................ 33 
11.6.5 
Vital Signs ................................................................................. 33 
11.6.6 
Physical Measurements ............................................................ 33 
11.6.7 
Electrocardiogram ..................................................................... 33 
11.6.8 
Antibody Formation ................................................................... 34 
11.6.9 
Exposure to Investigational Product .......................................... 34 
11.6.10 
Exposure to Other Protocol-specified Treatment ....................... 34 
11.6.11 
Exposure to Concomitant Medication ........................................ 34 
11.7 
Other Analyses ......................................................................................... 34 
11.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints. ........................ 34 
11.7.2 
Analyses of Clinical Outcome Assessments .............................. 35 
11.7.3 
Analyses of Health Economic Endpoints ................................... 35 
12. 
Changes from Protocol-specified Analyses ........................................................... 35 
13. 
Literature Citations / References ........................................................................... 36 
14. 
Appendices ........................................................................................................... 37 
Appendix A.  Reference Values/Toxicity Grades ........................................................... 37 
Appendix B.  Phase 2 Statistical Analysis Plan .............................................................. 38 
15. 
Introduction ........................................................................................................... 39 
16. 
Phase 2 Objectives, Endpoints and Hypotheses ................................................... 39 
16.1 
Objectives and Endpoints .......................................................................... 39 
16.2 
Hypotheses and/or Estimations ................................................................. 40 
17. 
Study Overview .................................................................................................... 41 
17.1 
Study Design ............................................................................................. 41 
17.2 
Sample Size .............................................................................................. 42 
18. 
Covariates and Subgroups ................................................................................... 45 
18.1 
Planned Covariates ................................................................................... 45 
18.2 
Subgroups ................................................................................................. 45 


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19. 
Definitions ............................................................................................................. 46 
20. 
Analysis Sets ........................................................................................................ 51 
20.1 
Primary Analysis Set (PAS) ....................................................................... 51 
20.2 
Safety Analysis Set ................................................................................... 51 
20.3 
Per Protocol Set(s) .................................................................................... 51 
20.4 
Interim Futility Analyses Set(s) .................................................................. 51 
20.5 
VXLD/ VPLD Analysis Set (VAS) .............................................................. 52 
20.6 
Chemotherapy Analysis Set (CAS) ........................................................... 52 
21. 
Planned Analyses ................................................................................................. 52 
21.1 
Interim Analysis and Early Stopping Guidelines ........................................ 52 
21.2 
Primary Analysis ....................................................................................... 53 
21.3 
Final Analysis ............................................................................................ 53 
22. 
Data Screening and Acceptance ........................................................................... 53 
22.1 
General Principles ..................................................................................... 53 
22.2 
Data Handling and Electronic Transfer of Data ......................................... 53 
22.3 
Handling of Missing and Incomplete Data ................................................. 53 
22.4 
Outliers ..................................................................................................... 54 
22.5 
Distributional Characteristics ..................................................................... 54 
22.6 
Validation of Statistical Analyses ............................................................... 54 
23. 
Statistical Methods of Analysis.............................................................................. 55 
23.1 
General Considerations ............................................................................. 55 
23.2 
Detection of Bias ....................................................................................... 55 
23.3 
Subject Accountability ............................................................................... 55 
23.4 
Important Protocol Deviations ................................................................... 56 
23.5 
Demographic and Baseline Characteristics ............................................... 57 
23.6 
Efficacy Analyses ...................................................................................... 57 
23.6.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 62 
23.6.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 64 
23.6.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 66 
23.7 
Safety Analyses ........................................................................................ 66 
23.7.1 
Analyses of Safety Endpoint(s) .................................................. 66 
23.7.2 
Adverse Events ......................................................................... 66 
23.7.3 
Laboratory Test Results ............................................................ 67 
23.7.4 
Vital Signs ................................................................................. 68 
23.7.5 
Physical Measurements ............................................................ 68 
23.7.6 
Karnofsky or Lansky Performance Status .................................. 68 
23.7.7 
Electrocardiogram ..................................................................... 69 
23.7.8 
Echocardiogram ........................................................................ 69 
23.7.9 
Antibody Formation ................................................................... 69 
23.7.10 
Exposure to Investigational Product .......................................... 69 


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23.7.11 
Exposure to Non-investigational Product ................................... 69 
23.7.12 
Exposure to Concomitant Medication ........................................ 70 
23.8 
Other Analyses ......................................................................................... 70 
23.9 
Changes from Protocol-specified Analyses ............................................... 70 
24. 
Literature Citations / References ........................................................................... 70 
 
 
 
 
 
 
 
 
Appendix F.  Handling of Incomplete Dates and Missing Dates ..................................... 81 
F1. Imputation Rules for Adverse Events and Concomitant Medications 
(other than the new anti-leukemia therapy) dates ...................................... 81 
F2. Imputation of the Subsequent Anti-cancer Therapy Start Date ....................... 82 
F3. Imputation of Partial/Missing Death Dates ...................................................... 82 
F4. Imputation for Date of Initial ALL Diagnosis .................................................... 82 
F5. Imputation for Start Date and End Date of Prior ALL Therapy 
Medication, Date of Prior Hematopoietic Stem Cell Transplant, 
Date of Remission (CRi or Better) to Prior ALL Therapy, and 
Date of Relapse to Prior ALL Therapy ....................................................... 83 
 
List of Table 
Table 11.1. Efficacy Endpoint Summary Table .............................................................. 30 
Table 17.1  Sample Size and Power Estimates for Hypothesized Treatment Effect ....... 43 
Table 23.1. Primary Efficacy Endpoint Summary Table ................................................. 57 
Table 23.2. Secondary Efficacy Endpoint Summary Table ............................................ 58 
Table 23.3. Exploratory Efficacy Endpoint Summary Table ........................................... 62 
Table C-1. Prognostic Factors Included in Propensity Score Model for Primary  
Analysis ....................................................................................................... 73 
Table C-2. Potential Prognostic Factors for Sensitivity Analyses ................................... 74 
Table F-1. Imputation Rules for Partial or Missing Start Dates ....................................... 81 
 


Product:  AMG 981 (Carfilzomib) 
Protocol Number:  20140106 
Date:  29 August 2023 
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List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
ANC 
Absolute Neutrophil Count 
ALL 
Acute Lymphoblastic Leukemia  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under Curve 
BLR 
Bayesian Logistic Regression 
BFM 
Berlin-Frankfurt--Münster 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CAR-T cell 
Chimeric Antigen Receptor T cell 
CAS 
Chemotherapy Analysis Set 
CBC 
Complete Blood Count 
CFZ 
Carfilzomib 
CI 
Confidence Interval 
Cmax 
Maximum Plasma Concentration 
CNS 
Central Nervous System 
COG 
Children’s Oncology Group 
CR 
Complete Remission 
CRh 
Complete Remission with partial hematological recovery  
CRi 
Complete Remission with incomplete hematologic recovery 
CRp 
Complete Remission without Platelet Recovery 
CRR 
Complete Remission Rate 
CSRC 
Cohort Safety Review Committee  
DE 1 
Dose Escalation Cohort 1 
DE 2 
Dose Escalation Cohort 2 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DMP 
Data Management Plan 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EFS 
Event Free Survival 


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eCRF 
Electronic Case Report Form 
GSO-DM 
Global Study Operations – Data Management 
IA 
Interim Analysis 
IBG 
Independent Biostatistics Group 
ID 
Induction Death 
IPTW 
Inverse Probability Treatment Weights 
IT 
Intrathecal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
Minimal Residual Disease 
MTD 
Maximum Tolerated Dose 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for 
Adverse Events 
NE 
Not Evaluable 
NGS 
Next Generation Sequencing  
NCRM 
New Continual Reassessment Method 
OR 
Odds ratio  
ORR 
Overall Response Rate 
OS 
Overall Survival 
PAS 
Primary Analysis Set 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PK 
Pharmacokinetics  
PoCR 
Probability of CR 
PR 
Partial Response 
PS 
Propensity Score 
R3 backbone 
Dexamethasone, Mitoxantrone, PEG asparaginase, Vincristine 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCT 
Stem Cell Transplant 
SD 
Stable Disease; Standard Deviation 
SoC 
Standard of Care 
TEAE 
Treatment-emergent Adverse Event 
Tmax 
Time to maximum plasma concentration  
TMP-SMX 
Trimethoprim-Sulfamethoxazole 


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VAS 
VXLD/VPLD Analysis Set 
VIF 
Variance Inflation Factor 
VXLD 
Daunorubicin, Dexamethasone, PEG asparaginase, Vincristine 
 
 


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2. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the phase 1b and 2 protocol for study 20140106, 
AMG 981/Carfilzomib dated 28 August 2023. This SAP also provides details of utilizing 
an external control arm from the observational study 20180065 to be used for the 
analysis of phase 2 in study 20140106 after propensity score adjustment.  The details 
are included in Appendix B. The scope of this document includes the interim analysis, 
the primary analysis and the final analysis that are planned and will be executed by the 
Amgen Global Biostatistical Science department unless otherwise specified, e.g., 
standard PK analysis may be provided by Clinical Pharmacology, Modeling and 
Simulation (CPMS). 
3. 
Phase 1 Objectives, Endpoints and Hypotheses 
4. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of 
carfilzomib, alone and in combination with 
induction chemotherapy, for the treatment of 
children with relapsed or refractory ALL 
Safety and tolerability of carfilzomib alone and 
in combination with induction chemotherapy 
as defined by the type, incidence, severity, 
and outcome of adverse events (AEs); 
changes from baseline in key laboratory 
analytes, vital signs, and physical findings. 
Time to toxicity will be evaluated to 
differentiate single-agent carfilzomib from 
carfilzomib in combination with induction 
chemotherapy 
To determine the MTD of carfilzomib in 
combination with induction chemotherapy and 
to recommend a phase 2 dose of carfilzomib 
in combination with induction chemotherapy 
Incidence of DLT  
(definition of DLT per protocol Section 8.3) 
Secondary 
To evaluate the combined rate of bone 
marrow CR and bone marrow CRp at the end 
of the Induction Cycle 
Combined proportion of subjects who achieve 
CR or CRp at the end of the Induction Cycle 
To characterize the PK of carfilzomib alone 
and in combination with induction 
chemotherapy 
Pharmacokinetic parameters, principally 
maximum plasma concentration (Cmax) and 
area under the curve (AUC), alone and in 
combination with induction chemotherapy, 
derived from levels of carfilzomib assayed in 
PK samples 
To estimate the proportion of subjects who 
achieve MRD status  10-3 and  10-4 
lymphoblasts at the end of the Induction Cycle 
Proportion of subjects who achieve Minimal 
Residual Disease (MRD) status  10-3 and 
 10-4 lymphoblasts at the end of the Induction 


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Cycle as assessed by next generation 
sequencing (NGS) 
 
Exploratory 
4.1 
Hypotheses and/or Estimations 
The number of DLTs and AEs at each dose level will be summarized separately for the 
carfilzomib single-agent Lead-in Window and the Induction Cycle.  Adverse events will 
also be summarized separately for subjects who receive the optional cycle of 
consolidation chemotherapy.  
5. 
Phase 1 Study Overview 
5.1 
Study Design 
This is a nonrandomized, multicenter, Phase 1b dose-escalation and dose-expansion 
study of carfilzomib in combination with induction chemotherapy, comprising either an 
R3 backbone of dexamethasone, mitoxantrone, PEG-asparaginase, and vincristine as 
Dose Escalation 1 (DE 1) or a VXLD backbone of vincristine, dexamethasone, 


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PEG-asparaginase and daunorubicin as Dose Escalation 2 (DE 2) in children with 
relapsed or refractory ALL. During the DE 1 portion of the study only, the Induction Cycle 
will be preceded by a 1-week carfilzomib single-agent Lead-in Window. Subjects in both 
dose escalation portions of the study will receive a 4-week cycle of induction 
chemotherapy and have the option to receive a 4-week cycle of consolidation 
chemotherapy, if stable disease or better response is achieved at the end of the 
Induction Cycle. 
The dose-escalation design will use the Bayesian 2-parameter logistic regression model, 
the new continual reassessment method (NCRM) applied to observed dose limiting 
toxicities (DLTs) occurring during the Lead-in Window and Induction Cycle 
(Neuenschwander 2008). The definition of DLT is provided in Section 8.3 of the protocol. 
Before starting a new cohort, the data available from the DLT evaluable subjects are 
applied to an algorithm that computes the posterior distribution of the DLT rate at each 
dose level using the prespecified prior distributions. The evaluation of posterior 
probabilities of the estimated DLT rate at each dose will be used in the dose-escalation 
decision and the final determination of the MTD: the target toxicity interval is 
(20 – 33) and the excessive/unacceptable toxicity interval is ( 33 – 100). 
A cohort size of 2 will be used in DE 1. The starting dose is 20 mg/m2; the maximum 
planned dose and the minimum planned dose are 45 mg/m2 and 20 mg/m2, respectively. 
One or more cohorts of 2 subjects may be enrolled to each dose level, depending on the 
observed toxicity. After every cohort has completed the 4-week Induction Cycle, the 
Cohort Safety Review Committee (CSRC) will review the safety data and dose level 
recommended by the algorithm. The CSRC will decide on expanding the dose level by 2 
subjects, advancing to the next dose level, de-escalating to a lower dose level, or 
determining the MTD. Unlike for de-escalation decisions, no dose level skipping will be 
allowed in dose escalation decisions. The algorithm will stop when the sample size 
reaches 18 or when the DLT rate of the recommended MTD has a 95 posterior 
credible interval within the pre-specified range of 5 to 60. 
A cohort size of 3 will be used in DE 2. The starting dose level is 27 mg/m2, while the 
planned dose levels are 27, 36, 45, 56 and 70 mg/m2. One or more cohorts of 3 subjects 
may be enrolled to each dose level, depending on the observed toxicity. After every 
cohort has completed the 4-week Induction Cycle, the CSRC will review the safety data 
and dose level recommended by the algorithm. The CSRC will decide on expanding the 


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dose level by 3 subjects, advancing to the next dose level, de-escalating to a lower dose 
level or determining the MTD. Unlike for de-escalation decisions, no dose-level skipping 
will be allowed in dose-escalation decisions.   
The algorithm will stop when the sample size reaches 24 or if both of the first two 
criteria, or the third criterion are met: 
 
The probability of the Target Toxicity interval at the candidate MTD exceeds 40 
AND 
 
A minimum of 2 cohorts (6 subjects) are accrued and treated at the candidate 
MTD 
OR 
 
The algorithm recommends a dose level that has been recommended twice and with 
6 subjects treated, and the CSRC agrees with the recommendation 
If clinically justified, CSRC may halt enrollment and recommend the MTD or the dose for 
the phase 2 study based on available data and the rules of the CSRC charter 
(See protocol Section 13.4). 
A minimum of 2 subjects (1 cohort) will be enrolled at the starting dose level in DE 1. A 
minimum of 3 subjects (1 cohort) will be enrolled at the starting dose level in DE 2.  
After each update from the NCRM algorithm, the results will be evaluated for the 
recommendation. The next dose level will be the dose with the highest posterior 
probability of having a toxicity rate in the target toxicity interval, (i.e., 20 – 33), and 
under the constraint that the probability of excessive/unacceptable toxicity 
(i.e.,  33 – 100), is less than 40. 
The MTD will be selected based on the above criteria or the stopping rules as specified 
in Section 5.2 of protocol and the recommendation of the CSRC. When the protocol 
conditions for ending the study are met, the CSRC will review the data and recommend 
on a dose for the Phase 2 study.  
5.2 
Sample Size 
The estimated sample size is based on the NCRM algorithm. A minimum 1 cohort 
(of 2 DLT-evaluable subjects) will be enrolled before the trial stops in the DE 1 portion of 
the study. A minimum 1 cohort (of 3 DLT-evaluable subjects) will be enrolled before the 
trial stops in the DE 2 portion. Based on previous simulation results, the algorithm 
generally finds the MTD with reasonable probability under various dose toxicity 


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distribution and prior assumptions with a maximum of 18 subjects in each dose 
escalation. 
Initially, approximately 18 subjects were planned to participate in each of the 2 dose 
escalations. After revising the protocol to add 2 dose levels, the sample size for VXLD 
portion has been expanded to 24 subjects. Additional subjects may be enrolled to treat 
up to 12 subjects at the MTD. A minimum of 3 subjects are targeted to be enrolled in 
each of the following age groups at the time of their enrollment onto this study: 
 
12 to  24 months old 
 
2 to  12 years old 
 
12 to 18 years old 
A minimum number for subject enrollment will not be applied to subjects over 18 years of 
age. No infants ( 12 months of age) will be enrolled, although subjects originally 
diagnosed with ALL during infancy are eligible if they are at least 12 months old at the 
time of study treatment initiation. 
5.3 
Adaptive Design 
Not Applicable. 
6. 
Covariates and Subgroups 
6.1 
Planned Covariates 
Not Applicable. 
6.2 
Subgroups 
Not Applicable 
7. 
Definitions 
Investigational Product (IP) 
IP for this study refers to Carfilzomib.  
Study Treatments 
Study treatments include carfilzomib, chemotherapy backbone of R3 or VXLD, and IT 
chemotherapy drugs. 
Study Day 1 
The date of the first dose of carfilzomib or any chemotherapy components of R3 or 
VXLD. 


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Study Day 
The number of days from the study day 1 to a date of interest, inclusive: 
Study day  (date of interest – study day 1)  1. 
End of Study Date for a Subject 
The end of study date is the date recorded on the End of Study page for an enrolled 
subject. 
Duration of Treatment 
Duration of treatment of a drug of interest is defined as the number of days  (date of 
last dose of the drug of interest – date of first dose of the drug of interest) 1. Duration of 
treatment with the chemotherapy combination is defined as the number of days  (date 
of last dose of any drug in the chemotherapy combination – date of first dose of any drug 
in the chemotherapy combination) 1. 
Number of Actual Treatment Days 
Number of actual treatment days is defined as the total number of days when a drug of 
interest was administered.   
Total Dose  
Total dose received of a drug of interest is defined as the cumulative total quantity that 
was actually administered for the specific drug of interest.  
Average Dose 
Average dose of a drug of interest is defined as the total dose received divided by the 
number of doses administered.  
Actual Dose Intensity 
Actual dose intensity of a drug of interest is defined as total dose of this drug divided by 
the product of baseline Body Surface Area (BSA) if applicable, and duration of treatment 
(days). 
Relative Dose Intensity 
Relative Dose Intensity () reflects whether the dose intensity of a drug of interest was 
implemented as planned. It is defined as 100 times the ratio of actual dose intensity to 
the intended dose intensity. Actual dose intensity is defined as above. Intended dose 
intensity is the planned cumulative dose divided by the protocol specified treatment 
duration in days.  Specifically, planned cumulative dose is the sum of protocol specified 


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dose (details in Section 8.1.1, Section 8.1.2, Figure 2, Section 8.1.3, and Figure 3 in 
protocol).  
Baseline Value 
Baseline value is the closest of recorded measurements prior to or on the Study day 1.  
If there are multiple valid lab measurements for the same analyte collected on the same 
date and time, then the baseline will be decided conservatively. The change from 
baseline is defined as the value of interest minus baseline value. 
Treatment emergent adverse events  
Treatment emergent adverse events (TEAEs) are defined as adverse events (AEs) that 
start on or after the first administration of study drug and within the end of the study or 
30 days of the last day of any study treatment, whichever occurs earlier.  An AE that is 
present before the first administration of study treatment and subsequently worsens in 
severity during treatment is also considered to be treatment emergent.  
DLT evaluable population  
DLT evaluable population is defined as all subjects who received all planned dose of 
carfilzomib and the chemotherapy backbone per protocol during the Lead-in window and 
Induction Cycle, or received at least one dose of carfilzomib and the chemotherapy 
backbone per protocol and experienced a DLT prior to completion of the Lead-in 
Window or Induction Cycle, or as clinically indicated. The DLT evaluable status is 
collected separately on a log reviewed and approved by the study team. 
Subject Incidence Rate 
The subject incidence rate for a given event is defined as the number of subjects with 
one or more reported occurrence of the event divided by the number of subjects who 
had the opportunity to experience the event. 
Primary refractory  
Primary refractory is defined as failure to achieve a CR, CRp, or CRi within 42 days 
(inclusive) after the start of therapy following the initial diagnosis. 
Refractory relapse  
A subject with refractory relapse has received 1 or more cycles of anti-leukemia therapy 
(exclusive of Section 6.2 of the protocol) between the most recent relapse and the 
enrollment in this study, and failed to achieve a CR, CRp, or CRi. Number of refractory 
therapies is the number of therapies a subject has received and failed to achieve a CR, 


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CRp, or CRi, between the most recent relapse and the time they were enrolled in this 
study.  
Duration of remission  
Duration of remission is defined as the time from the date of a response to a prior 
therapy with a remission, i.e., a response at least CR, CRp, or CRi, to the date of 
relapse. (e.g., the time between the date of the first remission to the date of the first 
relapse is the duration of first remission, the time between the date of the second 
remission to the date of the second relapse is the duration of the second remission, etc). 
Disease Response 
Disease response will be assessed by investigator and includes the following categories: 
complete remission (CR), complete remission without platelet recovery (CRp), 
complete remission with incomplete hematologic recovery (CRi), partial response (PR), 
stable disease (SD), progressive disease (PD), induction death (ID) and not evaluable 
(NE). The criteria for determining treatment response are defined in Section 10.2 of the 
protocol.  
Lead-in Window 
The Lead-in Window consists of 1 week of carfilzomib administration as a single agent, 
during the DE 1 portion of the study. More details are presented in Section 8.1.1 of the 
protocol. 
Induction Cycle 
The Induction Cycle consists of a 4-week cycle of treatment that includes carfilzomib and 
a combination chemotherapy backbone. During the DE 1, the Induction Cycle begins on 
Day 8 of the carfilzomib single agent Lead-in-Window. During the DE 2, Induction is the 
first cycle of therapy that the subject will receive starting with Day 1. More details are 
presented in Section 8.1 of the protocol. 
Consolidation Cycle 
The Consolidation Cycle begins on day 36 of the Induction Cycle (7 days after the 
Day 29 response assessment of the Induction period), or when the absolute neutrophil 
count (ANC) is  750/mcl and platelet count  75000/mcl, whichever comes later. It 
consists of a single 4-week cycle of carfilzomib in combination with Children’s Oncology 
Group (COG)- modified Berlin-Frankfurt-Münster (BFM) chemotherapy, and appropriate 
Central Nervous System (CNS) therapy. More details are presented in Section 8.1.3 of 
the protocol. 


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Subjects who reached SD, PR, CRp, CRi or CR at the end of their Induction Cycle may 
continue with this optional cycle. 
8. 
Analysis Sets 
8.1 
Safety Analysis Set 
The safety analysis set corresponds to the Safety Evaluable Population, defined as 
subjects receiving any amount of the study treatment regimen (chemotherapy backbone, 
carfilzomib, and any IT chemotherapy drugs). 
Based on the treatment period that subjects have started during the trial, the safety 
analysis set will be further defined as: 
 
The Lead-in Window Safety Analysis set, which includes the safety evaluable 
subjects who started carfilzomib in the Lead-in Window 
 
The Induction Safety Analysis set, which includes the safety evaluable subjects 
who started the Induction cycle.  
 
The Consolidation Safety Analysis set, which includes the safety evaluable 
subjects who started the Consolidation Cycle. 
8.2 
Response-Evaluable Analysis Set 
Response-evaluable analysis set corresponds to the Efficacy Evaluable Population, 
defined as the Safety Evaluable subjects who have a baseline disease assessment and 
at least one post-baseline disease assessment, or who dropped out due to AE prior to 
the first post-baseline disease assessment. Subsets of efficacy evaluable subjects will 
be further created based on the Safety Analyses subsets, as defined in Section 8.1, as 
needed. 
8.3 
Interim Analyses Set(s) 
Not Applicable. 
9. 
Planned Analyses 
9.1 
Interim Analysis and Early Stopping Guidelines 
No interim analysis is planned for this study.   
9.2 
Primary Analysis 
No primary analysis is planned for this study. 
9.3 
Final Analysis 
The trial will stop enrolling subjects when any of the stopping criteria specified in the 
protocol is satisfied. The Final analysis will be performed when the last subject enrolled 
had the opportunity to complete the study regimen and all required follow-up 
assessments. 


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10. 
Data Screening and Acceptance 
10.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
10.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. The database will be subject to edit checks outlined in the Clinical Data 
Management Plan (DMP). 
10.3 
Handling of Missing and Incomplete Data 
Assumptions for missing or partially missing dates for important variables will be made to 
allow inclusion of appropriate data records in the analyses.  
Imputed dates will not be presented in the listings. However, if the partial AE onset date 
information does not indicate whether the AE started prior to treatment or after the TEAE 
period, the AE will be classified as TEAEs. 
The handling of incomplete and partial dates for adverse events, concomitant 
medications, and death are described in Appendix F1 and Appendix F3. 
10.4 
Detection of Bias 
Not Applicable. 
10.5 
Outliers 
Outlier data will not be excluded unless scientifically justified. 
10.6 
Distributional Characteristics 
Not Applicable. 
10.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, while output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software. All statistical summaries and analyses will be 
performed in SAS System version 9.4 or later. The Bayesian algorithm is validated 
independently with EAST version 6 or higher.   


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11. 
Statistical Methods of Analysis 
11.1 
General Considerations 
Summaries of all data will be presented by initial dose level cohorts for each dose 
escalation, separately. Unless otherwise specified, the data will be presented for Safety 
Analysis Set. 
Summary statistics will be provided for selected endpoints.  For continuous variables, 
the number of subjects with non-missing data (n), mean, standard deviation, median, 
minimum, and maximum will be presented.  For discrete data, the frequency and percent 
distribution will be presented.  Unless otherwise indicated, percentages will be calculated 
with respect to the number of subjects in the analysis population in each dose group.   
Confidence intervals, when presented, will be constructed at the 2-sided 95 level. For 
binomial variables, exact distribution methods will be employed.   
Individual subject listings will be produced for selected endpoints using data recorded on 
the electronic case report forms (eCRFs) or derived data. 
11.2 
Subject Accountability 
The following subject disposition information will be summarized descriptively: 
 
Number of enrolled subjects 
 
Number of treated subjects (Safety population)  
 
Number () of subjects who discontinued investigational product and 
non-investigational products and the primary reasons for discontinuation. The 
percentage is calculated with respect to Safety population. 
 
Number () of subjects who discontinued study and the primary reason for 
discontinuation. The percentage is calculated with respect to Safety population. 
 
Number of subjects who have initiated Lead-in Window, Induction Cycle and 
Consolidation Cycle. 
11.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study and prior 
to the database lock.  These definitions of IPD categories, sub-category codes, and 
descriptions will be used during the study. The final IPD list provided by the study team 
will be used for the summary table and listing. Violations of the inclusion and exclusion 
criteria in the protocol will be included. 


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11.4 
Demographic and Baseline Characteristics 
11.4.1 
Demographics 
Demographic data includes age (continuous, categorical:  2, 2-11, 12-17,   18, and 
EMA-specified age groups: New born 0-27 days, Infants and toddlers 
28 days-23 months, Children 2-11 years, Adolescents 12-17 years, 18-64 years), sex, 
ethnicity, race, weight (kg), height (cm), BSA (m2), and BMI (kg/m2) at baseline.  
11.4.2 
Medical History 
The number () of subjects who experienced a prior disease or disorder will be 
summarized by system organ class and preferred term.   
11.4.3 
Disease Characteristics 
The following baseline disease characteristics will be summarized: 
 
Type of ALL 
 
Duration from initial diagnosis of ALL (in months) 
 
WBC result at diagnosis 
 
Primary refractory (a.k.a. Induction failure) 
 
Relapse 
o Refractory relapse  
▪ 
Number of refractory therapies after the qualifying relapse 
 
Number of relapses to any prior therapy 
 
Location(s) of the most recent relapse (bone marrow, CNS, testicular, and more 
as indicated by investigator) 
 
Number of prior therapies 
 
Duration of first remission ( 18 months, 18 to 36 months, and  36 months) 
 
Duration of last remission prior to the qualifying relapse  
 
If received, days from prior allogeneic stem cell transplant to enrollment (days) 
 
Lansky Play-Performance Scale 
 
Peripheral Lymphoblasts Count  
 
Peripheral white blood cell count (WBC)  
 
Platelet counts 
 
Cytogenetics 
The date of receiving prior stem cell transplant (SCT) is imputed as the stop date of the 
last drug in the corresponding regimen2 days. The prior regimen corresponding to a 
SCT was determined as regimen containing total body radiation, busulfan, thio-tepa, 


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anti-thymocytes globulin, or specified as a stem cell transplant in ALL prior therapy 
history. The final list of subjects with prior SCT will be determined by clinical review.  
11.5 
Efficacy Analyses 
The efficacy analyses will be based on subject data collected through study 
discontinuation or at the end of maximal treatment duration plus 30 days of safety 
follow-up, whichever occurs first. Although the primary analyses will use the Safety 
Analysis Set, additional efficacy analyses may be performed on the Response Evaluable 
Analysis Set. 
Response assessment data including the response status and the MRD status 
( 10-3 and  10-4 lymphoblasts) will be listed. 


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Table 11.1.  Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method 
(Specify Analysis Set if FAS is Not Used) 
Sensitivity 
Analysis 
Secondary Endpoints 
Combined proportion of 
subjects who achieve CR or 
CRp at the end of the 
Induction Cycle 
 
Summarize proportion of subjects who 
achieve CR or CRp at the end of the 
Induction Cycle. Generate 2-sided exact 
Clopper-Pearson 95 confidence 
interval. The analysis will be done in 
Induction Safety Analysis Set and 
Induction Response Evaluable Analysis 
Set. 
NA 
Proportion of subjects who 
achieve MRD status  10-3 and 
 10-4 lymphoblasts at the end 
of the Induction Cycle  
 
Summarize proportion of subjects who 
achieve MRD status  10-3 and 
 10-4 lymphoblasts at the end of the 
Induction Cycle for each assessment 
method. Generate 2-sided exact 
Clopper-Pearson 95 confidence 
interval. The analysis will be done in 
Induction Safety Analysis Set and 
Induction Response Evaluable Analysis 
Set. 
 
Additionally, the proportion of subjects 
who do not have adequate data 
regarding the MRD status will be 
summarized, and the reasons for 
inadequate data will be tabulated. 
NA 
11.5.1 
Analyses of Primary Efficacy Endpoint(s) 
Not Applicable. 
11.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The following analyses will be done on the induction safety analysis set and on the 
induction response evaluable set. 
Summarize proportion of subjects who achieve CR or CRp at the Induction Cycle 
Day 29. The 2-sided exact Clopper-Pearson 95 confidence interval will be generated. 
The analysis will be done in Induction Safety Analysis Set and Induction Response 
Evaluable Analysis Set. 
Summarize proportion of subjects who achieve MRD status  10-3 and 
 10-4 lymphoblasts at the Induction Cycle Day 29. Generate 2-sided exact 
Clopper-Pearson 95 confidence interval. The analysis will be done in Induction Safety 
Analysis Set and Induction Response Evaluable Analysis Set. Additionally, the 


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proportion of subjects who do not have adequate data regarding the MRD status will be 
summarized, and the reasons for inadequate data will be tabulated. 
11.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
11.6 
Safety Analyses 
The safety analyses will be based on the safety evaluable population and will be 
presented separately for each dose escalation and each dose level. All summaries will 
be presented by the assigned dose level for each safety analysis subset as defined in 
Section 8.1.  
11.6.1 
Analyses of Primary Safety Endpoint(s) 
The safety and tolerability will be assessed through summaries of study drug 
administration, review of the incidence of TEAEs, SAEs, selected search strategies for 
specified medical concepts, changes from baseline in selected laboratory analytes, vital 
signs, and physical findings. These primary safety endpoints will be summarized 
separately for the carfilzomib single-agent Lead-in Window and the Induction Cycle 
treatment periods.   
For Lead-in window safety analysis set, TEAEs that started within the first dose of 
Lead-in window treatment (inclusive) to the earlier of the end of safety follow-up 
(inclusive), or the first dose of induction cycle treatment (not inclusive), will be included in 
this analysis.   
For the Induction safety analysis set, TEAEs that started within the first dose of induction 
cycle treatment (inclusive) to the earlier of the end of safety follow-up (inclusive), or the 
first dose of consolidation cycle treatment (not inclusive) will be included in this analysis. 


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11.6.2 
Analyses of Exploratory Safety Endpoints 
11.6.3 
Adverse Events  
Each reported AE term will be mapped to a preferred term (PT) and a system organ 
class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA, 
version 23.1).  
The subject incidence of TEAEs will be summarized for all TEAES, TEAEs of grade 3 or 
higher, treatment-related AEs, serious AEs, AEs leading to discontinuation of 
investigational product, fatal AEs, tabulated by SOC and PT in descending order of 
frequency and by PT in descending order of frequency without regard to SOC. The 
maximum NCI - CTCAE 4.03 toxicity grade and strongest causal relationship to study 
treatment will be evaluated, and the TEAEs will be also summarized by severity and 
relationship to the study drugs.  
Subject incidence of events of interest (EOI), grade 3 or higher EOI, and serious EOI as 
standardized MedDRA queries and/or Amgen customized queries will be summarized by 
PT in descending order of frequency.  
An overall summary of TEAEs will present the number () of subjects with:  
o with at least one TEAE 
o with at least one treatment-related TEAE 
o with at least one carfilzomib-related TEAE 
o with at least one grade   3,  5 TEAE  
o with at least one treatment-related grade   3,  5 TEAE 
o with at least one SAE 
o with at least one grade 3 or higher hematological AEs 
o with TEAE leading to discontinuation of all study drugs 
o death within 30 days of last dose of study drug 
Hematological AEs includes the Blood and Lymphatic system disorders SOC and the 
Haematology investigations (including blood groups) HLGT.   
The DLTs are assessed by investigators according to the definition described in 
Section 8.3 of the protocol.  


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The subjects who experienced DLT, the detail of subject’s DLT(s), and subjects’ DLT 
evaluable status will be summarized in subject level listings. 
All TEAE data will be listed by study site, dose level, subject identification number, and 
study day.  Similar listings will be produced separately for all SAEs.  
11.6.4 
Laboratory Test Results 
Actual values and change from baseline for laboratory measurements will be 
summarized.  
The hematology laboratory analytes of interest are: 
 
CBC with differential (i.e., Total Neutrophils, Eosinophil, Basophils, Lymphocytes, 
Monocytes, Lymphoblasts) and platelet count 
The chemistry laboratory analytes of interest are: 
 
Electrolytes: Sodium, Potassium, Chloride, Bicarbonate, Corrected Calcium, 
Magnesium, Phosphorus, Phosphate 
 
Blood glucose 
 
Renal function: blood urea nitrogen (BUN), Creatinine 
 
Hepatic function: Aspartate Aminotransferase (AST), Alanine Aminotransferase 
(ALT), total and direct bilirubin, Alkaline Phosphatase (ALP), albumin 
 
Pancreatic function: amylase, lipase 
 
Uric acid 
 
Bone-specific ALP 
All laboratory data will be summarized by NCI-CTCAE grade. Shift of grade in laboratory 
test results will be summarized. 
11.6.5 
Vital Signs 
Actual value and change from baseline for vital sign results including blood pressure, 
pulse, respiratory rate, and temperature will be summarized.  
11.6.6 
Physical Measurements 
Actual value and change from baseline for the physical measurements, including height, 
weight, and BSA, will be summarized. 
11.6.7 
Electrocardiogram 
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring and will be presented in subject 
listings.   


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11.6.8 
Antibody Formation 
Not Applicable. 
11.6.9 
Exposure to Investigational Product 
Descriptive statistics in terms of treatment duration (days), number of actual treatment 
days, total dose received, number of dose administered, average dose per 
administration, actual dose intensity, and relative dose intensity will be produced to 
describe the exposure to carfilzomib.  
11.6.10 
Exposure to Other Protocol-specified Treatment 
All the analyses planned for IP will be carried over for each drug in any chemotherapy 
combination and CNS treatment combination, if applicable. For CNS combination drugs, 
exposure will be summarized for CNS positive and negative separately. Number of oral 
administration and total dose received will be summarized for 
trimethoprim-sulfamethoxazole (TMP-SMX). 
11.6.11 
Exposure to Concomitant Medication 
The number () of subjects receiving concomitant medication will be summarized by 
medication PT as coded by the World Health Organization Drug (WHO DRUG) 
dictionary version September 2018 or later in descending order of frequency. 
11.7 
Other Analyses 
11.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/
 
Endpoints. 
The PK parameter estimates for carfilzomib will be estimated from plasma 
concentration-time profiles using standard noncompartmental approaches over the 
complete sampling interval.  Carfilzomib PK parameters may include area under the 
concentration-time curve (AUC), maximum observed plasma concentration (Cmax), and if 
feasible, plasma terminal half-life.  Parameter estimates will be tabulated and 
summarized (i.e., mean, standard deviation).  These data will also be used in a 
population PK analysis to evaluate the effects of subject demographic characteristics 
and covariates on carfilzomib PK parameters.  
 


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PK 
 analyses will be provided by Clinical Pharmacology, Modeling & 
Simulation (CPMS).  Details of this analysis will be reported separately. 
  Details of 
this analysis will be reported separately. 
11.7.2 
Analyses of Clinical Outcome Assessments 
Not Applicable. 
11.7.3 
Analyses of Health Economic Endpoints 
Not Applicable. 
12. 
Changes from Protocol-specified Analyses 
In protocol Section 13.6.4, it is specified that “For the proportion of subjects with a 
decreased percentage of lymphoblasts in the bone marrow at the end of a 1-week 
carfilzomib single-agent Lead-in Window, the 1-sided exact Clopper-Pearson 
95 confidence interval will be generated”. In this SAP, the confidence interval was 
changed to 2-sided. 


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In protocol Section 13.6.2, it is specified that “Relevant laboratory and vital sign 
(temperature, heart rate, respiratory rate, and blood pressure) data will be displayed by 
visit and time (when available), with NCI-CTCAE (Version 4.03) Grade 3 and 4 values 
identified where appropriate.” In this SAP, vital signs will not be graded by NCI-CTCAE 
(version 4.03) and not displayed with NCI-CTCAE (version 4.03) grade 3 and 4 values.  
In protocol Section 13.1.1, the primary endpoint is specified that ‘Determination of the 
MTD as the dose that has the highest posterior probability of having a DLT rate within 
the target toxicity interval (20–33), while the posterior probability of 
excessive/unacceptable toxicity ( 33–100) is less than 40 (per BLRM algorithm), 
or the stopping rules as specified in Section 5.2, and per CSRC recommendation.’  In 
this SAP, the endpoint for the primary objective of determination of MTD is incidence of 
DLT.  
13. 
Literature Citations / References 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach 
to phase I cancer trials. Statist Med. 2008; 27:2420–39. 


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14. 
Appendices 
Appendix A.  Reference Values/Toxicity Grades 
Laboratory Values 
Safety laboratory values below a distinct limit (e.g., detection limit documented as 
“ [limit]”) will be substituted by half of the limit and values above a distinct limit 
(documented as “ [limit]”) will be substituted by the limit itself for all analyses. A Grade 
will be assigned to each laboratory based on CTCAE version 4.03. Values not meeting 
any of the criteria will be assigned a grade 0. 
 


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Appendix B.  Phase 2 Statistical Analysis Plan 


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15. 
Introduction 
This part of the document includes the details of the Statistical Analysis Plan (SAP) that 
have been outlined within the phase 2 protocol amendment 12 for study 20140106, dated 
28 August 2023. The scope of this plan includes the interim futility analysis, the 
primary analysis and the final analysis that are planned and will be executed by the 
Amgen Global Biostatistical Science department unless otherwise specified.   
16. 
Phase 2 Objectives, Endpoints and Hypotheses 
16.1 
Objectives and Endpoints 
All primary and secondary objectives will be analyzed for T-cell and B-cell acute 
lymphoblastic leukemia (ALL) populations separately, unless otherwise specified. For 
the primary and secondary endpoint evaluation, treatment response will be 
derived by the sponsor based upon local evaluation of bone marrow, peripheral 
blood, and extramedullary disease status.  The definitions of complete remission 
(CR), complete remission without platelet recovery (CRp), complete remission 
with partial hematological recovery (CRh), complete remission with incomplete 
hematologic recovery (CRi), stable disease (SD) and progressive disease (PD) are 
described in Appendix G according to the criteria in Table 26 of protocol. Minimal 
residual disease (MRD) status will be determined per central lab review of bone 
marrow MRD using NGS.  
 
Objectives 
Endpoints 
Primary 
 Compare the rate of CR of CFZ-VXLD at 
the end of induction therapy to an 
appropriate external control.  
  CR after induction therapy  
Secondary 
 Evaluate the safety and tolerability of CFZ-
VXLD 
 Incidence of treatment-emergent and 
treatment-related adverse events and 
severe adverse events and laboratory 
abnormalities during the induction therapy 
and consolidation therapy 
 Compare the rate of CR, CRp, CRh, and 
CRi of CFZ-VXLD at the end of induction 
therapy relative to an appropriate external 
control 
 CR, CRp, CRh and CRi at the end of 
induction therapy  
 Compare EFS for CFZ-VXLD to an 
appropriate external control 
 EFS, defined as time from initiation of 
therapy until treatment failure (defined as 
failure to reach at least a CRi after 
consolidation or after induction in subjects 


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that do not receive consolidation), relapse, 
or death from any cause 
 Compare OS for CFZ-VXLD relative to an 
appropriate external control 
 OS defined as time from initiation of 
therapy until death from any cause 
 Estimate the DOR for CFZ-VXLD and an 
appropriate external control 
 DOR, defined as time from earliest of CR, 
CRp, CRh, or CRi to relapse or death from 
any cause 
 Estimate the rate of MRD[-] at the end of 
induction in subjects receiving CFZ-VXLD 
 MRD status using NGS less than 10-4 
after induction therapy in subjects 
achieving CR 
 Estimate the rate of (MRD[-]) bone marrow 
after induction and consolidation therapy in 
subjects with B-cell ALL or T-cell ALL 
receiving CFZ-VXLD 
 MRD status using NGS less than 10-3 and 
less than 10-4 in subjects achieving CR, 
CRp, CRh, or CRi after induction and 
consolidation therapy, separately 
 Estimate the proportion of subjects that 
bridge to stem cell transplant or CAR-T cell 
therapy in subjects receiving CFZ-VXLD 
 Occurrence of a stem cell transplant or 
CAR-T, without an intervening relapse after 
protocol specified therapy 
 Estimate the rate of CR, CRp, CRh and 
CRi of CFZ-VXLD at the end of 
consolidation therapy in subjects receiving 
CFZ-VXLD 
 CR, CRp, CRh, and CRi after consolidation 
therapy  
 Estimate the pharmacokinetics of 
carfilzomib when administered as part of 
VXLD regimen 
 Carfilzomib pharmacokinetics parameters, 
including AUC, Cmax, and if feasible t1/2 
Exploratory 
 
16.2 
Hypotheses and/or Estimations 
The primary hypothesis is that CFZ-VXLD is superior to standard-of-care with regards to 
CR rate.  This corresponds to evaluating whether the 95 CI for the adjusted odds ratio 


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(OR) between CR rate of CFZ-VXLD subjects versus external control subjects excludes 
1 for each phenotype (B-cell/T-cell) independently (H0: lower bound of 95% CI for OR 
is less than or equal to 1; H1: lower bound of 95% CI for OR is higher than 1). 
17. 
Study Overview 
17.1 
Study Design 
The phase 2 portion of the study is a multicenter, single-group, externally-controlled 
study of carfilzomib in combination with VXLD in a minimum of 100 pediatric subjects, 
unless futility is met.  Eligible subjects must be greater than or equal to 1 month to less 
than 21 years old, with their original diagnosis at less than 18 years of age, and must 
have ALL with bone marrow relapse (greater than or equal to 5 leukemia blasts in 
bone marrow) or refractory relapse with or without extramedullary disease of the T-cell 
phenotype or of the B-cell phenotype after having received a targeted B-cell immune 
therapy (e.g., blinatumomab, inotuzumab, or CAR-T therapy).  Infants enrolling on this 
study will receive a modified VXLD and optional consolidation based on the dose and 
schedule used in COG AALL15P1 study.   
The carfilzomib dose for phase 2 will be 20 mg/m2 on day 1 of induction, 56 mg/m2 on 
days 2, 8, 9, 15, and 16 of induction and days 1, 2, 8, 9, 15, and 16 of consolidation. 
Eligible subjects will be treated with VXLD plus carfilzomib for 1 cycle (induction), 
followed by assessment of treatment response. All subjects who do not show 
progression during induction will undergo a bone marrow and extramedullary disease 
evaluation after completion of induction therapy between day 29 to 45 of induction 
(between day 35 to 50 for infants), based on blood count recovery but before the start of 
post-induction therapy, whichever comes first. Response will be assessed per local 
and central laboratory review of bone marrow, peripheral blood and differential, and 
local assessment for sites of extramedullary disease.  MRD will be assessed by NGS 
central laboratory review and local evaluation by flow cytometry and/or PCR or NGS 
when available. 
Subjects without disease progression (as defined in protocol Table 26) after induction 
may, at the investigator’s discretion, be treated with 1 cycle of consolidation 
chemotherapy plus carfilzomib. Subjects who do not show disease progression during 
consolidation will be assessed for treatment response between day 29 to 45 of 
consolidation (between day 36 to 50 for infants), based on blood count recovery prior to 
the start of alternative therapy. 


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Treatment response after consolidation therapy will also be assessed per local and 
central laboratory review of bone marrow, peripheral blood counts and differential, and 
local assessment for sites of extramedullary disease. MRD will be assessed by NGS 
central laboratory review and local evaluation by flow cytometry and/or PCR or 
NGS when available. The consolidation treatment will consist of one 28-day cycle of 
Children’s Oncology group-modified Berlin-Frankfurt-Munster (BFM) therapy as detailed 
in the protocol. After completion of study therapy, subjects will be followed for 
subsequent treatment(s), event-free survival, overall survival, duration of 
remission and ability to bridge to transplant. 
For selected objectives, the treatment response to induction of subjects receiving CFZ-
VXLD will be compared to an external control arm of subjects from an observational 
study of relapsed or refractory pediatric ALL (study 20180065) that received standard-of-
care (SoC) therapy, after appropriate adjustment using logistic regression model with 
inverse probability treatment weights (IPTW) for the average treatment effect of the 
treated (ATT). These weights are derived for each CFZ-VXLD and control subject based 
on their propensity score (PS) for receiving CFZ-VXLD. More details provided in Section 
23.6.1 
 
17.2 
Sample Size 
The sample size was determined based on practical considerations and limited phase 1 
data available as per Section 18.2.4 of the protocol. Due to the rarity of the subject 
population, at least 100 subjects are expected to receive at least one dose of 
carfilzomib in phase 2 part of the study. A minimum of 50 B-cell ALL subjects and 
a minimum of 30 T-cell ALL subjects are planned to be enrolled, in order to reach more 
than 70 power for testing the primary hypothesis for at least one phenotype (B-cell or/ 
and T-cell) at 2-sided alpha of 0.05 without multiplicity adjustment, with a non-binding 
interim futility analysis. 
The external control arm will be selected from the observational study 20180065 
which retrospectively collects data on pediatric patients with relapsed and 
refractory T-cell and B-cell ALL treated with contemporary salvage therapy. The 
external control arm will be selected to be as similar as possible to subjects 
enrolled in Study 20140106, as described in study 20180065 protocol/statistical 
analysis plan (SAP).  


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The external control arm is expected to include approximately 74 B-cell ALL subjects 
and approximately 60 T-cell ALL subjects as per the Primary Analysis Sets (T-PAS/B-
PAS) included in Study 20180065 protocol/SAP.  
For selected objectives, the response and disease status for each subject will be 
derived by the sponsor based upon the local assessments and following the 
definitions included in protocol Table 26. The details of the derivation algorithm 
are specified in the Appendix G. 
Additionally, based on the characteristics of subjects enrolled into the phase 1b part of 
the study, and after appropriate propensity score adjustment, the CR rates in the 
external control arms are expected to be 25 for B-cell and 15 for T-cell subjects 
respectively, and approximately 60 for B-cell and 30 for T-cell subjects from CFZ-
VXLD arm. As these estimates are based on data available so far, as detailed in 
Section 18.2.4 of the study 20140106 protocol, additional scenarios proposed for 
experimental arm CR rates, sample sizes and the power/external control sample 
sizes expected in these cases are included in Table 17.1.  
Table 17.1 Sample Size and Power Estimates for Hypothesized Treatment Effect 
Phenotype Control Arm 
CRR 
CFZ-VXLD 
Arm CRR 
Control Arm 
Sample Size  
CFZ-VXLD 
Arm Sample 
Size  
Power* 
B-cell  
0.25  
0.5  
74  
50  
0.70  
B-cell  
0.25  
0.55  
74  
50  
0.85  
B-cell  
0.25  
0.6  
74  
50  
0.94  
B-cell  
0.25  
0.5  
66  
56  
0.72  
B-cell  
0.25  
0.55  
66  
56  
0.86  
B-cell  
0.25  
0.6  
66  
56  
0.94  
B-cell  
0.25  
0.5  
62  
60  
0.71  
B-cell  
0.25  
0.55  
62  
60  
0.87  
B-cell  
0.25  
0.6  
62  
60  
0.95  
T-cell  
0.15 
0.3 
60 
30 
0.24 
T-cell  
0.15 
0.3 
60 
40 
0.27 
 
a The power was adjusted by a factor of 0.99 due to the interim analysis for futility.  
CRR= complete remission rate 
 
 
The hypothesized treatment effect size was determined based on the covariates 
predictive of CR observed in the phase 1 portion of the trial and the CR rates reported in 


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the literature for those characteristics (more details are provided in protocol Section 
18.2.4). 
For each phenotype separately (B-cell/T-cell), H0 will be rejected at the primary 
analysis if the 95 confidence interval (CI) of the adjusted OR from the propensity 
adjusted model is above 1. The power was estimated assuming that both treatment 
arms will be balanced with respect to baseline prognostic factors after propensity score 
adjustment, the control arm probability of CR (PoCR) will be consistent at the time of 
interim futility analysis and primary analysis, the odds ratio of PoCR is 1 under H0, and 
the power loss is at most 0.01 under H1. The power was adjusted by a factor of 0.99 
due to futility check. 
Since the variance of the log odds ratio will be inflated with the IPTW-ATT method 
compared to a non-weighted model, the estimates were adjusted by a variance 
inflation factor of 1.4 obtained via simulation using data from the blinatumomab B-cell 
ALL pediatric US study 20140228 and EU study 20120299.  The inflation factor was 
selected as the empirical 95 confidence interval upper limit using the sandwich 
estimator of the log odds ratio standard error. A grid search approach was used to 
estimate the sample size needed for the test.  For each candidate number of subjects 
for the test arm, the lower bound of the 95 CI of the odds ratio (incorporating variance 
inflation factor) for each possible pair of outcomes was calculated and compared with 
1. Power was derived as the summation of the joint probabilities of those pairs of 
outcomes with a lower bound greater than 1. T
 
  
The final selection of external control arm subjects included in the Primary Analysis 
Set (PAS) is anticipated to occur prior to the primary analysis, but not prior to initiation 
of study enrollment.  The interim futility analysis set will include approximately 60 
subjects (60% of the planned number of subjects) from the experimental CFZ-
VXLD arm who have received at least one dose of carfilzomib and have had the 
opportunity to complete a post induction response evaluation, and all available 
subjects from the external control arm by the time of interim analysis (as defined 
in Interim Analysis Set [T-IAS/B-IAS] of Study 20180065 protocol/SAP). 


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18. 
Covariates and Subgroups 
18.1 
Planned Covariates 
 
 
18.2 
Subgroups 
Primary endpoint (CR) and selected secondary endpoints (CRi or better, EFS, and OS) 
will be explored in the following subgroups of interest using the Primary Analysis Set (as 
defined in Section 20.1.1).  Analyses will be performed separately for B-cell and T-cell 
ALL populations, unless otherwise specified. When the number of subjects in the 
subgroup is not sufficient (i.e., less than 20 of subjects in a treatment arm), relevant 
subgroups may be combined. In these subgroup analyses, all treatment arm subjects will 
receive a weight of 1 while control arm subjects will be IPTW-ATT weighted, with the 
same weights used for the primary analysis of the primary endpoint. Odds Ratio (OR) and 
95 CI will be produced for CR, and CRi or better.  Hazard Ratio (HR) and 95 CI will be 
produced for EFS and OS. 
 
History of prior allogeneic HSCT (yes, no) 
 
History of primary induction failure (yes vs no)  
 
Relapse time from prior allogeneic HSCT (months) [<12, ≥12, unknown 
(including patients without HSCT)] 
 
Early T cell precursor phenotype at time of initial diagnosis (yes, no, unknown) 
(for T cell phenotype only) 
 
Number of prior relapses (1, 2,  2) 
 
Refractory qualifying relapse (yes, no) 
 
Cytogenetic risk at time of initial diagnosis (high risk, non-high risk, 
unknown. High risk  t [9:22], MLL translocation, hypodiploidy [ 44 
chromosomes]) (only for B-cell phenotype) 
 
Duration of first remission (months) ( 18, 18 to 36,   36, missing) 
 
Age at diagnosis (years) (<1, 1 to  2, 2 to  10,  10) 
 
Sex (male, female, unknown) 
 
Isolated bone marrow at relapse (yes, no) 
 
Blast percent in bone marrow prior to the qualifying treatment (<50%, ≥50%) 
 
Geographical region (Region 1, Region 2)  
- 
Region 1 includes countries that participated in 20140106 phase 1 
(US, Denmark, France, Italy, Spain, Austria, Australia)  


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- 
Region 2 includes all other countries added to 20140106 phase 2 
that did not participate in phase 1 
The additional secondary endpoints:  occurrence of a SCT or CAR-T, and MRD [-] status 
will be estimated in the same subgroups listed above, using the Safety Analysis set with 
no adjustment. 
19. 
Definitions 
Average Dose 
Average dose of a drug of interest is defined as the total dose received divided by the 
number of doses administered. 
Actual Dose Intensity 
Actual dose intensity of a drug of interest is defined as total dose of this drug divided by the 
product of baseline Body Surface Area (BSA) if applicable, and the number of actual 
treatment days. The days without dosing during the treatment period will not be 
included. For BSA calculation rule, please refer to protocol.  
Relative Dose Intensity 
Relative Dose Intensity () of a drug of interest reflects whether the dose intensity of the 
specified drug was implemented as planned. It is defined as 100 times the ratio of actual 
dose intensity to the intended dose intensity. Intended dose intensity is defined as the 
planned cumulative of study treatment per the schedule listed in protocol divided by the 
number of the protocol specified treatment days.  
Number of Actual Treatment Days 
Number of actual treatment days of a drug of interest is defined as the total number of 
days when a drug of interest was administered.   
Baseline Value 
Baseline value is the closest of recorded measurements prior to or on the Study day 1. The 
change from baseline is defined as the value of interest minus baseline value. 
Cytogenetics Risk 
The high risk cytogenetics for subjects in the B cell ALL group is defined by the presence of 
t (9:22), MLL translocation, or hypodiploidy (44 chromosomes). The non-high risk group 
consists of subjects with known cytogenetics data that is none of the above three 
cytogenetic findings. 
 


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Complete remission (CR) rate 
The CR rate is the proportion of subjects whose best response is CR at the end of 
induction therapy.  
Rate of CRi or better 
The rate of CRi or better will be used to summarize the secondary endpoints of CR, 
CRp, CRh, and CRi (i.e., CRi or better) after induction therapy and consolidation 
therapy, separately.  
 
The rate of CRi or better after induction is defined as the proportion of 
subjects whose best response after induction therapy and prior to 
consolidation is CRi, CRh, CRp or CR in Induction Safety Analysis Set.   
 
The rate of CRi or better after consolidation is defined as the proportion of 
subjects in Consolidation Safety Analysis Set whose best response after 
consolidation therapy is CRi, CRh, CRp or CR.  
MRD status using NGS less than 10-4 after induction therapy in subjects achieving 
CR 
It is defined as the proportion of subjects in Induction Safety Analysis Set with 
achievement of CR and MRD negativity as assessed by NGS method at a 10-4 
threshold after induction therapy. 
MRD status using NGS less than 10-3 and less than 10-4 in subjects achieving CRi 
CRi, CRh, CRp, or CR after induction and consolidation therapy 
It is defined as the proportion of subjects in CFZ-VXLD arm with achievement of 
CRi or better and MRD negativity as assessed by NGS method at 10-3 and 10-4 
threshold after induction therapy (in Induction Safety Analysis Set) and 
consolidation therapy (in Consolidation Safety Analysis Set) separately. 
MRD status less than 10-3 and less than 10-4 by flow cytometry and/or PCR or NGS 
in subjects achieving CRi, CRh, CRp, or CR after induction and consolidation 
therapy 
It is defined as the proportion of subjects in CFZ-VXLD arm with achievement of 
CRi or better and MRD negativity as assessed by flow cytometry and/or PCR or 
NGS method (if one assessment method used, or, if MRD negative in all 
assessments; if MRD detectable in any method used subject not considered MRD 
negative)  at 10-3 and 10-4 threshold performed by local site after induction therapy 


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(in Induction Safety Analysis Set) and after consolidation therapy (in 
Consolidation Safety Analysis Set) separately. 
Duration of Treatment 
Duration of treatment of a drug of interest (days)  (date of last dose of the drug of interest 
– date of first dose of the drug of interest) 1.  
Duration of treatment with the chemotherapy combination (days)  (date of last dose of any 
drug in the chemotherapy combination – date of first dose of any drug in the chemotherapy 
combination) 1. 
Duration of Remission (DOR) 
Duration of remission is defined as the number of days between the date of the first 
tumor assessment indicating CRi or better (CRi, CRh, CRp or CR) through to the 
subsequent date of relapse/progression or death due to any cause, or where applicable 
date of censoring.  Subjects who reached CRi or better and have not relapsed nor died 
by the analysis date will be censored at last known alive date. Subjects who do not 
achieve CRi or better will be excluded from the analysis of duration of remission.   
DOR (days) = relapse/death date or censoring date – the first date of CRi or better  1 
Event-free survival (EFS) 
EFS will be measured from the initiation of therapy until treatment-failure (defined as failure 
to reach CRi or better after consolidation therapy or after induction therapy in subjects that 
do not receive consolidation), relapse or death to any cause, whichever occurred first. 
The treatment failure date is the date of PD or SD or non-evaluable (NE) per 
sponsor’s response assessment. The relapse date is captured on the eCRF form 
Relapse Status & Subsequent Anti-Cancer. Subjects who are alive and event free are 
censored at last known alive date through the DCO date. 
EFS (months) = (treatment failure/relapse/death date or censoring date – first dose 
date of IP + 1) / 30.4 
End of Study Date  
The end of study date is defined as the date when the last surviving subject completes the 
safety follow-up, discontinues the study due to death, is lost to follow-up, withdraws full 
consent from the study, or the sponsor in consultation with regulatory authorities decides to 
close the study, whichever occurs first.   
 


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History of primary induction failure  
Failure to achieve a response (i.e., CR/CRp/CRh/CRi) within 16 days after 
completion of the initial induction treatment following the subject’s diagnosis of 
ALL. 
Investigational Product (IP) 
IP for this study refers to carfilzomib.  
Last Known Alive Date 
Last known alive date is the latest date before the death date during the study, 
according to the dates recorded on eCRFs and the dates in the data collected by the 
vendors. 
Overall Survival (OS) 
Overall survival is defined as the time in months from initiation of therapy until death due to 
any cause through the analysis data cutoff (DCO) date. OS is censored at the last known 
alive date through the DCO date. Data available after the DCO date will not be used to 
derive overall survival. Subjects with partial dates will be imputed according to Section 22.3 
and Appendix F. 
OS (months) = (death date or censoring date – first dose date of IP + 1) / 30.4 
Study Day 1 
Study day 1 corresponds to the date of first dose of carfilzomib. 
Study Day 
Study day  (date of interest – study day 1)  1. 
Study Treatments  
Study treatments (including protocol approved alternative agents) include 
carfilzomib, chemotherapy backbone of VXLD, modified BFM therapy and IT 
chemotherapy drugs. 
Study Treatment 
Induction 
Therapy 
Consolidation 
Therapy 
Carfilzomib 
✓ 
✓ 
Vincristine (VXLD, Modified BFM) 
✓ 
✓ 
Dexamethasone (VXLD) 
(alternatives: Prednisone, Prednisolone, 
Methylprednisolone) 
✓ 
 
PEG-asparaginase (VXLD, Modified BFM) 
(alternatives: L-asparaginase, Erwinia, Rylaze) 
✓ 
✓ 


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Daunorubicin (VXLD) 
(alternatives: Doxorubicin, Epirubicin, Idarubicin) 
✓ 
 
Cytarabine (Modified BFM) 
 
✓ 
6-Mercaptopurine (Modified BFM) 
 
✓ 
Cyclophosphamide (Modified BFM) 
 
✓ 
Methotrexate (IT chemotherapy) 
✓ 
✓ 
Cytarabine (IT chemotherapy) 
✓ 
✓ 
Hydrocortisone (IT chemotherapy)  
(alternatives: other steroids) 
✓ 
✓ 
 
Subject Incidence  
The subject incidence for a given event is defined as the number of subjects with one or 
more reported occurrence of the event divided by the number of subjects who had the 
opportunity to experience the event. 
Total Dose  
Total dose received of a drug of interest is defined as the cumulative total quantity that was 
actually administered for the specific drug of interest.  
Treatment Emergent Adverse Event 
Treatment-emergent adverse events (TEAEs) are defined as Adverse Events (AEs) starting 
on or after the first administration of study drug and within the end of the study or 30 days of 
the last day of any study treatment, whichever is earlier.  
Treatment Response 
For the main analysis of primary and selected secondary endpoints, treatment 
response will be derived by sponsor based upon local evaluation of bone marrow, 
peripheral blood, and extramedullary disease status. The definitions of the following 
response categories are described in Appendix G according to the criteria included 
in Table 26 of protocol amendment 12: complete remission (CR), complete remission 
without platelet recovery (CRp), complete remission with partial hematological recovery 
(CRh), complete remission with incomplete hematologic recovery (CRi), stable disease 
(SD), progressive disease (PD), and non-evaluable (NE). The criteria for determining 
treatment response for study 20140106 are consistent with the criteria used in study 
20180065 protocol as detailed in Section 9.3.2.  


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20. 
Analysis Sets 
Unless otherwise specified, all analysis sets below will be analyzed for B-cell and T-cell 
phenotypes separately.  
20.1 
Primary Analysis Set (PAS) 
The primary analysis set will include subjects enrolled in the experimental CFZ-VXLD 
arm who received at least 1 dose of carfilzomib and all external control subjects 
included in the T-PAS/B-PAS as defined in Study 20180065 protocol/SAP. If external 
control subjects have multiple qualifying therapies, the last qualifying therapy will be 
chosen.   
20.2 
Safety Analysis Set 
This analysis set will include subjects enrolled to the experimental CFZ-VXLD arm who 
received at least 1 dose of carfilzomib.  
The following two analysis sets will be further defined based on the treatment period 
that subjects have started during the trial. 
 
Induction Safety Analysis Set includes subjects who started the Induction 
cycle and received at least 1 dose of carfilzomib during the induction 
period.  
 
Consolidation Safety Analysis Set includes subjects who started the 
consolidation cycle and received at least 1 dose of carfilzomib during the 
consolidation period. 
20.3 
Per Protocol Set(s) 
This analysis set will include subjects enrolled to the experimental CFZ-VXLD arm who 
receive at least one dose of carfilzomib and do not have any major protocol deviations 
that might impact the efficacy endpoints. Subjects with the following important 
protocol deviation (IPD) will be excluded from the per protocol set. The IPD 
numbers and descriptions are documented in the study level IPD list document. 
 
Major inclusion criteria related IPD: 111, 112, 113, 114, 118, 119 
 
Major exclusion criteria related IPD: 211, 214, 215, 216, 219, 220, 222, 228 
 
Major treatment non-compliance related IPD: 401, 403, 908 
20.4 
Interim Futility Analyses Set(s) 
The interim futility analysis set will include approximately 60 subjects (60% of the 
planned number of subjects) from the experimental CFZ-VXLD arm who have received 


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at least one dose of CFZ and have had the opportunity to complete a post induction 
response evaluation and all available subjects from the external control arm by the 
time of Interim Analysis (as defined in Interim Analysis Set [T-IAS/ B-IAS] of Study 
20180065 protocol/SAP).   
20.5 
VXLD/ VPLD Analysis Set (VAS) 
This analysis set will include all subjects in experimental CFZ-VXLD arm who have 
received at least 1 dose of CFZ, while the external control arm includes only subjects 
who have been treated with VXLD/VPLD as defined in Study 20180065 protocol/SAP. 
20.6 
Chemotherapy Analysis Set (CAS) 
This analysis set will include all subjects in experimental CFZ-VXLD arm who received 
at least 1 dose of carfilzomib, while the external control arm includes only subjects 
who have been treated with any ALL chemotherapy regimen, including proteasome 
inhibitors other than carfilzomib as defined in Study 20180065 protocol/SAP.  
21. 
Planned Analyses 
For each of the following planned analysis, data will be subject to ongoing checks 
for integrity, completeness, and accuracy in accordance with the Data 
Management Plan with the expectation that all outstanding data issues are 
resolved ahead of the snapshot.  The data will be locked to prevent further 
changes, and a snapshot of the locked database will be used in the analysis.  
21.1 
Interim Analysis and Early Stopping Guidelines 
An interim analysis for non-binding futility assessment in terms of the primary 
endpoint (CR after induction therapy) will be conducted independently for each 
phenotype (T-cell and B-cell) on the Interim Futility Analysis Set. The interim 
futility analysis will occur after at least 60 subjects in the experimental CFZ-VXLD 
arm have received at least one dose of carfilzomib and had the opportunity to 
complete a post induction response evaluation. The futility criterion will be 
derived such that the probability of futility is at least 70% under H0 and the power 
loss is at most 0.01 under H1, using a Bayesian predictive probability approach. 
Additional details for the interim futility assessment are described 
 
An Independent Biostatistics Group (IBG) will perform the interim futility analyses 
according to the steps described 
 and provide the results as part of a 
closed session report to an independent Data Monitoring Committee (DMC). To 
minimize the potential introduction of bias to the conduct of the study, members of the 


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DMC and IBG will not have any direct contact with study site personnel or subjects.  The 
DMC will communicate major safety concerns and recommendations regarding study 
modification or termination based on a risk/ benefit assessment using the safety and 
efficacy summaries produced by IBG in accordance with the DMC charter. 
Over the course of the study, DMC will review all available safety and efficacy data every 6 
months using as-is cumulative snapshots. The IBG will generate and provide routine 
open-session and closed-session reports to the DMC.  
Records of all meetings will be maintained by the IBG and DMC for the duration of the 
study. These records will be transferred and stored in the eTMF (in accordance with SOP-
427356) after the termination of DMC meetings. Further details are provided in the DMC 
charter.  
21.2 
Primary Analysis 
The primary analysis for each phenotype will occur when the external control subjects have 
been selected from T-PAS/B-PAS and at least 100 enrolled subjects in the experimental 
arm have received at least one dose of carfilzomib and had the opportunity to complete 
a post induction response evaluation. All the available data on primary, secondary and 
exploratory endpoints will be summarized at this time.  
21.3 
Final Analysis 
The final analysis will occur after the end of the study, and it will be performed on all 
subjects included in the Primary Analysis Set. 
22. 
Data Screening and Acceptance 
22.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses.  
22.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will provide 
all data of the experimental CFZ-VXLD arm to be used in the planned analyses.  This study 
will use the RAVE database. Data from the observational study will be collected and 
provided to Amgen by TACL as specified in the study 20180065 protocol. The data will be 
managed according to the Data Management Plan. 
22.3 
Handling of Missing and Incomplete Data 
Assumptions for missing or partially missing dates for important variables will be made to 
allow inclusion of appropriate data records in the analyses.  


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Imputed dates will not be presented in the listings. However, if the partial AE onset date 
information does not indicate whether the AE started prior to treatment or after the TEAE 
period, the AE will be classified as TEAEs. 
The handling of incomplete and partial dates for adverse events, concomitant 
medications, death, subsequent anti-cancer therapy, initial ALL diagnosis, prior ALL 
therapy medication, prior HSCT, remission to prior ALL therapy, and relapse to 
prior ALL therapy are described in Appendix F. 
The following imputation rules may be considered for the baseline missing (or unknown) 
value of covariates within each phenotype and the treatment arm where it occurred: for 
continuous covariates, the mean of the observed data will be considered, while for 
categorical covariate, the missing/unknown values will be combined with the category 
observed on the most subjects if the missing/unknown rate is at most 10 of the 
observed data, or they will be classified into a separate category if the missing/unknown 
rate is more than 10.   A sensitivity analysis may be conducted to evaluate the primary 
analysis outcome based on a threshold other than 10 for a separate missing category. 
If the covariates are also used as subgroup variables, the imputed values of subgroup 
variables will not be used for subgroup categorization.   
22.4 
Outliers 
Pharmacokinetic (PK) [plasma] concentration data will be evaluated for outliers, and 
decisions to re-assay individual samples will be made in accordance with standard 
pharmacokinetic evaluation practice.   
22.5 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies will 
be assessed. If required, data transformations or alternative non-parametric methods of 
analyses will be utilized. 
22.6 
Validation of Statistical Analyses 
Programs will be developed, maintained, and the output will be verified in accordance with 
current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 


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23. 
Statistical Methods of Analysis 
23.1 
General Considerations 
Unless otherwise specified, the data will be presented for the Safety Analysis Set for B-
cell and T-cell phenotypes analyzed separately. 
Summary statistics will be provided for selected endpoints.  For continuous variables, 
the number of subjects with non-missing data (n), mean, standard deviation, median, 
minimum, and maximum will be presented.  For discrete data, the frequency and percent 
distribution will be presented.  Unless otherwise indicated, percentages will be calculated 
with respect to the number of subjects in the analysis set.  Confidence intervals, when 
presented, will be constructed at the 2-sided 95 level.  For binomial variables, exact 
distribution methods will be employed. The distribution of time-to-event endpoints will be 
summarized by Kaplan-Meier method when applicable.   
Individual subject listings will be produced for selected endpoints using data recorded on 
the electronic case report forms (eCRFs) or derived data. 
23.2 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations. The clinical study 
team will identify and document the criteria for important protocol deviations. 
23.3 
Subject Accountability 
The following subject disposition information will be summarized descriptively: 
 
Number of enrolled subjects 
 
Number of subjects with screen failures 
 
Number of treated subjects (Safety population) 
 
Number () of subjects who discontinued study treatment (including the 
protocol approved alternatives) and the primary reason for discontinuation. 
The percentage is calculated with respect to Safety population. 
 
Number () of subjects who completed the study, and who discontinued 
study and the primary reason for discontinuation. The percentage is calculated 
with respect to Safety population. 
 
Number () of subjects who discontinued each study treatment due to COVID-
19 control measures. 


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Key study dates for the first subject enrollment, last subject enrollment, last subject 
last dose of investigational product, last subject end of study and data cut-off date 
will be presented. 
The number () of subjects who were enrolled will be tabulated by region, country, and 
investigator site, by age group defined in Section 18.2 for safety analysis set. 
MRD sample disposition will be summarized for subjects after induction therapy 
(Induction Safety Analysis Set) and consolidation therapy (Consolidation Safety 
Analysis Set) separately. The number (%) of subjects with MRD sample at 
baseline/post-baseline, and the number (%) of subjects without MRD sample at 
baseline/post-baseline along with the reasons will be presented. 
In addition, the number () of subjects in each analysis set will be summarized, 
including the external control arm. 
23.4 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories potentially affecting efficacy and safety 
are defined by the study team before the first subject’s initial visit and updated during 
the IPD reviews throughout the study prior to database lock. During the course of the 
study these definitions will be used to identify the IPDs that will be summarized at 
primary and final analysis. Additionally, the major IPDs that will exclude patients from 
Per Protocol analysis set will be clarified prior to any planned analysis. Eligibility 
deviations are defined in the protocol. The following information of IPD and protocol 
deviation will be summarized, where applicable, with respect to the following: 
 
Number () of subjects with IPDs and total number of IPDs will be summarized 
by category and sub-category  
 
Number () of subjects with IPDs related to COVID-19 control measures will be 
summarized  
 
Number () of subjects with COVID-19 protocol deviations by protocol deviation 
category (940 series, 950 series and 960 series of protocol deviations codes)  
 
Subject listing of IPD in Safety Analysis Set, including COVID-19 related IPDs 
with the descriptions. 
 
Subject listing of COVID-19 protocol deviations based on protocol deviations 
category (940 series, 950 series and 960 series of protocol deviations codes)  


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23.5 
Demographic and Baseline Characteristics 
Demographic (age at diagnosis (years): continuous; with categories of <1, 1 to  2, 2 
to  10,  10; age at study entry: continuous (years); with categories of <1 month, 1 
month - ≤ 17 years, > 17 years, sex, ethnicity, race, region), baseline characteristics 
(weight (kg), height (cm), BSA (m2), and BMI (kg/m2) at baseline) and baseline disease 
characteristics (defined in Section 11.4.3) will be summarized using descriptive statistics in 
Safety Analysis Set. The baseline characteristics for subgroups (Section 18.2) and 
 
Additional demographics summary will be presented in side-by-side for phase 1 
total, phase 2 total, and total of phase 1 and phase 2 data. 
23.6 
Efficacy Analyses 
Unless otherwise specified, all efficacy endpoints will be analyzed for B-cell and T-cell 
phenotype independently.  The details on endpoint definitions are included in Section 16.1 
and Section 19.  The comparison analyses for CR, CRh (or better), CRp (or better), CRi 
(or better), EFS, and OS endpoints will use the PAS, while for all the other efficacy 
endpoints the Safety Analysis Set will be used.  DOR will be analyzed only on responders 
from PAS (i.e., subjects who reached a response of CR, CRp, CRh, or CRi). 
Table 23.1.  Primary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method  
Sensitivity Analysis 
CR after induction 
therapy: 
 
As described in 
 The odds ratio 
(OR) for the probability of CR (PoCR) for 
CFZ-VXLD versus control will be estimated 
from a logistic regression model with inverse 
probability treatment weights (IPTW) for the 
average treatment effect of the treated (ATT). 
These weights are derived for each CFZ-
VXLD and control subject based on their 
propensity score (PS) for receiving CFZ-
VXLD. Outlier weights will be trimmed via a 
tuning process. The 95 confidence interval 
of the OR will be calculated using robust 
sandwich covariance estimator and the lower 
bound of the 95 CI will be compared to 1. 
The CR rate and 95 CI by arm will also be 
estimated using the same logistic regression 
model.  
The CR rate at the end of Induction will also 
be summarized descriptively along with the 
Clopper Pearson 95 CI without any PS 
adjustment for Induction Safety Analysis 
Set and Per Protocol Set. 
 Treatment 
response based on 
investigator 
assessment 
 Sponsor derived 
treatment response 
using central lab 
data  
 Outliers in weights 
will be trimmed to 
different threshold 
values  
 Add additional 
potential prognostic 
covariates in PS 
model 
 Rule-out method 
 Chemotherapy 
Analysis Set (CAS) 
 VXLD/VPLD 
Analysis Set (VAS) 
 Covariates that 
remain imbalanced 


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Endpoint 
Primary Summary and Analysis Method  
Sensitivity Analysis 
after PS adjustment 
will be added in the 
analysis model 
 Missing baseline 
covariate imputed 
with a threshold 
other than 10 for a 
separate missing 
category 
 Model selection 
algorithm may be 
applied to the pre-
specified covariates 
 
 
Table 23.2. Secondary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method  
Sensitivity Analysis 
CRi or better at 
the end of 
induction therapy 
 
Similar to primary endpoint, the rate of CRi 
or better per arm and OR for CFZ-VXLD 
versus external control, along with their 95 
CI will be estimated from weighted models 
as for the primary endpoint analysis via 
IPTW-ATT.  
The unadjusted rate and 95CI will also be 
estimated for CFZ-VXLD arm without any 
PS adjustment for Induction Safety 
Analysis Set and Per Protocol Set. 
 Treatment response 
based on 
investigator 
assessment 
 Sponsor derived 
treatment response 
using central lab 
data  
 Outliers in weights 
will be trimmed to 
different threshold 
values 
 Add additional 
potential prognostic 
covariates in PS 
model 
 Rule-out method 
 CAS 
 VAS 
 Covariates that 
remain imbalanced 
after PS adjustment 
will be added in the 
analysis model. 
 Missing baseline 
covariate imputed 
with a threshold other 
than 10 for a 
separate missing 
category 
 Model selection 
algorithm may be 


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applied to the pre-
specified covariates 
EFS 
 
EFS will be summarized by Kaplan-Meier 
method.  The distribution of EFS time 
including median and other quartiles will be 
summarized descriptively using the KM 
method. The corresponding 95 CI for the 
median and other quartiles will be 
constructed using KM method with log-log 
transformation. Survival rates at 6, 12, 18, 
and 24 months will be estimated, and the 
corresponding 95 CIs will be calculated 
using the method of Kalbfleisch and 
Prentice (1980). The duration of the follow-
up for EFS will be estimated by reverse 
Kaplan-Meier method (Schemper and Smith 
1996). KM curves will also be presented. 
The hazard ratio (HR) for CFZ-VXLD vs 
external control arm will be derived using 
Cox regression. This analysis will be 
adjusted following a similar approach and 
weights as for primary endpoint analysis.  
 
The above analyses will also be 
performed for CFZ-VXLD arm without 
any PS adjustment for Safety Analysis 
Set and Per Protocol Set. 
 Treatment response 
based on 
investigator 
assessment 
 Outliers in weights 
will be trimmed to 
different threshold 
values 
 Add additional 
potential prognostic 
covariates in PS 
model 
 Rule-out method 
 CAS 
 VAS 
 Same analysis 
approach as for the 
primary analysis with 
control subjects 
being censored at 2 
years since initiation 
of therapy, only if the 
follow-up time is 
different between 
treatment and control 
arms.  
 Covariates that 
remain imbalanced 
after PS adjustment 
will be added in the 
analysis model. 
 Missing baseline 
covariate imputed 
with a threshold other 
than 10 for a 
separate missing 
category 
 Model selection 
algorithm may be 
applied to the pre-
specified covariates 


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OS 
 
OS will be summarized by Kaplan-Meier 
method. The distribution of OS time 
including median and other quartiles will be 
summarized descriptively using the KM 
method. The corresponding 95 CI for the 
median and other quartiles will be 
constructed using KM method with log-log 
transformation. Survival rates at 6, 12, 18, 
and 24 months will be estimated, and the 
corresponding 95 CIs will be calculated 
using the method of Kalbfleisch and 
Prentice (1980). The duration of the follow-
up for OS will be estimated by reverse 
Kaplan-Meier method (Schemper and Smith 
1996). KM curves will also be presented. 
The hazard ratio (HR) for CFZ-VXLD vs 
external control arm will be derived using 
Cox regression. This analysis will be 
adjusted following a similar approach and 
weights as for primary endpoint analysis.   
 
The above analyses will also be 
performed for CFZ-VXLD arm without 
any PS adjustment for Safety Analysis 
Set and Per Protocol Set. 
 Outliers in weights 
will be trimmed to 
different threshold 
values 
 Add additional 
potential prognostic 
covariates in PS 
model 
 Rule-out method 
 CAS 
 VAS 
 Same analysis 
approach as for the 
primary analysis with 
control subjects 
being censored at 2 
years since initiation 
of therapy, only if the 
follow-up time is 
different between 
treatment and control 
arms 
 Covariates that 
remain imbalanced 
after PS adjustment 
will be added in the 
analysis model. 
 Missing baseline 
covariate imputed 
with a threshold other 
than 10 for a 
separate missing 
category 
 Model selection 
algorithm may be 
applied to the pre-
specified covariates 


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DOR of CRi or 
better 
 
DOR will be summarized by treatment arm 
on subjects who reach CRi or better by the 
end of study treatment using the Kaplan-
Meier method. The distribution of DOR time 
including median and other quartiles will be 
summarized descriptively using the KM 
method. The corresponding 95 CI for the 
median and other quartiles will be 
constructed using KM method with log-log 
transformation. Survival rates at 6, 12, 18, 
and 24 months will be estimated, and the 
corresponding 95 CIs will be calculated 
using the method of Kalbfleisch and 
Prentice (1980). 
 
The above analyses will also be 
performed for CFZ-VXLD arm without 
any PS adjustment for Safety Analysis 
Set and Per Protocol Set. 
 NA 
MRD status using 
NGS less than 
10-4 after induction 
therapy in subjects 
achieving CR  
 
Estimate the proportion of subjects whose 
MRD level using NGS is less than 10-4 after 
induction therapy in subjects achieving CR.  
Generate Clopper Pearson 95 confidence 
interval for CFZ-VXLD arm (Induction 
Safety Analysis Set). 
 NA 
MRD status using 
NGS less than 
10-3 and less 
than 10-4 in 
subjects achieving 
CRi or better, after 
induction and   
consolidation 
therapy, 
separately 
 
Estimate the proportion of subjects whose 
MRD level using NGS less than 10-3 and 
less than 10-4 separately in subjects 
achieving CRi or better, after induction 
and consolidation therapy, respectively, and 
generate Clopper Pearson 95 confidence 
interval in each case for the subjects in 
CFZ-VXLD arm (Induction Safety 
Analysis Set, Consolidation Safety 
Analysis Set, respectively). 
 NA 
Occurrence of a 
stem cell 
transplant or CAR-
T, without an 
intervening 
relapse after 
protocol specified 
therapy 
 
Estimate the proportion of subjects that 
bridge to stem cell transplant or chimeric 
antigen receptor T cell. Generate Clopper 
Pearson 95 confidence interval for CFZ-
VXLD arm (Safety Analysis Set). 
 NA 
CRi or better after 
consolidation 
therapy 
 
Estimate the proportion of subjects who 
began consolidation therapy and 
achieved CRi or better after the 
consolidation therapy and its Clopper 
Pearson 95 CI for CFZ-VXLD arm 
(Consolidation Safety Analysis Set). 
 NA 
 


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Table 23.3. Exploratory Efficacy Endpoint Summary Table 
 
 
 
 
23.6.1 
Analyses of Primary Efficacy Endpoint(s) 
To evaluate the treatment effect with respect to the outcome of CR rate among pediatric 
R/R ALL subjects, an external control arm representing pediatric ALL subjects receiving 
SoC without Carfilzomib will be selected from the observational Study 20180065 according 
to the study protocol and the definition of each analysis set as specified in Section 20.  For 
the primary analysis, the 20140106 study will be analyzed as a virtual randomized 
controlled trial comparing enrolled subjects treated with the CFZ-VXLD regimen versus the 
external control arm adjusted via propensity score (PS) methods. To control confounding 
for measurable variables, each subject in the analysis will have a PS estimated via 
multivariable logistic regression models constructed 
  
The odds ratio (OR) for the probability of CR (PoCR) for CFZ-VXLD versus control will be 
estimated from a logistic regression model with inverse probability treatment weights for the 
average treatment effect of the treated (IPTW-ATT). These weights are derived for each 
CFZ-VXLD and control subject based on the PS for receiving CFZ-VXLD. Conditioned on 
these weights, the distribution of the observed baseline covariates will be balanced 
CCI


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between the 2 arms. If identified, outlier weights will be trimmed to a maximum non-outlying 
value (i.e., max of 5 or 99th percentile of weight distribution) (Lee, 2011).   
The 95 confidence interval (CI) of the OR will be calculated using a robust sandwich 
covariance estimator and the lower bound of the 95 CI will be compared to 1. The CR rate 
and 95 CI by arm will also be estimated using the same logistic regression model. 
. 
Estimated CR rate and 95 CI by arm along with OR (95 CI) of CR between 
appropriately weighted CFX-VXLD and external control using PS will be calculated via the 
weighted logistic regression for the subgroups listed in Section 18.2. The same weights as 
those included in the primary analysis will be used for subgroup analyses. A forest plot will 
be produced for the estimated ORs (95 CIs). 
 
 
 If the balance criteria are not met, then a sensitivity analysis will 
be considered for estimating the OR (95 CI) using IPTW adjusted models constructed 
only considering subjects in the subgroup. The re-adjusted summaries would provide 
ancillary information on how well balance is or is not achieved within each subgroup and 
may help aid in the interpretation. This sensitivity analysis will be done only if the number of 
subjects within each category (for the number of subjects in a subgroup 20, the category 
is for the combined category) is more than 40 from overall sample size per arm. The CFZ-
VXLD subjects reaching CR at the end of Induction will also be summarized along with their 
Clopper Pearson 95 CI without any PS adjustment. 
Several sensitivity analyses will be considered to evaluate the robustness of the results.  
Depending on the outlier weights identified during the primary endpoint analysis, several 
threshold values will be used for trimming and applied to the models used for primary 
endpoint analysis.   
In order to address NCCN recommendation for standard of care therapies in pediatric 
ALL, a sensitivity analysis will be performed on Chemotherapy Analysis Set (CAS).  
Similar adjustment as for the primary analysis will be considered.  
Despite the attempt to balance covariates using a PS strategy, possible residual bias 
due to unmeasured confounding may still exist. In order to address this limitation, 
additional sensitivity analyses will be considered. One will expand the list of covariates to 
a larger set, 
 Another one will apply quantitative bias 


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analyses to assess the extent of unmeasured confounding that would be required to 
refute an observed difference in outcome incidence between cohorts. The rule-out 
method is used in the quantitative bias analyses to assess how strong a confounder 
(or set of confounders) would need to be to fully explain the observed association 
between an exposure and the outcome. This method has been described previously 
(Schneeweiss et al 2006), is publicly available at www.drugepi.org  and HR variant has 
been previously applied in the literature (Weintraub et al 2012).  An alternative method of 
evaluating unmeasured confounding involves assessing the strength of the measured 
confounders by removing each confounder individually from the model to develop a 
distribution of the point estimate of the hazard ratios to display the strength of the 
measured confounding. Assuming the unmeasured confounders are similarly distributed, 
this distribution can be used to inform the potential magnitude and direction of the 
unmeasured confounders on the validity of the effect estimate. One or more of these 
methods will be explored, as appropriate. Covariates that remain imbalanced after PS 
adjustment will be added in the analysis model as a sensitivity analysis. A sensitivity 
analysis will be performed for missing baseline covariate imputed with a threshold other 
than 10 for separate missing category. Model selection algorithm may be applied to 
the pre-specified covariates as a sensitivity analysis, 
 
 
Another sensitivity analysis will be performed for VXLD/VPLD analysis set by estimating 
the CRR and 95CI by arm with no PS adjustment.  
In addition, historical estimates of CR in patients treated with best available therapy will 
be provided via a literature search. Descriptive summaries will be made in order to 
evaluate whether the experimental arm provides benefit over available therapy. 
23.6.2 
Analyses of Secondary Efficacy Endpoint(s) 
The proportion of safety analysis subjects and corresponding Clopper Pearson 95 CI will 
be estimated for the below secondary endpoints. The analysis set used for each 
endpoint is specified in Table 23.2.   
 
 
MRD status using NGS less than 10-4 after induction therapy in subjects 
achieving CR 
 
Occurrence of a stem cell transplant or CAR-T, without an intervening relapse 
after protocol specified therapy 
 
CRi, CRh, CRp, or CR after induction therapy 


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 
CRi, CRh, CRp, or CR after consolidation therapy  
 
MRD status using NGS less than 10-3 and less than 10-4 in subjects achieving 
CRi CRi, CRh, CRp, or CR after induction and consolidation therapy, separately 
All secondary endpoints that will be included in the comparative analyses will be 
included in adjusted models similarly as the primary endpoint.   
The rate of CR, CRp, CRh and CRi at the end of induction and at the end of 
consolidation per arm and the OR for CFZ-VXLD versus control will be estimated from 
a logistic regression model with IPTW-ATT adjustment along with their 95 CIs. This 
analysis will be performed following a similar approach and sensitivity analyses as for 
primary endpoint analysis. 
EFS, OS, and DOR will be summarized by Kaplan-Meier method.  The distribution of 
EFS/OS/DOR time including median and other quartiles will be summarized descriptively 
using the KM method (Klein and Moeschberger, 1997). The corresponding 95 CI for the 
median and other quartiles will be constructed using KM method with log-log 
transformation. Survival rates at 6, 12, 18, and 24 months will be estimated for EFS/OS, 
and the corresponding 95 CIs will be calculated using the method of Kalbfleisch and 
Prentice (1980). The duration of the follow-up will be estimated by reverse Kaplan-Meier 
method (Schemper and Smith 1996). KM curves will also be presented for OS and EFS. 
The hazard ratio (HR) for CFZ-VXLD vs external control arm will be derived for OS/ EFS 
using Cox regression. This analysis will be adjusted following a similar approach and 
weights as for primary endpoint analysis. If the sample size is small and/ or censoring is 
high, then the KM method may not provide reliable estimates for DOR, and in this case, 
only descriptive statistics or listings will be provided.   
Similar sensitivity analyses as for primary endpoint analysis will be considered for EFS/OS, 
as described in Table 23.2. Additionally, if the follow-up time from control arm is different 
than experimental arm, then a sensitivity analysis similar to the primary analysis will be 
performed with control subjects being censored at 2 years since initiation of therapy.    
The proportion of subjects and corresponding Clopper Pearson 95 CI will be 
estimated for MRD status in subjects achieving CR and CRi or better (CRi, CRp, CRh, 
CR) as described in Table 23.2.  


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23.6.3 
Analyses of Exploratory Efficacy Endpoint(s) 
23.7 
Safety Analyses 
23.7.1 
Analyses of Safety Endpoint(s) 
The safety analysis will be based on the safety analysis set analyzed by B-cell, T-cell 
separately and pooled. The summaries will be presented in side-by-side displays for B-
cell/ T-cell/ Total (i.e., pooled sample). The safety analysis will be also performed for 
Induction and Consolidation phase separately.  
The analysis for induction treatment period will be based on the Induction Safety 
Analysis Set (Section 20.2). TEAEs that started within the first dose of induction 
treatment (inclusive) to the earlier of 30 days after the last dose date of any study 
treatment, or the first dose of consolidation treatment (not inclusive) will be 
included in this analysis. 
The analysis for consolidation treatment period will be based on the 
Consolidation Safety Analysis Set (Section 20.2). TEAEs that started within the 
first dose of consolidation treatment (inclusive) to the earlier of the end of study 
(inclusive), or 30 days after the last dose date of any study treatment will be 
included in this analysis. 
The analysis will include the descriptive summary statistics for Adverse events, 
Laboratory measures, Vital Signs, Physical measurements, Karnofsky or Lansky 
Performance Status, ECHO and ECG by age group defined in Section 18.2. Details are 
described in respective section below. 
23.7.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 25.1 or later will be used 
to code all events categorized as adverse events to a system organ class and a preferred 


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term. The events of interest (EOI) search strategies will be based on the standardized 
MedDRA query (SMQ) and/or Amgen MedDRA query (AMQ). Incomplete AE start 
dates will be imputed according to the specifications described in Appendix F1. 
The subject incidence of TEAEs will be summarized for all treatment-emergent adverse 
events (TEAEs), TEAEs of grade 3 or higher, treatment related TEAEs, serious TEAEs 
(SAEs), treatment related SAEs, TEAEs leading to discontinuation of study treatment, 
fatal TEAEs and treatment-emergent EOI, tabulated by system organ class (SOC) in 
alphabetical order and preferred term (PT) in descending order of frequency and by PT in 
descending order of frequency without regard to SOC. The maximum NCI – CTCAE 4.03 
toxicity grade and strongest causal relationship to study treatment will be evaluated, and 
the TEAEs will be also summarized by severity and relationship to the study drugs. 
If a subject experiences repeated episode of the same TEAE, the subject will be counted 
only once within each SOC and similarly counted once within each PT and the event with 
the highest severity grade will be used for purposes of incidence tabulations. 
A summary of the number of deaths and the cause of death, classified by deaths within 30 
days of last dose of study drug and deaths more than 30 days after the last dose of study 
drug, will be provided. A listing of deaths will be provided. 
23.7.3 
Laboratory Test Results 
Laboratory test results will be graded for severity using the NCI-CTCAE version 4.03 and 
will be summarized using descriptive statistics for baseline values and changes from 
baseline values by assessment visit (per Table 14, Table 16, Table 18 and Table 20 
from protocol), and a summary of subject incidence of grade 3 and 4 laboratory 
abnormalities for all laboratory parameters of interest.  
Shifts in laboratory toxicity grades to outside the normal range will be evaluated for 
laboratory parameters by assessing the maximum increase and/or decrease observed 
during the course of study treatment relative to the baseline toxicity grade. 
For the summary of changes from baseline values, subjects without a baseline and/or 
post-baseline value will be excluded. Laboratory results from samples taken  30 days 
after the last administration of protocol therapy will be excluded from all laboratory 
summaries. 
The laboratory analytes of interest are: 


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 
CBC with differential (i.e., Total Neutrophils, Eosinophil, Basophils, 
Lymphocytes, Monocytes, Lymphoblasts) and platelet count 
 
Electrolytes: Sodium, Potassium, Chloride, Bicarbonate, Calcium, Magnesium, 
Phosphorus 
 
Serum glucose 
 
Renal function: blood urea nitrogen (BUN), Creatinine 
 
Hepatic function: AST, ALT, total and direct bilirubin, ALP, albumin 
 
Pancreatic function: amylase, lipase 
 
Uric acid 
The subject incidence and percentage of potential Hy’s Law cases will also be summarized. 
23.7.4 
Vital Signs 
Actual value and change from baseline for vital sign results including systolic/diastolic blood 
pressure, heart rate, respiratory rate, and temperature will be summarized using 
descriptive statistics for baseline values and changes from baseline by assessment visit 
(per Table 14, Table 16, Table 18 and Table 20 from protocol). 
For the summary of changes from baseline, subjects without a baseline and/or 
post-baseline value will be excluded. Vital sign results taken  30 days after the last 
administration of protocol therapy will be excluded from all vital sign summaries. 
23.7.5 
Physical Measurements 
Actual value and change from baseline for the physical measurements including 
height(cm), weight(kg), and BSA(m2) will be summarized using descriptive statistics by 
assessment visit (per Table 14, Table 16, Table 18 and Table 20 from protocol). For the 
summary of changes from baseline, subjects without a baseline and/or post-baseline value 
will be excluded. Physical measurements results taken  30 days after the last 
administration of protocol therapy will be excluded from all physical measurements 
summaries. 
23.7.6 
Karnofsky or Lansky Performance Status 
Shifts in scores for Karnofsky (age 16 years), Lansky (16 years) performance status 
scores between screening and safety follow up will be tabulated. Performance status will be 
assessed by the Karnofsky and Lansky scales per Section 24.2.1.7 of the protocol. 


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23.7.7 
Electrocardiogram 
The electrocardiogram (ECG) measurements from this clinical study were performed as per 
standard of care for routine safety monitoring, rather than for the purposes of 
assessment of potential QTc.  ECG data may be presented in listings. 
23.7.8 
Echocardiogram 
Echocardiogram, including assessments of systolic and diastolic left ventricular function 
and right ventricular function, will be summarized at baseline using descriptive statistics 
based on the Safety Analysis Set. Additionally, the unscheduled ECHO assessments 
(as clinically indicated, such as congestive heart failure) will be summarized using 
descriptive statistics, based on the number of adverse events that trigger the 
unscheduled ECHO assessments. 
23.7.9 
Antibody Formation 
Not Applicable  
23.7.10 
Exposure to Investigational Product 
Exposure will be summarized separately for induction therapy (per Induction Safety 
Analysis Set) and consolidation therapy (per Consolidation Safety Analysis Set). 
Descriptive statistics in terms of treatment duration (days), number of actual treatment 
days, total dose received, number of doses administered, average dose per administration, 
actual dose intensity, and relative dose intensity will be produced to describe the exposure 
to carfilzomib. Number () of subjects with carfilzomib dose modifications (missed doses, 
dose delays, dose reductions, and dose interruptions, if applicable) will be summarized. If 
the reason for dose modification is due to COVID-19 control measures which is reported on 
the CRF, then the number () with COVID-19 control measures will also be presented. 
Descriptive statistics will be produced to describe the exposure to investigational product.  
23.7.11 
Exposure to Non-investigational Product 
All the analyses planned for IP will be carried over for each drug in any chemotherapy 
combination (VXLD and modified BFM therapy including protocol approved 
alternative agents) except that the total dose received, average dose per 
administration, actual dose intensity and relative dose intensity will not include 
the alternative agents. For IT chemotherapy drugs (methotrexate, cytarabine, and 
hydrocortisone), only (1) number of doses administered; and (2) ratio of number 
of actual doses to number of the protocol specified doses will be summarized and 
presented for CNS positive and negative separately. Exposure to non-IP will also be 


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summarized separately for induction therapy (per Induction Safety Analysis Set) 
and consolidation therapy (per Consolidation Safety Analysis Set).  
In addition, the number and percentage of subjects who received V (vincristine), X 
(dexamethasone), L (PEG-asparaginase) and D (daunorubicin), or an approved 
alternate agent, in induction chemotherapy will be summarized for each agent. 
23.7.12 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving therapies of interest will be summarized 
by preferred term or category as coded by the World Health Organization Drug (WHO 
DRUG) dictionary. 
23.8 
Other Analyses 
23.8.1 
Analyses of Pharmacokinetic or Pharmacokinetic/
 
Endpoints 
Pharmacokinetic 
 analyses will be conducted as was done for the 
phase 1b part of the study (please refer to Section 11.7.1).  
23.9 
Changes from Protocol-specified Analyses 
There are no changes to the protocol-specified analyses.   
24. 
Literature Citations / References 
Clopper CJ and Pearson ES (1934) The use of confidence or fiducial limits illustrated in 
the case of the binomial, Biometrika. 26(4):404-413. 
Kalbfleisch, J. and Prentice, R. (1980) The Statistical Analysis of Failure Time Data. 
John Wiley, New York. 
Klein and Moeschberger (1997) Survival Analysis Techniques for Censored and 
truncated data, Springer. 
Schemper and Smith (1996) A Note on Quantifying Follow-up in Studies of Failure Time. 
Controlled Clinical Trials 17:343 – 346 
Schneeweiss S. Sensitivity analyses and external adjustment for unmeasured 
confounders in epidemiologic database studies of therapeutics. Pharmacoepi Drug 
Safety 2006; 15:291–303 
Weintraub WS et al Comparative Effectiveness of Revascularization Strategies. N Engl J 
Med. 2012 Apr 19; 366(16): 1467–1476. 


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Appendix F.  Handling of Incomplete Dates and Missing Dates 
 
F1. Imputation Rules for Adverse Events and Concomitant Medications (other than 
the new anti-leukemia therapy) dates  
The following data will be imputed using the following algorithm: 
Adverse Events  
Concomitant Medications (other than anti-cancer therapy) 
Table F-1. Imputation Rules for Partial or Missing Start Dates 
 Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial:  
yyyymm 
Partial:  
yyyy 
missing 
 1st 
dose 
 1st 
dose 
 1st 
dose 
yyyymm 
 1st 
dose 
yyyymm 
 1st 
dose 
yyyy 
 1st 
dose 
yyyy 
Partial: 
yyyymm 
 1st dose 
yyyymm 
2 
1 
n/a 
1 
n/a 
1 
1 
 1st dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
 1st dose 
yyyy 
3 
1 
3 
1 
n/a 
1 
1 
 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1  Impute the date of first dose 
2  Impute the first day of the month 
3  Impute January 1 of the year 
4  Impute January 1 of the stop year 
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date. 
Imputation rules for partial or missing stop dates: 
For partial stop date mmyyyy, impute the last day of the month. 
For partial stop date yyyy, impute December 31 of the year. 
For completely missing stop date, do not impute. 
If the stop date imputation leads to a stop date that is after the death date, then 
impute the stop date as the death date. 
If the stop date imputation leads to a stop date that is before the start date, then 
there is a data error and do not impute the stop date. (i.e., set the stop date as 
missing). 


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F2. Imputation of the Subsequent Anti-cancer Therapy Start Date 
The subsequent anti-cancer therapy start date will be imputed using the following 
algorithm. If the start day of subsequent anti-cancer therapy is missing and month and 
year are not the same as last dosing date of study treatment, it will be assumed to be the 
first day of the month. If the start day of subsequent anti-cancer therapy is missing and 
month and year are same as last dosing date of study treatment, the start date will be 
assumed as last dosing date of study treatment. In other situations, do not impute. 
F3. Imputation of Partial/Missing Death Dates 
The following rules will be applied to impute partial or missing death dates. 
 
If death year and month are available but day is missing:  
 
If YYYYMM for the date last known to be alive equals YYYYMM for death date, 
set death date to the day after the date last known to be alive.  
 
If YYYYMM for the date last known to be alive is less than the YYYYMM for 
death date, set death date to the first day of the death month.  
(Below two situations will be evaluated at time of analysis by using a more 
conservative way) 
 
[If YYYYMM for the date last known to be alive is greater than YYYYMM for 
death date, assume date last known to be alive is in error, set death date to the 
first day of the death month. 
or 
 
If YYYYMM for the date last known to be alive is greater than YYYYMM for death 
date, data error, do not impute and censor subject survival time.] 
 
If month and day are missing and year of death is known: 
 
If YYYY for the date last known to be alive equals the YYYY for death date, 
set death date to the day after last known to be alive date.  
 
If YYYY for the date last known to be alive is less than the YYYY for death 
date, set death date to the first day of the death year. 
 
If YYYY for the date last known to be alive is greater than YYYY for death 
date, data error, do not impute and censor the subject survival time. 
 
If a death date is totally missing, do not impute and censor the subject survival 
time. 
F4. Imputation for Date of Initial ALL Diagnosis 
If the day is missing but month and year are available, then impute the day to 1st of 
the month. If month and/or year is missing or the date is completely missing, then 
do not impute. 


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F5. Imputation for Start Date and End Date of Prior ALL Therapy Medication, Date of 
Prior Hematopoietic Stem Cell Transplant, Date of Remission (CRi or Better) to Prior 
ALL Therapy, and Date of Relapse to Prior ALL Therapy 
If the day is missing but month and year are available, then impute the day to 15th 
of the month. If month and/or year is missing or the date is completely missing, 
then do not impute. 
 
 




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