A Phase 1 Dose-Escalation and Exploratory Dose Expansion Study of KRT-232 (AMG 232) in Combination With Carfilzomib, Lenalidomide, and Dexamethasone in Relapsed and/or Refractory Myeloma
Phase: PHASE1
Conditions: Plasmacytoma, Recurrent Multiple Myeloma, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

 i
SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment # to:  "A Phase 1 Dose-Escalation and Exploratory Dose Expansion 
Study of KRT-232 (AMG 232) in Combination with Carfilzomib, Lenalidomide, and 
Dexamethasone in Relapsed and/or Refractory Myeloma.” 
 
NCI Protocol #: 10076 
Local Protocol #: NCI10076 
 
NCI Version Date: 01/15/2024 
Protocol Date: 01/15/2024 
 
THIS AMENDMENT IS BEING SUBMITTED IN RESPONSE TO REQUEST FOR RAPID 
AMENDMENT (RRA) FROM DR. LORRAINE PELOSOF (CTEP MEMO DATED ON 12/29/2023) 
 
Section 
Change 
1 
Protocol 
Cover 
Page 
 Protocol version date has been updated from 01/24/2022 to 01/15/2024.  No 
change in the content of the protocol. 
2 
Section 
7.1.1. 
 
(Pages 58-
60) 
Inserted revised language as per KRT-232 CAEPR on Version 2.4, December 8, 2023 
 
• 
Added New Risk:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10076  
Version Date: 1/15/2024 
 
 
 
 
 
   
 
  
 
 
 
 
  
 
 
   
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
THE FOLLOWING ARE PREVIOUS CTEP ADMINSTRTIVE AMMENDMENT 
RECOMMENDATIONS FROM PREVIOUS CTEP AMENDMENT APPROVAL MEMO 
DATED 03/23/2021  
# 
Section 
Comments 
1. 
Protocol 
Cover 
Page 
Please revise the Corresponding Organization as indicated: 
The University of Texas MD Anderson Cancer Center LAO (LAO-TX035) 
Please revise the Participating Organizations table as indicated: 
Participating Organizations  
LAO-CA043 / City of Hope Comprehensive Cancer Center 
LAO 
LAO-11030 / University Health Network Princess Margaret 
Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana Farber – Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
LAO 
LAO-NC010 / Duke University  Duke Cancer Institute  
LAO-OH007 / Ohio State University Comprehensive Cancer 
Center LAO 
LAO-PA015 / UPMC Hillman Cancer Center LAO University 
of Pittsburg Cancer Institute  

NCI Protocol #: 10076  
Version Date: 1/15/2024 
 
 
 
iii 
# 
Section 
Comments 
LAO-TX035 / University of Texas MD Anderson Cancer 
Center LAO 
LAO-NCI / National Cancer Institute LAO 
PI Response:  Completed 
2. 
4.1 
Page 35 
Please revise the excerpt below as indicated. 
Food and Drug Administration (FDA) regulations and National Cancer 
Institute (NCI) policy require all individuals contributing to NCI-sponsored 
trials to register and to renew their registration annually. To register, all 
individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus 
(AP) (i.e., clinical site staff requiring write access to Oncology Patient 
Enrollment Network (OPEN), Rave, or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and 
Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr. 
RCR utilizes five person registration types. 
• IVR: MD, DO, or international equivalent, 
• NPIVR: advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD), 
• AP: clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System (RUMS), OPEN, 
Rave, acting as a primary site contact, or with consenting privileges, (e.g., 
Roster Update Management System [RUMS], OPEN, Rave,), 
• Associate (A): other clinical site staff involved in the conduct of NCI-
sponsored trials, and 
• Associate Basic (AB): individuals (e.g., pharmaceutical company employees) 
with limited access to NCI-supported systems. 
PI Response:  Completed 
3. 
4.1 
Page 36 
Please revise the excerpt below as indicated. 
RCR requires the following registration documents: 
 

NCI Protocol #: 10076  
Version Date: 1/15/2024 
 
 
 
v 
# 
Section 
Comments 
4. 
4.1 
Page 37 
Please revise the excerpt below as indicated. 
In addition, all investigators act as the Site-Protocol PI (Investigator listed on 
the IRB approval), consenting/treating/drug shipment investigator in OPEN, or 
as the Clinical Investigator (CI) on the DTL must be rostered at the enrolling 
site with a participating organization.  
, consenting/treating/drug shipment, or as the CI on the DTL must be rostered 
at the enrolling site with a participating organization (i.e., Alliance). 
PI Response:  Completed 
5. 
4.2 
Page 38 
Please revise the following bullet point as specified. 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO), and 
PI Response:  Completed 
6. 
4.2.1 
Page 38 
Please revise the excerpt below as indicated. 
Download the site registration forms from the protocol-specific page located 
on the CTSU members’ website. Permission to view and download this 
protocol and its supporting documents is restricted based on person and site 
roster assignment. To participate, the institution and its associated 
investigators and staff must be associated with the LPO or a PO Participating 
Organization on the protocol. One way to search for a protocol is listed below. 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your 
CTEP-IAM username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, 
or 
o Click on the By Lead Organization folder to expand, then select LAO-
TX035, and protocol number 10076, 
• Click on Documents, select Site Registration, and download and complete 
the forms provided. (Note: For sites under the CIRB initiative, IRB data will 
load automatically to the CTSU as described above.) 
Protocol Specific Requirements For 10076 Site Registration 
• Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating 
site will need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be 
submitted to the CTSU through the Regulatory Submission Portal. 

NCI Protocol #: 10076  
Version Date: 1/15/2024 
 
 
 
vi 
# 
Section 
Comments 
o The training is a one-time only requirement per individual. If an individual 
has previously completed the training for another ETCTN study, the training 
does not need to be completed again nor does the certificate of completion 
need to be resubmitted to the CTSU. However, new versions of the Specimen 
Tracking System may require new training. 
o This training will need to be completed before the first patient enrollment at 
a given site. 
o Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com, Theradex phone: 609-799-7580). 
o Peter Clark and Diana Vulih are the main points of contact at Theradex for 
the training (PClark@theradex.com and DVulih@theradex.com, Theradex 
phone: 609-799-7580). 
PI Response:  Completed 
7. 
4.2.2 
Page 39 
Please revise the excerpt below as indicated. 
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal, log on to the CTSU members’ 
website, go to the Regulatory section, and select Regulatory Submission. 
 → Regulatory →Regulatory Submission.  
Institutions with patients waiting that are unable to use the Regulatory 
Submission Portal should alert the CTSU Regulatory Office immediately at 1-
866-651-2878 in order to receive further instruction and support.  
 
Checking Site Registration Status 
Site’s registration status may be verified on the CTSU website.  
• Click on Regulatory at the top of the screen, 
• Click on Site Registration, and  
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration 
Status, Protocol Status, and/or IRB Type. 
Note:  The status shown only reflects institutional compliance with site 
registration requirements as outlined within the protocol.  It does not reflect 
compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with NCI or their affiliated 
networks. 
Checking Site Registration Status  

NCI Protocol #: 10076  
Version Date: 1/15/2024 
 
 
 
vii 
# 
Section 
Comments 
You can verify your site’s registration status on the members’ side of the 
CTSU website.  
• Log on to the CTSU members’ website  
• Click on Regulatory at the top of your screen  
• Click on Site Registration  
• Enter your 5 character CTEP Institution Code and click on Go  
Note: The status shown only reflects institutional compliance with site 
registration requirements as outlined above. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks.  
PI Response:  Completed 
8. 
4.3.1 
Page 40 
Please delete the information within this subsection and replace with the 
following language. 
4.3.1 OPEN / IWRS 
The Oncology Patient Enrollment Network (OPEN) is a web-based 
registration system available on a 24/7 basis.  OPEN is integrated with CTSU 
regulatory and roster data and with the LPOs registration/randomization 
systems or the Theradex Interactive Web Response System (IWRS) for 
retrieval of patient registration/randomization assignment.  OPEN or IWRS 
will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
Requirements for OPEN access:   
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Must be on an 
LPO roster, ETCTN corresponding roster, or PO roster with the role of 
Registrar.  Registrars must hold a minimum of an Associate Plus (AP) 
registration type. 
• If a DTL is required for the study, the registrar must hold the OPEN 
Registrar task on the DTL for the site. 
• Have an approved site registration for the protocol prior to patient 
enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving 
investigator for a patient transfer in OPEN, the IVR or NPIVR must list the 
IRB number used on the site’s IRB approval on their Form FDA 1572 in RCR.  
If a DTL is required for the study, the IVR or NPIVR must be assigned the 
appropriate OPEN-related tasks on the DTL. 

NCI Protocol #: 10076  
Version Date: 1/15/2024 
 
 
 
viii 
# 
Section 
Comments 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated 
timeframes, and  
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  IWRS system also sends an email 
confirmation of the registration.  You may print this confirmation for your 
records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website.  Further instructional information is in the OPEN section of 
the CTSU website at https://www.ctsu.org or https://open.ctsu.org.  For any 
additional questions, contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
Patient enrollment for this study will be facilitated using the Slot Reservation 
System in conjunction with the registration system in OPEN.  Prior to 
discussing protocol entry with the patient, all site staff must use the CTSU 
OPEN Slot Reservation System or the IWRS Slot Reservation System to 
ensure that a slot on the protocol is available to the patient.  Once a slot 
reservation confirmation is obtained, site staff may then proceed to CTSU 
OPEN Step 1 to enroll the patient to this study.  
This Study will use the ETCTN Specimen Tracking System (STS).  
• All biospecimens collected for this trial must be submitted using the 
ETCTN Specimen Tracking System (STS) unless otherwise noted.   
• The system is accessed through Rave user roles:  “Rave CRA” and 
“Rave CRA (Labadmin)” for data entry at the treating institutions and 
“Biorepository” for users receiving the specimens for processing and 
storage at reference labs and the NCI Early-Phase and Experimental 
Clinical Trials Biospecimen Bank (EET Biobank, formerly known as 
the ETCTN Biorepository).   
• Please refer to the Medidata Account Activation and Study Invitation 
Acceptance link on the CTSU website in the Data Management section  
under the Rave Home tab and then under Rave Resource Materials. 
• Important:  Failure to complete required fields in STS may result 
in a delay in sample processing.  Any case reimbursements associated 
with sample submissions will not be credited if samples requiring STS 
submission are not logged into STS. 
Detailed instructions on use of the STS can be found in Section Error! R
eference source not found.. 
PI Response:  Completed 

NCI Protocol #: 10076  
Version Date: 1/15/2024 
 
 
 
ix 
# 
Section 
Comments 
9. 
4.3.3 
Page 43 
Please revise the Theradex Helpdesk number as indicated below. 
Theradex has developed a Slot Reservations and Cohort Management User 
Guide, which is available on the Theradex website: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-
NCI-11 This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the 
Theradex Helpdesk at 855-828-6113 609-619-7802 or Theradex main number 
609-799-7580; CTMSSupport@theradex.com. 
PI Response:  Completed 
10. 
5.2 
Page 44 
Based on the recent PK data, KRT-232 (AMG-232) can now be taken with or 
without food.  Please revise the administration guidance to take with a glass 
of water with or without food. 
PI Response: Completed 
11. 
Appendix 
E 
Pages 117-
118 
 
 
   
PI Response: Completed 
 

NCI Protocol #: 10076  
Version Date: 01/15/2024 
 
 
 
1 
NCI Protocol #: 
10076 
 
Local Protocol #: 
NCI10076 
 
ClinicalTrials.gov Identifier:  NCT03031730 
 
TITLE:  A PHASE 1 DOSE-ESCALATION AND EXPLORATORY DOSE 
EXPANSION STUDY OF KRT-232 (AMG 232) IN COMBINATION WITH 
CARFILZOMIB, LENALIDOMIDE, AND DEXAMETHASONE IN RELAPSED 
AND/OR REFRACTORY MYELOMA 
 
Corresponding Organization: University of Texas MD Anderson Cancer Center (LAO 
TX035) 
 
Principal Investigator: 
Hans Lee, M.D. 
University of Texas MD Anderson Cancer Center 
1515 Holcombe Boulevard, Unit 429 
Houston, TX 77030 
Telephone: 713-745-8430 
Fax: 713-563-5067 
E-mail: hclee@mdanderson.org 
 
 
Participating Organizations  
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana Farber – Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer LAO  
 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / UPMC Hillman Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
Statistician: 
 
 
Coordinating Molecular Pathologist 
Heather Lin, MS 
 
 
 
 
Keyur Patel, M.D., Ph.D. 
 
 
 
6565 MD Anderson Blvd, Unit 1062 
  
 
 
 
Houston, TX 77030 
  
 
 
 
Phone: 713-563-6780 
 
 
 
 
 
Fax: 832-750-0248 
 
 
 
 
kppatel@mdanderson.org 
 
 

NCI Protocol #: 10076  
Version Date: 01/15/2024 
 
 
 
2 
Responsible Research Nurse:                      
 
Responsible Data Manager & TP53 
Astrid Murga, MD 
 
 
 
 
Eligibility Reporter 
1515 Holcombe Blvd., Unit 429 
 
 
Gabriela Rodriguez Mendez, MD 
Houston, TX 77030  
 
 
 
1515 Holcombe Blvd., Unit 429 
Telephone: 713-792-3664 
 
 
 
Houston, TX 77030 
Fax 713-794-5656 
 
 
 
 
Telephone: 713-563-5090 
ADMurga@mdanderson.org 
 
 
grodriguez14@mdanderson.org 
 
 
 
NCI-Supplied Agent: KRT-232 (AMG 232) (NSC 789723)  
 
 
Other Agent(s):   Carfilzomib (NSC 756640, Commercial) 
                              Lenalidomide (NSC 703813, Commercial) 
                              Dexamethasone (NSC 34521, Commercial) 
 
IND #:  134935 
IND Sponsor:  DCTD, NCI 
 
Protocol Type / Version # / Version Date: 
Original/Version Date: 12/1/2016 
 
 
 
 
Revision/Version Date: 01/31/2017 
                                                                              Revision/Version Date: 03/23/2017 
 
 
 
 
Revision/Version Date: 06/09/2017 
 
 
 
 
Revision/Version Date: 06/26/2017 
 
 
 
 
Revision/Version Date: 07/11/2017 
 
 
 
 
Revision/Version Date: 10/12/2017 
 
 
 
 
Revision/Version Date: 02/08/2018 
 
 
 
 
Revision/Version Date: 06/07/2018 
 
   Revision/Version Date: 08/03/2018 
 
   Revision/Version Date: 08/17/2018 
 
   Revision/Version Date: 11/06/2018 
 
   Revision/Version Date: 05/23/2019 
                                                                              Revision/Version Date: 07/30/2019 
 
 
 
 
Revision/Version Date: 09/23/2019 
 
 
 
 
Revision/Version Date: 02/06/2020 
 
 
 
 
Revision/Version Date: 07/02/2020 
                                                                              Revision/Version Date: 08/04/2020 
 
 
 
 
Revision/Version Date: 02/23/2021 
 
 
 
 
Revision/Version Date: 12/07/2021 
 
 
 
 
Revision/Version Date: 01/24/2022 
 
 
 
 
 
 
 

NCI Protocol #: 10076  
Version Date: 01/15/2024 
 
 
 
3 
 
 
PROTOCOL SYNOPSIS 
Study Title: 
Phase 1 Dose-Escalation and Exploratory Dose Expansion Study of KRT-232 (AMG 232) 
in Combination with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) in Relapsed 
and/or Refractory Multiple Myeloma 
IND Number: 
134935 
Investigational 
Product: 
KRT-232 (AMG 232) 
Study Phase: 
Phase 1 
Study Sponsor: 
Cancer Therapy Evaluation Program (CTEP) 
Indication: 
Relapsed or refractory multiple myeloma with one to three lines of prior therapy 
Study Objectives: 
Part A: Dose-escalation  
 
Primary Objectives: 
1) Evaluate safety and tolerability of KRT-232 (AMG 232) in combination with 
carfilzomib, lenalidomide, and dexamethasone (KRd). 
2) Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 
Dose (RP2D) of KRT-232 (AMG 232) in combination with carfilzomib, 
lenalidomide, and dexamethasone (KRd). 
 
Secondary Objectives: 
1) Evaluate PD effects of KRT-232 (AMG 232) through serum MIC-1 levels. 
2) Assess KRT-232 (AMG 232) exposure-response relationships (PD, toxicity, and 
efficacy) 
 
Exploratory Objectives: 
1) Evaluate the overall response rate of KRT-232 (AMG 232) in combination with 
carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory 
myeloma by International Myeloma Working Group (IMWG) criteria (Kumar et 
al., 2016). 
2) Evaluate RNA expression levels of relevant genes in the TP53 pathway that may 
predict response to therapy using pre- and post-treatment bone marrow biopsies. 
 
Part B: Dose-expansion  
 
Primary Objectives: 
1) Confirm the safety and tolerability of KRT-232 (AMG 232) in combination with 
carfilzomib, lenalidomide, and dexamethasone (KRd) at MTD/tentative RP2D in 
a goal of 10 subjects with relapsed and/or refractory myeloma 
 
Secondary Objectives: 
1) Evaluate the overall response rate of KRT-232 (AMG 232) in combination with 
carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory 
myeloma by International Myeloma Working Group (IMWG) criteria (Kumar et 
al., 2016). 
2) Evaluate PD effects of KRT-232 (AMG 232) through serum MIC-1 levels. 
3) Assess KRT-232 (AMG 232) exposure-response relationships (PD, toxicity, and 
efficacy) 
 

NCI Protocol #: 10076  
Version Date: 01/15/2024 
 
 
 
4 
Exploratory Objectives: 
1) Evaluate RNA expression levels of relevant genes in the TP53 pathway that may 
predict response to therapy using pre- and post-treatment bone marrow biopsies. 
 
Study Design: 
This will be a two-part Phase 1 dose-escalation and exploratory dose-expansion study of 
KRT-232 (AMG 232) in combination with carfilzomib, lenalidomide, and dexamethasone 
(KRd) in relapsed and/or refractory TP53 WT myeloma subjects with 1-3 lines of prior 
therapy.  Part A will consist of a dose-escalation phase of KRT-232 (AMG 232) to assess 
its safety and tolerability and identify an MTD/tentative RP2D in combination with KRd.   
After the MTD has been established, Part B of the study will involve an exploratory-dose 
expansion study of a goal of 10 additional subjects with relapsed and/or refractory 
myeloma who will be enrolled at the tentative RP2D.  
 
Due to the timely need to initiate treatment in relapsed myeloma, TP53 mutation status at 
screening is NOT required prior to KRT-232 (AMG 232) dosing.  However, subjects 
found to have TP53 mutation and/or deletion from screening bone marrow biopsy will be 
removed from study after C1 and continue on standard-of-care KRd alone.  Toxicity 
monitoring of such subjects removed from active therapy with KRT-232 (AMG 232) will 
continue as described in the Treatment Plan.    During the dose-expansion phase, subjects 
removed from study after Cycle 1 based on the TP53 mutation and/or deletion status will 
be replaced to ensure that a goal of 10 subjects with TP53 wild-type status are enrolled in 
the dose-expansion cohort.   
 
Treatment Plan: 
Dose Regimen 
KRT-232 (AMG 232) + carfilzomib, lenalidomide, and dexamethasone (KRd) will be 
administered per the following schedule: 
Cycles 1-12 (28 day cycle) 
• 
KRT-232 (AMG 232) once daily by mouth 7 out of 28 days 
• 
Carfilzomib 20 mg/m2 IV on Days 1 and 2 of Cycle 1, escalating to 27 
mg/m2 IV on Days 8, 9, 15, 16 of Cycle 1 and continuing on Days 1, 2, 
8, 9, 15, 16 of Cycles 2 through Cycle 12 
• 
Lenalidomide 25 mg PO on Days 1-21 
• 
Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
 
Cycles 13-18 (28 days each) 
• 
KRT-232 (AMG 232) once daily by mouth 7 out of 28 days 
• 
Carfilzomib 27 mg/m2 IV on Days 1, 2, 15, and 16  
• 
Lenalidomide 25 mg PO on Days 1-21 
• 
Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
 
Cycles 19+ (28 days each) 
• 
KRT-232 (AMG 232) once daily by mouth 7 out of 28 days 
• 
Lenalidomide 25 mg PO on Days 1-21 
• 
Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
Part A (Dose-escalation scheme) 
The MTD is defined as the highest dose at which six subjects have been treated and 
less than two subjects experienced DLT within the first cycle of treatment in Phase I 

NCI Protocol #: 10076  
Version Date: 01/15/2024 
 
 
 
5 
of the trial. To determine the MTD, escalation for KRT-232 (AMG 232) will be 
conducted following the “3+3” design with de-escalation.  A cohort of three subjects 
will be treated at the starting dose level and observed until the end of the first cycle 
(subjects non-evaluable for DLT will be replaced).  The dose level will be escalated 
with each new cohort until at least one out of three subjects of a cohort experiences 
DLT.  If one subject experiences a DLT, then three additional subjects will be treated 
at the same dose level; if none of the three additional subjects experiences a DLT, then 
the dose escalation will be continued by treating the next cohort of three subjects at the 
next higher dose level.  If at least two out of up to six subjects at a dose level 
experience a DLT, the MTD will be considered to have been exceeded, and up to 3 
more subjects will be treated at the next lower dose if there are less than 6 subjects 
already treated at that dose.  The dose steps for escalation are displayed below: 
 
Dose-Escalation Schedule 
Dose Level 
KRT-232 (AMG 232) Dose 
- 1 
30 mg/day PO x 7 days out of 28 day cycle 
+ 1 
60 mg/day PO x 7 days out of 28 day cycle 
+ 2 
90 mg/day PO x 7 days out of 28 day cycle 
+ 3 
120 mg/day PO x 7 days out of 28 day cycle 
+ 4 
180 mg/day PO x 7 days out of 28 day cycle 
+ 5 
240 mg/day PO x 7 days out of 28 day cycle 
 
If dose-de-escalation is needed for Dose level 1, Dose level -1 is defined as  30 mg/day x 7 
days out of 28 day cycle. 
 
Part B (Dose-expansion scheme) 
After determination of the KRT-232 (AMG 232) MTD or proven tolerability of the 
highest planned dose, a goal of 10 additional subjects will be treated in the Part 2 dose 
expansion in combination with KRd.  The tentative RP2D will be determined based on 
the review of safety data at the MTD.  The primary objective of this dose-expansion 
phase is to confirm the safety and tolerability of KRT-232 (AMG 232) + KRd at the 
MTD and tentative RP2D in a goal of 10 subjects with relapsed and/or refractory 
multiple myeloma. 
 
Dose-Limiting Toxicity (DLT) Definition 
A DLT is defined as any treatment emergent adverse event (TEAE) during the first 
treatment cycle that does not have a clear alternative cause (e.g., disease under study, 
concomitant therapy) based on the following criteria using NCI-CTCAE v5.0: 
 
There should be no dose modifications of KRT-232 (AMG 232) and KRd during the DLT-
evaluable period (Cycle 1).  Subjects requiring dose-reductions during the DLT-evaluable 
period will be considered a DLT. 
 
For hematologic events, a DLT is defined as follows: 
• 
Grade 3 or 4 neutropenia with fever ≥ 380 C lasting > 48 hours   

NCI Protocol #: 10076  
Version Date: 01/15/2024 
 
 
 
6 
• 
Grade 4 neutropenia lasting > 7 days 
• 
Grade 3 or 4 thrombocytopenia associated with > grade 1 bleeding.  
Grade 4 thrombocytopenia that persists for > 14 days, despite holding 
treatment 
• 
Grade 4 anemia, unexplained by underlying disease 
• 
Any other grade 4 hematologic toxicity that does not resolve to subject’s 
pre-treatment baseline level within 72 hours 
For non-hematologic events, a DLT is defined as follows: 
• 
Grade ≥ 3 nausea, vomiting or diarrhea lasting longer than 72 hours 
despite optimal medical support 
• 
Grade ≥ 3 non-hematological toxicity (excluding increased serum 
creatinine, or electrolyte abnormalities that are not clinically significant 
and require no treatment) 
• 
Any grade 3 electrolyte abnormalities that do not resolve to grade ≤2 
within 72 hours 
• 
Grade 3 fatigue persisting > 7 days 
• 
Grade ≥ 3 acute kidney injury (creatinine > 3 × baseline or > 4.0 mg/dL) 
lasting > 72 hours 
• 
Any other grade 3 or 4 non-hematologic toxicities not predefined above 
will be considered a DLT. 
• 
A delay of ≥ 14 days in commencing Cycle 2 Day 1 due to lack of 
adequate recovery of KRT-232 (AMG 232) +KRd-related toxicities will 
be considered a DLT. 
Subjects who receive < 75% of the planned study drug doses during the first cycle of  (i.e. 
≤ 5/7 daily doses of KRT-232 (AMG 232) will considered nonevaluable for purposes of 
determining the MTD (unless due to a DLT) and will be replaced.  Subjects who 
experience a DLT during the DLT-evaluable period will be considered evaluable for the 
purposes of determining the MTD as per Section 13.1.4. 
 
Study Duration: 
Subjects will receive KRT-232 (AMG 232) + KRd at a dose defined by the treatment 
outline above.  This therapy will be continued without a cap on the number of allowed 
cycles, unless one of the following occurs: 
• 
Disease progression by IMWG criteria (Appendix 15.6). 
• 
Unacceptable adverse event(s) defined as: 
o 
Occurrence of an AE that is related to treatment with the study 
drug which, in the judgment of the investigator, compromises the 
subject's ability to continue study-specific procedures, or is 
considered to not be in the subject's best interest. 
o 
Persistent AE requiring a delay of therapy for more than 4 
weeks (28 days) 
• 
Subject decides to withdraw from the study 
• 
Pregnancy 
 
o 
All women of child bearing potential should be instructed to contact 

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the investigator immediately if they suspect they might be pregnant 
(e.g., missed or late menstrual period) at any time during study 
participation. 
 
o 
The investigator must immediately notify CTEP in the event of a 
confirmed pregnancy in a subject participating in the study. 
 
• 
Termination of the study by sponsor 
 
• 
The drug manufacturer can no longer provide the study agent 
 
• 
Subject achieves complete remission (CR), and the subject and investigator feel 
that discontinuation of KRT-232 (AMG 232) + KRd is in the subject’s best 
interests, or 
 
• 
Subject achieves a level of response that qualifies him or her for another therapy, 
such as high dose therapy with autologous stem cell transplantation, and the 
subject and investigator feel that discontinuation of KRT-232 (AMG 232) + KRd 
is in the subject’s best interests 
 
At the completion or early discontinuation of treatment, subjects will be followed for an 
additional 30 days after the last administration of treatment or up until the initiation of the 
next line of treatment, whichever comes first.  Subjects with adverse events until the event 
has resolved or the condition has stabilized.   
Subject Eligibility 
Criteria: 
Key Inclusion Criteria: 
1. 
Subjects must have histologically confirmed diagnosis of multiple myeloma.  
2. 
Subjects must have measurable disease, as defined by at least one of the 
following: 
a. 
Serum monoclonal protein M-protein level ≥0.5 g/dL  
b. Urinary M-protein excretion of ≥200 mg over a 24-hour period 
c. 
Involved free light chain level ≥10 mg/dL, along with an abnormal free light 
chain ratio 
3. 
Subjects must have disease that has relapsed and/or refractory after their most 
recent therapy, with progressive disease (PD) being defined as an increase of 25% 
from the lowest response value in any one or more of the following: 
a. 
Serum M-component protein (the absolute increase must be ≥0.5 g/dL) 
and/or 
b. Urine M-component protein (the absolute increase must be ≥200 mg/24 
hours) and/or 
c. 
Only in subjects without a measurable serum and urine M protein level: the 
difference between involved and uninvolved free light chain (FLC) levels 
(absolute increase) must be >10 mg/dL 
d. Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas 
e. 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that 
can be attributed solely to the plasma cell proliferative disorder. 

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4. 
Subjects with one to three lines of therapy for their disease, with a line of therapy 
defined as one or more cycles of a planned treatment program.  Using this 
definition, treatment with induction therapy, followed by high dose chemotherapy 
and autologous stem cell transplantation, and finally by maintenance therapy, 
would constitute one line, provided that multiple myeloma did not meet criteria 
for progression at any time during this period.   
 
5. 
Subjects must have completed their most recent drug therapy directed at multiple 
myeloma in the following timeframes: 
a. 
Antitumor therapy (chemotherapy, antibody therapy, molecular targeted 
therapy, retinoid therapy, hormonal therapy, or investigational agent) at least 
21 days prior to C1D1 KRT-232 (AMG 232) + KRd. 
b. Corticosteroids at least 3 weeks prior to starting KRT-232 (AMG 232) + 
KRd, except for a dose equivalent to dexamethasone of ≤4 mg/day 
c. 
Autologous stem cell transplantation at least 12 weeks prior to starting KRT-
232 (AMG 232) + KRd 
d. Allogeneic stem cell transplantation at least 24 weeks prior to starting KRT-
232 (AMG 232) + KRd, and these subjects must also NOT have moderate to 
severe active acute or chronic graft versus host disease (GVHD). 
 
6. 
Subjects must be ≥ 18 years old.   Because no dosing or adverse event data are 
currently available on the use of KRT-232 (AMG 232) in combination with KRd, 
subjects < 18 years of age are excluded from this study. 
 
7. 
Subjects must have ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see 
Appendix A). 
 
8. 
Subjects must have normal organ and marrow function as defined below: 
a. 
Absolute neutrophil count (ANC) ≥ 1,000/mcL without growth factors within 
2 week of initiation of treatment 
b. Platelets ≥50,000 cells/mm3 if marrow plasmacytosis < 50% OR platelet 
count  ≥30,000 cells/mm3 if marrow plasmacytosis ≥ 50%. 
c. 
Hemoglobin ≥8 g/dL within 2 weeks of the initiation of treatment 
d. Total bilirubin < 1.5 × institutional upper limit of normal (ULN) (< 2.0 × 
ULN for subjects with documented Gilbert’s syndrome or < 3.0 × ULN for 
subjects for whom the indirect bilirubin level suggests an extrahepatic source 
of elevation) 
e. 
AST(SGOT)/ALT(SGPT) ≤ 2.5 × ULN 
f. 
Alkaline phosphatase < 2.0 × ULN (if liver or bone disease are present, < 3.0 
× ULN) 
g. Creatinine clearance (eGFR) ≥ 50 mL/min/1.73 m²  
 
9. 
Subjects must have adequate coagulation laboratory assessments, as follows: 
Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 × upper limit 
of normal (ULN), OR International normalized ratio (INR) < 1.5. 
 
10. 
Subjects who have received radiation therapy targeting > 10% of the bone 
marrow space must have completed this at least 2 weeks prior to starting therapy 
with KRT-232 (AMG 232) + KRd. 
 
11. 
Subjects must be able and willing to provide bone marrow biopsies/aspirates and 
buccal swab as requested by the protocol. 
 
12. 
Subjects must be willing to undergo myeloma genotyping for TP53 mutation, 
insertion, or deletion at screening.  

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13. 
Subjects must have an estimated life expectancy of at least 3 months. 
 
14. 
The effects of KRT-232 (AMG 232) on the developing human fetus are unknown.  
For this reason and because lenalidomide is known to be teratogenic, women of 
child-bearing potential must commit to either abstaining continuously from 
heterosexual sexual intercourse or agree to use 2 forms of adequate contraception 
or continuously abstain from the time of informed consent for the duration of 
study participation through 5 weeks (women) after receiving the last dose of 
KRT-232 (AMG 232), lenalidomide, or carfilzomib.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately.  Men treated or 
enrolled on this protocol must also agree to use adequate contraception prior to 
the study, for the duration of study participation, and 3 months after completion 
of KRT-232 (AMG 232) administration.  This includes one highly effective form 
of contraception (e.g. intrauterine device [IUD], hormonal [birth control pills, 
injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) 
and one additional effective contraceptive method (e.g. male latex or synthetic 
condom, diaphragm, or cervical cap). 
 
15. 
Subjects must be able to swallow medication. 
 
16. 
Ability to understand and the willingness to sign a written informed consent 
document. 
 
Key Exclusion Criteria: 
1. Subjects with myeloma that is relapsed and/or refractory to KRd when used in 
combination defined as progression of disease while on therapy or within 60 days 
of completing therapy. 
 
2. Subjects must show evidence of wild-type (WT) p53 status on somatic tissue 
specimens as assessed by DNA sequencing. Note that since patients with 
relapsed myeloma have a rapidly proliferating disease, patient can be enrolled 
and begin treatment prior to obtaining the results of this test. Patients who are 
discovered to have a TP53 mutation will be removed from study after cycle 
one and can continue on carfilzomib, lenalidomide, and dexamethasone 
(KRd). All enrolled patients will be followed for toxicity. 
 
3. Subjects who have not recovered from toxicities from prior anti-tumor therapy, 
defined as not having resolved to Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility 
criteria with the exception of alopecia (Grade 2 or 3 toxicities from prior 
antitumor therapy that are considered irreversible [defined as having been present 
and stable for > 6 months], such as grade 2 chemotherapy-induced peripheral 
neuropathy, may be allowed if they are not otherwise described in the exclusion 
criteria AND there is agreement to allow by both the investigator and sponsor). 
 
4. Subjects who are receiving any other investigational agents. 
 
5. Subjects who have undergone major surgery within 28 days of study day 1. 
Vertebroplasty and/or kyphoplasty, which must have been performed at least 1 
week prior to starting KRT-232 (AMG 232) + KRd 
 
6. Subjects with known central nervous system involvement of myeloma should be 
excluded from this clinical trial because of their poor prognosis and because they 

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often develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events. 
 
7. Subjects with history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to KRT-232 (AMG 232) or carfilzomib, 
lenalidomide, or dexamethasone.   
 
8. Subjects’ medication list such a herbal medicines (e.g., St. John’s wort), vitamins, 
and supplements will be reviewed before starting first dose of KRT-232 (AMG 
232) and at each clinic visit.  Any potential drug interactions will be brought and 
discussed with the Principle Investigator.  Use of any known CYP3A4 substrates 
with narrow therapeutic window (such as alfentanil, astemizole, cisapride, 
dihydroergotamine, pimozide, quinidine, sirolimus, or terfanide) within the 14 
days prior to receiving the first dose of KRT-232 (AMG 232) is not permitted.  
Other medications (such as fentanyl and oxycodone) may be allowed per 
investigator’s assessment/evaluation. 
 
9. Treatment with medications known to cause QTc interval prolongation within 7 
days of study day 1 unless is not permitted unless approved by the sponsor.  Use 
of ondansetron is permitted for treatment of nausea and vomiting. 
 
10. Current use of warfarin, factor Xa inhibitors and direct thrombin inhibitors.  Note: 
Low molecular weight heparin and prophylactic low dose warfarin are permitted. 
PT/PTT must meet the inclusion criteria.  Subjects taking warfarin must have 
their INR followed closely. 
 
11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
Subjects with myocardial infarction within 6 months of study day 1, symptomatic 
congestive heart failure (New York Heart Association (NYHA) Class III and 
higher), unstable angina, or cardiac arrhythmia requiring medication are 
excluded. 
 
12. Subjects with GI tract disease causing the inability to take oral medication, 
malabsorption syndrome, requirement for intravenous alimentation, prior surgical 
procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., 
Crohn’s disease, ulcerative colitis). 
 
13. Subjects with history of bleeding diathesis. 
 
14. Subjects with active infection requiring IV antibiotics within 2 weeks of study 
enrollment (day 1) are excluded. 
 
15. Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic Hepatitis 
B), positive Hepatitis total core antibody with negative HBsAG (suggestive of 
occult hepatitis B), or detectable Hepatitis C virus RNA by a polymerase-chain 
reaction (PCR) assay (indicative of active Hepatitis C – screening is generally 
done by Hepatitis C Antibody (HepCAb), followed by Hepatitis C virus RNA by 
PCR if HepCAb is positive). Subjects with hepatitis B virus suppressed on 

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11 
therapy, and previously treated/eradicated hepatitis C virus are eligible for study.   
 
16. Subjects positive for human immunodeficiency virus (HIV) are NOT excluded 
from this study, but HIV-positive subjects must have:  
a. 
A stable regimen of highly active anti-retroviral therapy (HAART)  
b. 
No requirement for concurrent antibiotics or antifungal agents for the 
prevention of opportunistic infections.   
c. 
A CD4 count above 250 cells/mcL and an undetectable HIV viral load on 
standard PCR-based test 
 
17. Men and women of reproductive potential who are unwilling to practice 
acceptable methods of effective birth control while on study through 5 weeks 
(women) or 3 months (men) after receiving the last dose of KRT-232 (AMG 
232).  Acceptable methods of effective birth control include sexual abstinence 
(men, women); vasectomy; or a condom with spermicide (men) in combination 
with barrier methods, hormonal birth control or IUD (women). 
 
18. Pregnant women are excluded from this study because KRT-232 (AMG 232) is 
an agent with the potential for teratogenic or abortifacient effects.  Because there 
is an unknown but potential risk for adverse events in nursing infants secondary 
to treatment of the mother with KRT-232 (AMG 232), breastfeeding should be 
discontinued if the mother is treated with KRT-232 (AMG 232).  These potential 
risks may also apply to other agents used in this study. 
 
19. Women who are lactating/breast feeding or who plan to breastfeed while on study 
through 1 week after receiving the last dose of study drug. 
 
20. Subjects with prior treatment with an MDM2 inhibitor. 
 
Sample Size: 
The Dose Escalation phase of this study (Part 1) consists of 5 dose levels including at least 
3 and up to 6 subjects for a minimum of 15 subjects if no DLT is reached, or a maximum 
of 30 subjects. An exploratory expansion phase with a goal enrollment of 10 subjects at the 
recommended phase 2 dose is also planned for a total in both phases of 25-40 subjects. 
During the dose-expansion phase, subjects removed from study after Cycle 1 based on the 
TP53 mutation and/or deletion status will be replaced to ensure that a goal of 10 subjects 
with TP53 wild-type status are enrolled in the dose-expansion cohort.  Based on prior 
phase I and II studies at MDACC targeting a similar subject population, we estimate 1.5 
subjects will be accrued every month, suggesting that 16-26 months will be needed to meet 
the sample size.  Please note this assumes no interruption in accrual. 
 
For the Dose Expansion phase (Part 2), a goal of 10 additional subjects will be enrolled.  
The maximum half width of the 95% confidence interval for the response rate will be 32% 
for 10 subjects.  Including the 6 subjects enrolled at the MTD in the Part I (dose-escalation 
phase), the maximum half width of the 95% confidence interval for 16 subjects will be 
25%. 
 
Statistical 
Considerations: 
The primary analysis is to assess the safety and tolerability of KRT-232 (AMG 232) + 
KRd in subjects with relapsed and/or refractory myeloma and to determine the 
MTD/tentative RP2D of KRT-232 (AMG 232) + KRd. 
 
All subjects who receive any amount of the study drug will be evaluable for toxicity.   The 
DLT-evaluable period will be during cycle 1, although toxicity will be monitored 
throughout the course of treatment.   The primary analysis will occur after all subjects in 
Part B have either discontinued the study or completed at least 6 months of treatment. 
 

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Descriptive statistics will be provided for selected demographic, safety, PK, and PD data 
by dose and time as appropriate. Descriptive statistics on continuous data will include 
means, medians, standard deviations, and ranges, while categorical data will be 
summarized using frequency counts and percentages. Graphical summaries of the data 
may be presented.  
 
A full pharmacokinetic profile of KRT-232 (AMG 232) will be proposed in this protocol 
to assess exposure-response relationships with various PD endpoints (i.e., MIC-1 changes, 
toxicity, efficacy).  KRT-232 (AMG 232) concentrations in these samples will be 
quantitatively measured using liquid chromatography/tandem mass spectrometric 
(LC/MS/MS) method that will be developed by the Analytical Pharmacology Core 
Laboratory at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns 
Hopkins.  For KRT-232 (AMG 232), the individual PK parameters from a single dose will 
be estimated for Cmax, AUC, T1/2, apparent Cl/F, and apparent V/F using non-
compartmental or compartmental PK methods with the software WinNonlin.  For serum 
MIC-1 levels, each individual level will be normalized to the baseline level for that 
subject.  Advanced population PK methods may be employed to assess the link between 
drug exposure and biological effects and efficacy. The PK variables and changes in MIC-1 
will be tabulated and descriptive statistics (e.g., geometric means and coefficients of 
variation) calculated for each dose level.  PK parameters (i.e., T1/2, Cl, and AUC) and 
MIC-1 changes will be compared across dose level using nonparametic statistical testing 
techniques.  Exploratory correlative studies with pharmacodynamic (biological endpoints, 
toxicity and efficacy) will be analyzed using nonparametric statistics. Significance for 
comparisons will be at the p<0.05 level.   
 
Efficacy analysis will be performed for all subjects in the dose escalation and dose 
expansion part of the study.   Separate efficacy analyses will be performed on the full 
analysis set which includes all subjects enrolled on study, and the primary analysis set 
which includes only subjects who were biomarker positive (TP53 WT).  Parameters 
assessed will include minimal residual disease (MRD) negative, stringent complete 
response (sCR), complete response (CR), very good partial response (VGPR), and partial 
response (PR), minimal response (MR), and stable disease (SD) per IMWG Uniform 
Response criteria. In addition, overall response rate (defined as greater than or equal to PR 
across all cycles of treatment), response duration, time-to-response (TTR), PFS, and OS 
will be assessed. 
 
Best overall response categories will be tabulated by dose cohort and overall for the 
IMWG categories of MRD-negative, sCR, CR, VGPR, PR, MR, SD, progressive disease, 
and relapse. A two-sided 95% exact binominal CI will be calculated for each category.  
The myeloma response rate (responses ≥PR) will also be tabulated by dose cohort and 
overall. Time-to-event analyses will be done using Kaplan-Meier analyses and will include 
time to response, duration of response, progression-free survival (PFS), and overall 
survival (OS), as data allow. If there is not enough data to apply the Kaplan-Meier test, the 
data will be summarized by descriptive statistics. 
 
 
 
 

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TABLE OF CONTENTS 
 
TITLE:  A Phase 1 Dose-Escalation and Exploratory Dose Expansion Study of KRT-232 (AMG 232) in 
Combination with Carfilzomib, Lenalidomide, and Dexamethasone in Relapsed and/or Refractory 
Myeloma ....................................................................................................................................................... 1 
PROTOCOL SYNOPSIS .............................................................................................................................. 3 
TABLE OF CONTENTS ............................................................................................................................ 13 
1. 
OBJECTIVES .................................................................................................................................... 16 
1.1. 
Part A: Dose-Escalation ................................................................................................................. 16 
1.2. 
Part B: Dose-expansion ................................................................................................................. 16 
2. 
BACKGROUND ................................................................................................................................ 17 
2.1. 
Multiple Myeloma ............................................................................................................................ 17 
2.2. 
MDM2 regulation of TP53 ............................................................................................................. 17 
2.3. 
KRT-232 (AMG 232) ....................................................................................................................... 17 
2.4. 
Other Agent(s) .................................................................................................................................. 22 
2.5. 
Rationale of KRT-232 (AMG 232) + Carfilzomib, Lenalidomide, and Dexamethasone 
(KRd) in Multiple Myeloma ........................................................................................................................ 23 
2.6. 
Rationale of KRd + KRT-232 (AMG 232) Human Dosing ................................................... 27 
2.7. 
Correlative Studies Background ................................................................................................ 27 
3. 
SUBJECT SELECTION .................................................................................................................... 30 
3.1. 
Inclusion Criteria ............................................................................................................................. 30 
3.2. 
Exclusion Criteria ............................................................................................................................ 32 
3.3. 
Inclusion of Women and Minorities .......................................................................................... 35 
4. 
REGISTRATION PROCEDURES .................................................................................................... 35 
4.1. 
Investigator and Research Associate Registration with CTEP ........................................ 35 
4.2. 
Site Registration............................................................................................................................... 36 
4.3. 
Subject Registration ....................................................................................................................... 38 
4.4. 
General Guidelines .......................................................................................................................... 41 
5. 
TREATMENT PLAN ........................................................................................................................ 41 
5.1. 
KRT-232 (AMG 232) + Carfilzomib, Lenalidomide, and Dexamethasone (KRd) ...... 41 
5.2. 
KRT-232 (AMG 232) Administration ........................................................................................ 42 
5.3. 
Carfilzomib, Lenalidomide, and Dexamethasone Administration ................................ 42 
5.4. 
KRT-232 (AMG 232) + Carfilzomib, Lenalidomide, and Dexamethasone Treatment 
Plan 
43 
5.5. 
Prophylactic and Supportive Medications ............................................................................. 46 
5.6. 
Definition of Dose-Limiting Toxicity ........................................................................................ 46 
5.7. 
Dose Expansion Cohorts: .............................................................................................................. 47 
5.8. 
General Concomitant Medication and Supportive Care Guidelines .............................. 48 
5.9. 
Treatment Duration ....................................................................................................................... 49 
5.10. 
Duration of Follow Up .................................................................................................................... 50 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................................ 50 
6.1. 
Criteria for Beginning or Delaying a Subsequent Treatment Cycle .............................. 50 
6.2. 
Dose Reductions .............................................................................................................................. 51 
6.3. 
Non-Hematologic Toxicity Dose Delay/Dose Modification Guidelines. ....................... 51 
6.4. 
Hematologic Toxicity Dose Delay/Dose Modification Guidelines. ................................ 54 

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6.5. 
Dexamethasone Toxicity Dose Delay/Dose Modification Guidelines. ......................... 55 
6.6. 
Hepatotoxicity Stopping and Rechallenge Rules .................................................................. 56 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................................. 58 
7.1. 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ............................... 58 
7.2. 
Adverse Event Characteristics .................................................................................................... 67 
7.3. 
Expedited Adverse Event Reporting ......................................................................................... 68 
7.4. 
Routine Adverse Event Reporting ............................................................................................. 70 
7.5. 
Secondary Malignancy ................................................................................................................... 70 
7.6. 
Second Malignancy .......................................................................................................................... 71 
7.7. 
Pregnancy, Contraception, and Risk of Embryo-Fetal Toxicity ...................................... 71 
8. 
PHARMACEUTICAL INFORMATION .......................................................................................... 72 
8.1. 
CTEP IND Agent(s) ........................................................................................................................... 72 
8.2. 
Other Investigational Agent(s) ................................................................................................... 75 
8.3. 
Commercial Agent(s)...................................................................................................................... 75 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ......................................................... 79 
9.1. 
Integral Laboratory or Imaging Studies .................................................................................. 79 
9.2. 
Investigational Device Information .......................................................................................... 83 
9.3. 
Integrated Correlative Studies ................................................................................................... 83 
9.4. 
Exploratory/Ancillary Correlative Studies ............................................................................ 86 
9.5. 
Optional biobanking of blood and marrow samples .......................................................... 87 
9.6. 
Other studies:  Minimal Residual Disease Testing .............................................................. 88 
9.7. 
Summary of Bone Marrow Biopsy and Aspirate Studies ................................................... 89 
10. 
STUDY CALENDAR ................................................................................................................... 90 
10.1. 
Part A: Dose Escalation .................................................................................................................. 90 
10.2. 
Part B: Dose Expansion .................................................................................................................. 92 
11. 
MEASUREMENT OF EFFECT .................................................................................................... 94 
11.1. 
Multiple Myeloma Response Assessment ............................................................................... 94 
11.2. 
Other Response Parameters ........................................................................................................ 94 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS ........ 94 
12.1. 
Study Oversight ................................................................................................................................ 94 
12.2. 
Data Reporting ................................................................................................................................. 95 
12.3. 
CTEP Multicenter Guidelines ....................................................................................................... 98 
12.4. 
Collaborative Agreements Language ........................................................................................ 98 
12.5. 
Genomic Data Sharing Plan .......................................................................................................... 99 
13. 
STATISTICAL CONSIDERATIONS ........................................................................................... 99 
13.1. 
Analysis Sets ...................................................................................................................................... 99 
13.2. 
Study Design/Endpoints ............................................................................................................. 100 
13.3. 
Sample Size/Accrual Rate ........................................................................................................... 102 
13.4. 
Stratification Factors .................................................................................................................... 103 
13.5. 
Analysis of Secondary Endpoints ............................................................................................. 103 
13.6. 
Efficacy Analysis ............................................................................................................................. 103 
13.7. 
Analysis of Exploratory Endpoint ............................................................................................ 104 
14. 
REFERENCES ............................................................................................................................ 105 
15. 
APPENDICES ............................................................................................................................. 108 
15.1. 
APPENDIX A: PERFORMANCE STATUS CRITERIA ............................................................... 108 

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15.2. 
APPENDIX B: PATIENT DRUG Interactions handout and wallet card ......................... 109 
15.3. 
APPENDIX C: Drug-Induced Liver Injury (DILI) Reporting & Additional Assessments
 
114 
15.4. 
APPENDIX D: CASE REPORT FORM FOR TP53 NGS ASSAY .............................................. 116 
15.5. 
APPENDIX E: MEDICATION DIARY ........................................................................................... 117 
15.6. 
APPENDIX F: IMWG Response Criteria (Kumar et al., 2016) ......................................... 120 
15.7. 
APPENDIX G: COLLECTION OF BUCCAL SWAB AT SCREENING ...................................... 121 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. OBJECTIVES 
 
1.1. Part A: Dose-Escalation 
 
1.1.1. 
Primary Objective 
 
1) Evaluate safety and tolerability of KRT-232 (AMG 232) in combination with 
carfilzomib, lenalidomide, and dexamethasone (KRd). 
2) Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose 
(RP2D) of KRT-232 (AMG 232) in combination with carfilzomib, lenalidomide, and 
dexamethasone (KRd) 
 
1.1.2. 
Secondary Objectives 
 
1) Evaluate PD effects of KRT-232 (AMG 232) through serum MIC-1 levels. 
2) Assess KRT-232 (AMG 232) exposure-response relationships (PD, toxicity, and 
efficacy). 
 
1.1.3. 
Exploratory Objectives 
 
1) To observe and record anti-tumor activity of KRT-232 (AMG 232) in combination with 
carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory myeloma by 
International Myeloma Working Group (IMWG) criteria.  Although the clinical benefit of 
KRT-232 (AMG 232) has not yet been established, the intent of offering this treatment is 
to provide a possible therapeutic benefit, and thus the subject will be carefully monitored 
for tumor response and symptom relief in addition to safety and tolerability.   
2) Evaluate RNA expression levels of relevant genes in the TP53 pathway that may predict 
response to therapy using pre- and post-treatment bone marrow biopsies. 
 
1.2. Part B: Dose-expansion 
1.2.1. 
Primary Objectives: 
 
1) Confirm the safety and tolerability of KRT-232 (AMG 232) in combination with 
carfilzomib, lenalidomide, and dexamethasone (KRd) at MTD/tentative RP2D in a goal 
of 10 subjects with relapsed and/or refractory myeloma 
 
1.2.2. 
Secondary Objectives: 
 
1) Evaluate the overall response rate of KRT-232 (AMG 232) in combination with 
carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory myeloma by 
International Myeloma Working Group (IMWG) criteria (Kumar et al., 2016). 
2) Evaluate PD effects of KRT-232 (AMG 232) through serum MIC-1 levels. 
3) Assess KRT-232 (AMG 232) exposure-response relationships (PD, toxicity, and 
efficacy) 
 

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1.2.3. 
Exploratory Objectives: 
 
1) Evaluate RNA expression levels of relevant genes in the TP53 pathway that may  predict 
response to therapy using pre- and post-treatment bone marrow biopsies. 
 
 
2. BACKGROUND 
 
2.1. Multiple Myeloma 
 
Multiple myeloma is currently the second most common hematologic malignancy with over 
30,000 cases diagnosed annually in the United States (Dimopoulos et al., 2016).  It is 
characterized by a malignant proliferation of plasma cells and can lead to significant morbidity 
and mortality due to its effect on multiple organ systems.  The clinical signs and symptoms 
myeloma can vary, but most commonly involve bone pain due to myeloma-induced lytic bone 
lesions, anemia due to infiltration of plasma cell in the bone marrow, renal failure due to light 
chain cast nephropathy, and hypercalcemia.   Despite improvements in subject outcomes with 
the introduction of novel agents such as bortezomib and lenalidomide over the last decade, 
myeloma remains incurable (Kumar et al., 2008).  Eventual emergence of drug resistance 
continues to be a significant challenge that most subjects will encounter during their 
treatment course, highlighting the clear need and recognized approval path for new drugs that 
are active in this disease. 
 
2.2. MDM2 regulation of TP53 
 
The tumor suppressor protein 53 (p53) encoded by the TP53 gene plays a critical role in 
preventing cancer development in response to DNA damage and cellular stress by activating the 
transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA 
repair (Levine and Oren, 2009; Vazquez et al., 2008).  It has been suggested that inactivation of 
the p53 pathway may be required for tumor formation and survival (Vogelstein et al., 2000).  
Approximately 50% of all human cancers have mutant p53 (p53mut) resulting in attenuation or 
loss of p52 function (Rew and Sun, 2014).  However, a large percentage of tumors with the wild-
type p53 (p53WT) also display a reduced p53 function, which is due to mutations or alterations in 
other members of the p53 pathway (Rew and Sun, 2014; Vazquez et al., 2008).  For example, 
overexpression of MDM2 by gene amplification is common in human cancers.  MDM2 is a 
negative regulator of p53 that inhibits p53 activity by 1) directly binding to the N-terminal 
transcriptional activation domain of p53 and thus blocking p53 activity, 2) promoting export of 
p53 from the nucleus to the cytoplasm, and 3) targeting p53 for the proteasomal degradation 
through the MDM2 E3 ubiquitin ligase activity.  Disruption of the binding of MDM2 to p53 
blocks all three mechanisms and leads to reactivation of p53 in cancer cells.  Therefore, 
neutralizing the MDM2-p53 protein-protein interaction by small molecule inhibitors may be an 
effective therapeutic strategy for treatment of p53WT tumors. 
 
2.3. KRT-232 (AMG 232) 
 

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2.3.1. 
Non-Clinical Studies 
 
Nonclinical Studies: Mechanism of Action and Activity 
 
KRT-232 (AMG 232) is an orally (PO) bioavailable, selective small molecule inhibitor of 
MDM2 that blocks the protein-protein interaction between MDM2 and p53 (Investigator’s 
Brochure, 2015; Rew and Sun, et al., 2014; Sun et al., 2014).  KRT-232 (AMG 232) neutralizes 
interaction between the human MDM2 and p53 with a 50% inhibition achieved at the 
concentration (IC50) of 1.0 nM in a homogeneous time resolved fluorescence (HTRF)-based 
potency assay (15% human serum), and binds to human MDM2 with a dissociation constant 
(KD) of 0.069 nM as measured in a Biacore direct-binding assay (Investigator’s Brochure, 2015).  
KRT-232 (AMG 232) effectively inhibited proliferation of SJSA-1 human osteosarcoma cells in 
vitro (which displays MDM2 gene amplification and has p53WT) at IC50=9.1 nM, as assessed in a 
5-ethynyl-2’-deoxyuridine (EdU) cell proliferation assay (Sun et al., 2014).  KRT-232 (AMG 
232) demonstrated robust antitumor activity in vivo, resulting in dose-dependent reduction in 
tumor growth with half-maximal effective dose (ED50) of 9.1 mg/kg in the SJSA-1 xenograft 
mouse model following 14-day PO once daily (QD) dosing.  Complete tumor regression was 
observed in 10 of 12 animals at a dose of 60 mg/kg.  Activation of p53 signaling was determined 
by induction of p21 mRNA, which is a direct transcriptional target of p53 in three p53WT tumor 
cell lines, i.e., SJSA-1, HCT116 (non-amplified MDM2 colorectal [CRC] cell line), and ACHN 
(renal carcinoma) (Canon et al., 2015).  KRT-232 (AMG 232) increased p21 mRNA levels in 
these cell lines 34.9-, 9.8-, and 11.5-fold, respectively.  KRT-232 (AMG 232)-mediated 
induction of p21 mRNA was also tested in vivo in the SJSA-1 xenograft murine model; animals 
receiving only a vehicle served as negative control/baseline.  KRT-232 (AMG 232) 
demonstrated a robust time and concentration-dependent induction of the p21 transcript in SJSA-
1 tumors, with a 30-fold increase over the control observed 4 hours after the last dose in the 
group treated with 50 mg/kg PO QD for 4 days (Investigator’s Brochure, 2015). 
 
Selectivity of KRT-232 (AMG 232) antitumor activity for p53WT cells was examined via a 5-
bromo-2’-deoxyuridine (BrdU) cell proliferation assay (Sun et al., 2014).  Following 16 h 
incubation, KRT-232 (AMG 232) substantially inhibited growth of p53WT HCT116 (IC50=10 
nM) compared to no growth inhibition observed in p53-deficient (p53-/-) cell culture. 
 
In vivo antitumor activity of KRT-232 (AMG 232) was also assessed in xenograft mouse models 
of various tumor types, which have p53WT and non-amplified MDM2, i.e., A375sq2 (mutant 
BRAFV600E melanoma), HCT116 (mutant KRAS CRC), and NCI-H460 (mutant KRAS non-
small cell lung cancer [NSCLC]) (Canon et al., 2015).  KRT-232 (AMG 232) administered PO 
QD to mice demonstrated a 50% tumor growth inhibition over the vehicle control at a dose of 18 
mg/kg (HCT116), 31 mg/kg (A375sq2), and 78 mg/kg (NCI-H460).  These data highlight 
variable sensitivity among different tumor types with different genetic backgrounds beyond p53 
WT status.  Efforts are ongoing to develop profiles that might predict which tumors will respond 
best to this therapeutic approach (Investigator’s Brochure, 2015). 
 
Nonclinical Pharmacology 
 

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  Overall, the nonclinical PK and drug metabolism data support the clinical testing of 
KRT-232 (AMG 232) in human subjects. 
 
Nonclinical Toxicology 
 
The potential toxicity of KRT-232 (AMG 232) was evaluated in 28-day repeat-dose studies in 
rats and cynomolgus monkeys (Investigator’s Brochure, 2015).  
 
 
 
 
 
 
 
 
 
 
 
  All observed effects in rats and monkeys were reversible. 
 
 
 
 
 
 
 
 
KRT-232 (AMG 232) has demonstrated appropriate preclinical PK and acceptable safety profile 
in rats and monkeys to support clinical development.  
 
  
 
 
 

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preclinical species, additional potential toxicity risks include pancreatic toxicity, muscle tissue 
toxicity, and male and female reproductive system toxicity. 
 
 
2.4. Other Agent(s) 
 
In this phase 1 study, KRT-232 (AMG 232) will be dose-escalated in combination with 
evaluated with carfilzomib, lenalidomide, and low-dose dexamethasone (KRd).   
 
2.4.1. 
Carfilzomib 
 
Carfilzomib is a second-generation proteasome inhibitor, was initially approved by the FDA in 
2012 as a single-agent for the treatment of relapsed myeloma with at least two prior lines of 
therapy based on the Phase 2 PX-171-003-A1 study single-arm study (Siegel et al., 2012).  
Overall response rate (ORR, defined as ≥ PR) of 23.7%.  Most common grade 3 and 4 AEs were 
hematologic (24% anemia, 29% thrombocytopenia, 11% neutropenia).  Most frequent grade 3 
and 4 non-hematologic AEs were fatigue (7.5%), pneumonia (9.4%), and hyponatremia (8.3%).  
Importantly, only 12.4% of subjects experienced any treatment-emergent peripheral neuropathy 
(PN), and only 3 (1.1%) subjects grade 3 PN which was a significant improvement compared to 
its predecessor bortezomib.     
 
2.4.2. 
Lenalidomide and Dexamethasone 
 
Lenalidomide, a second-generation oral immunomodulatory (IMiD) drug, was approved by the 
FDA in combination with dexamethasone in relapsed myeloma in 2006 based on a phase 3 
randomized study of lenalidomide and high-dose dexamethasone versus high-dose 
dexamethasone (Weber et al., 2007).   ORR was 61.0% in the lenalidomide arm versus 19.9% in 
dexamethasone monotherapy group.  Most common grade 3 and 4 AEs in the lenalidomide and 
dexamethasone arm were hematologic (41.2% neutropenia, 13% anemia, and 14.7% 
thrombocytopenia), while the most common grade 3 and 4 non-hematologic AEs included 
infection (21.4%).  Moreover, venous thromboembolism (VTE) occurred in 14.7% of subjects in 
the lenalidomide and dexamethasone arm.  A subsequent study comparing lenalidomide with 
high-dose (40 mg on days 1-4, 9-12, and 17-20 on 28-day cycle) versus low-dose dexamethasone 
(40 mg on days 1, 8, 15, and 22 on 28-day cycle) showed a significant improvement in overall 
survival (OS) in the low-dose dexamethasone group compared to the high-dose dexamethasone 
group (96% vs. 87%, P = 0.0002), which was mainly attributable to a decrease incidence of 
infections with lower doses of glucocorticoids (Rajkumar et al., 2010).  Moreover, there was 
significant reduction in VTEs observed with lenalidomide was in combination with low-dose 
dexamethasone versus the high-dose dexamethasone (26% vs. 12%).  Therefore, it is 
recommended that lenalidomide be administered in combination with low-dose dexamethasone.  
 
2.4.3. 
Carfilzomib, Lenalidomide, and Dexamethasone (KRd) 
 
The combination of carfilzomib, lenalidomide, and dexamethasone (KRd) was studied in a phase 
1 trial in relapsed and refractory myeloma (Niesvizky et al., 2013), where the MTD was not 
reached and the maximum planned dose (Dose Level 6) of KRd (Carflzomib 27 mg/m2, 

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lenalidomide 25 mg, and dexamethasone 40 mg) was recommended for further study.. Based on 
the encouraging results of the safety, tolerability, and efficacy of this study and a subsequent 
phase 2 study (Wang et al., 2013), the combination of carfilzomib, lenalidomide, and low-dose 
dexamethasone (KRd) was then compared to lenalidomide and low-dexamethasone (Rd) in a 
phase 3 registration-enabling randomized study in relapsed myeloma patients with 1-3 lines of 
prior therapy (ASPIRE) (Stewart, 2015).  In this study, KRd was administered per the following 
schedule: 
 
Cycles 1-12 (28 day cycle) 
Carfilzomib 20 mg/m2 IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m2 
IV on Days 8, 9, 15, 16 of Cycle 1 and continuing on Days 1, 2, 8, 9, 15, 16 of 
Cycles 2 through Cycle 12 
Lenalidomide 25 mg PO on Days 1-21 
Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
 
Cycles 13-18 (28-day cycle) 
Carfilzomib 27 mg/m2 IV on Days 1, 2, 15, and 16 
Lenalidomide 25 mg PO on Days 1-21 
Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
 
Cycles 19+ (28-day cycle) 
Lenalidomide 25 mg PO on Days 1-21 
Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
 
Both ORR (87.1% vs. 66.7%) and PFS (26.3 vs. 17.6 months) were superior in the KRd arm 
compared to the Rd arm.  Most common grade 3 or 4 AEs in the KRd arm were anemia (17.9%) 
neutropenia (29.6%) and thrombocytopenia (16.6%).   Non-hematologic grade 3 or 4 AEs 
occurring in ≥ 5% of subjects included fatigue (7.7%) and hypokalemia (9.4%).  Based on the 
positive results of this study, KRd was granted FDA approval in 2015 for subjects with relapsed 
myeloma with 1-3 lines of therapy, and established itself as a standard-of-care in this patient 
population.   
 
 
2.5. Rationale of KRT-232 (AMG 232) + Carfilzomib, Lenalidomide, and 
Dexamethasone (KRd) in Multiple Myeloma 
 
The auto-regulatory relationship between the tumor suppressor p53 (TP53) and its 
transcriptional target murine double minute 2 (MDM2) has been well established.  In unstressed 
cells, MDM2 maintains low levels of p53 activity by directly inhibiting its transcriptional 
activity, and by targeting it for proteasomal-mediated degradation through its function as an E3 
ubiquitin ligase. However, in the presence of stress signals such as DNA damage, 
attenuation of the p53 and MDM2 interaction leads to increased apoptosis through 
stabilization of p53. Alterations in the MDM2-p53 axis have also been implicated in 
tumorigenesis, as cell survival signals such as AKT, which promotes MDM2 nuclear levels 
or increase MDM2 binding to p53, resulting in decreased apoptosis and cell cycle arrest. 

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Thus, inhibition of the MDM2-p53 interaction may be an effective therapeutic strategy in 
tumors that retain wild-type (WT) p53 (Shangary and Wang, 2008; Wade et al., 2013). In 
particular, while TP53 mutations have been implicated in the pathogenesis of more than fifty 
percent of all human cancers, myeloma represents a particularly attractive target for small 
molecule MDM2 inhibitors given its relatively low frequency of TP53 mutations or deletions 
(Lohr et al., 2014; Walker et al., 2015). 
 
Proof-of-principle of the encouraging activity of MDM2 inhibition in myeloma preclinical 
models was demonstrated in our group as part the NCI-funded MD Anderson Myeloma SPORE 
(Gu et al., 2014).  The MDM2 inhibitor KRT-232 (AMG 232) (Amgen, Inc) has also shown 
promise in preclinical myeloma models both in vitro (Figure 1) and in vivo (Figure 2), with anti-
myeloma activity strongly correlating with TP53 WT status.    Moreover, the combination of 
KRT-232 (AMG 232) with other FDA-approved myeloma agents including the 
immunomodulatory drug (IMiD) lenalidomide (Figure 3) or second generation proteasome 
inhibitor carfilzomib (Figure 4) shows synergistic activity when used in combination compared 
to the activity of either agent when used as monotherapy.   Finally, the combination of KRT-232 
(AMG 232), lenalidomide, and carfilzomib demonstrates additive to synergistic activity in vitro 
in TP53 WT myeloma cells compared to KRT-232 (AMG 232) in combination with either 
lenalidomide or carfilzomib (Figure 5).   
 
Several recent landmark studies have highlighted the clinical efficacy of novel drug 
combinations in relapsed and/or refractory myeloma that has transformed the therapeutic 
landscape in this subject population.  Among these include the combination of carfilzomib, 
lenalidomide, and dexamethasone (KRd) as demonstrated in the pivotal ASPIRE trial where 
KRd demonstrated a significantly longer progression free survival (PFS) compared to Rd (26.3 
months versus 17.6 months, P 0.0001), leading to the FDA approval of KRd in myeloma 
subjects with 1-3 lines of prior therapy (Stewart et al., 2015).  Although never compared head-to-
head, KRd also compares favorably to other recently FDA-approved 3-drug combinations 
evaluated in the same subject population, including elotuzumab, lenalidomide, and 
dexamethasone (PFS 19.4 months)(Lonial et al., 2015) and ixazomib, lenalidomide, and 
dexamethasone (PFS 20.6 months)(Moreau et al., 2016).  Therefore, based on the promising 
preclinical activity KRT-232 (AMG 232), lenalidomide, and carfilzomib, we herein propose a 
phase 1 dose-escalation and exploratory expansion study of KRT-232 (AMG 232) + KRd with 
the anticipation that this combination will further improve upon the clinically validated KRd 
backbone in TP53 WT relapsed and/or refractory myeloma.   
 
Figure 1.  KRT-232 (AMG 232) growth inhibition in vitro in TP53 WT (MOLP-8, MM1.S, 
MM1.R, IM-9, H929) and TP53 mutant (OPM-2, RPMI-8226, KMS-12-BM) myeloma cell lines 
(Amgen, Inc).  

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Figure 4.  KRT-232 (AMG 232) + Carfilzomib in H929 TP53 WT myeloma xenograft model.  
4/10 mice in combination group exhibited complete regression of tumors (Amgen, Inc). 
 
 
Figure 5.  KRT-232 (AMG 232) + Lenalidomide + Carfilzomib in TP53 WT MM1.S cell line. 

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2.6. Rationale of KRd + KRT-232 (AMG 232) Human Dosing 
 
Dosing for the KRd backbone for the current proposed study is modeled after the Phase 3 
ASPIRE study as described in Section 2.4, which was based on an earlier Phase 1 study where 
the MTD was not reached for KRd dosing (Niesvizky et al., 2013).  Hence, KRd at these dose 
levels (carfilzomib 27 mg/m2, lenalidomide 25 mg, and dexamethasone 40 mg) has an acceptable 
and well-studied safety profile.  In practice, carfilzomib is often given at higher doses (36 
mg/m2) in combination with lenalidomide and dexamethasone, based on a phase 1/2 study of 
KRd in newly diagnosed multiple myeloma (Jakubowiak et al., 2012), which gives added 
confidence that the addition of KRT-232 (AMG 232) to the KRd backbone at its standard dosing 
will be feasible from a safety and tolerability standpoint. 
 
Although the MTD of KRT-232 (AMG 232) was defined at 240 mg QD for 7 days on a 21-day 
cycle in the first-in-human (FIH) study of KRT-232 (AMG 232) in solid tumors (Section 2.2), 
the starting dose level of KRT-232 (AMG 232) for the current study will begin at 60 mg 7 days 
on a 28-day cycle to carefully evaluate for overlapping toxicities such as thrombocytopenia with 
the KRd backbone.  Dose-escalation will occur using a standard 3+3 design with increasing dose 
levels of KRT-232 (AMG 232) at 90 mg, 120 mg, 180 mg, and 240 mg 7 days on a 28-day cycle, 
with the highest planned dose level 5 being comparable to the MTD in the first-in-human trial of 
KRT-232 (AMG 232) monotherapy.  Using this standard 3+3 design, a DLT rate less than 33% 
would be considered acceptable.  
 
2.7. Correlative Studies Background 
 
2.7.1. 
TP53 Genotyping 
 

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KRT-232 (AMG 232) is an inhibitor of MDM2, the E3 ubiquitin ligase of p53, and a central 
hypothesis of this clinical study is that the mechanism of action of KRT-232 (AMG 232) is 
dependent on having intact wild-type p53 to exert its anti-tumor effect.  Therefore, TP53 
genotyping on plasma cells will be performed as an integral biomarker in this clinical study on 
pretreatment bone marrow aspirates that will be performed at screening.  Subjects with TP53 
mutations will be excluded from further participation in this study.  
 
A number of preclinical studies have suggested that wild-type TP53 may be a biomarker for 
response with the use of MDM2 inhibitors, including studies performed in myeloma (Gu et al., 
2014).   In the clinical setting, several studies have been reported to-date evaluating the use of 
MDM2 inhibition in various malignancies.  In a phase 1 trial of RG7112, a small molecule 
inhibitor MDM2, in relapsed leukemias, TP53 mutations were identified in 19 of 96 subjects 
tested, and all but two subjects failed to show any clinical response, suggesting that the presence 
of at least one wild-type TP53 allele is necessary for response.  However, wild-type TP53 alone 
was not sufficient to predict response to treatment in this study (Andreeff et al., 2016).   
 
In this study, TP53 genotyping will be performed by a CLIA laboratory test or NCI Molecular 
Characterization Laboratory (MoCha) 
 
2.7.2. 
Pharmacokinetic and Pharmacodynamic Studies 
 
Macrophage inhibitor cytokine-1 (MIC-1) 
 
MIC-1, a secreted p53 transcriptional target, will be evaluated as an integrated pharmacodynamic 
biomarker for p53 pathway activation in response to MDM2 inhibition in this study.  In 
preclinical studies, increases in MIC-1 levels were observed in vitro and in vivo in response to 
doxorubicin treatment, and correlated with increases in other downstream markers of p53 
pathway activation (Yang et al., 2003).   
 
In a clinical study with the MDM2 inhibitor RG7112 in liposarcoma, serum MIC-1 was been 
assessed as a pharmacodynamic marker using an ELISA at different time points and correlated 
with drug exposure levels of the study drug (Ray-Coquard et al., 2012).  In preliminary analyses 
of clinical trial data, there was an exposure-response correlation observed between changes in 
serum MIC-1 levels and KRT-232 (AMG 232) exposure (both maximal (Cmax) and total 
exposure (AUC) (KRT-232 (AMG 232) Investigators Brochure Date: 08 Dec. 2015).  
 
In this study, serum MIC-1 testing will be performed using an ELISA-based assay at the ETCTN 
central laboratory of Dr. Michelle Rudek at Johns Hopkins University.   For serum MIC-1 levels, 
each individual level will be normalized to the baseline level for that subject collected prior to 
KRT-232 (AMG 232) dosing. 
 
KRT-232 (AMG 232) pharmacokinetic profile 
 
These studies are necessary to characterize the exposure to KRT-232 (AMG 232).  KRT-232 
(AMG 232) is an orally bioavailable MDM2 inhibitor.  In cancer subjects, KRT-232 (AMG 232) 
exposure is dose proportional over the dose range proposed in this LOI (KRT-232 (AMG 232) 

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Investigators Brochure Date: 08 Dec. 2015).  
 
 
 
 
 
 
 
 
 
 
 
   
 
In this protocol, KRT-232 (AMG 232) will be combined with carfilzomib, lenalidomide, and 
dexamethasone.  Carfilzomib is primarily inactivated by pepitdases and hydrolysis with minor 
contributions by CYP450 isozymes (specific isozyme not listed).  Lenalidomide is not 
metabolized by CYP450 but is a P-glycoprotein substrate.  Dexamethasone is metabolized by 
CYP3A4 but does not have a narrow therapeutic window.  Therefore concerns of a drug-drug 
interaction are minimal with the combination.  Other narrow therapeutic window drugs 
predominantly cleared by CYP2C8 and/or CYP3A4 will be excluded. 
 
KRT-232 (AMG 232) drug-exposure measurements will be quantitatively measured using liquid 
chromatography/tandem mass spectrometric (LC/MS/MS) method that will be developed by the 
Analytical Pharmacology Core Laboratory at the Sidney Kimmel Comprehensive Cancer Center 
(SKCCC) at Johns Hopkins in collaboration with Dr. Michelle Rudek.  For KRT-232 (AMG 
232), the individual PK parameters from a single dose will be estimated for Cmax, AUC, T1/2, 
apparent Cl/F, and apparent V/F using non-compartmental or compartmental PK methods with 
the software WinNonlin.  Advanced population PK methods may be employed to assess the link 
between drug exposure and biological effects and efficacy. The PK variables and changes in 
MIC-1 will be tabulated and descriptive statistics (e.g., geometric means and coefficients of 
variation) calculated for each dose level.  PK parameters (i.e., T1/2, Cl, and AUC) and MIC-1 
changes will be compared across dose level using nonparametic statistical testing techniques.  
Exploratory correlative studies with pharmacodynamic (biological endpoints, toxicity and 
efficacy) will be analyzed using nonparametric statistics. Significance for comparisons will be at 
the p<0.05 level.   
 
2.7.3. 
Other myeloma gene sequencing 
 
Whole exome sequencing of frequently mutated genes in multiple myeloma will be performed 
on plasma cells from the screening bone marrow aspiration as an exploratory biomarker for 
baseline characterization of subjects (Lohr et al., 2014; Walker et al., 2015), such as KRAS, 
BRAF, NRAS, and FGFR3 by the NCI Molecular Characterization (MoCHa) Laboratory.  While 
no definitive relationship between these mutations and prognosis has been established in multiple 
myeloma, mutations in NRAS may predict sensitivity to proteasome inhibitors such as 
bortezomib or carfilzomib (Mulligan et al., 2014). 

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In this study, whole exome sequencing will be performed by the NCI Molecular Characterization 
Laboratory (MoCha). 
 
2.7.4. 
RNA expression of TP53-associated genes 
 
As an exploratory study, RNA expression levels will be assessed as pharmacodynamics 
biomarkers for TP53 pathway activation and to evaluate for potential biomarkers that may 
predict response to therapy with KRT-232 (AMG 232) in plasma cells from screening and post-
treatment bone marrow aspirations.  Genes of particular interest will be those relevant genes in 
the TP53 pathway including TP53, PUMA, BAX, p21, MDM2, MDM4, CDKN2A, Gadd45, and 
THBS1.  In a clinical study with the MDM2 inhibitor RG7112 in relapsed leukemias, increased 
baseline MDM2 expression levels assessed by qRT-PCR positively correlated with clinical 
responses (Andreeff et al., 2016).  In addition, PUMA, Gadd45, and THBS1 expression levels 
have been associated with a “p53 target signature” in myeloma datasets in which high expression 
of these genes corresponds to an intact functional p53 pathway (Teoh et al., 2014).   RNA 
sequencing will be performed by the NCI Molecular Characterization (MoCha) Laboratory.   
 
 
 
3. SUBJECT SELECTION 
 
3.1. Inclusion Criteria  
 
3.1.1. 
Subjects must have histologically confirmed diagnosis of multiple 
myeloma.  
 
3.1.2. Subjects must have measurable disease, as defined by at least one of the 
following: 
a) 
Serum monoclonal protein M-protein level ≥0.5 g/dL  
b) Urinary M-protein excretion of ≥200 mg over a 24-hour period 
c) 
Involved free light chain level ≥10 mg/dL, along with an abnormal free light 
chain ratio 
 
3.1.3. Subjects must have disease that has relapsed and/or refractory after their most 
recent therapy, with progressive disease (PD) being defined as an increase of 25% 
from the lowest response value in any one or more of the following: 
a) 
Serum M-component protein (the absolute increase must be ≥0.5 g/dL) 
and/or 
b) Urine M-component protein (the absolute increase must be ≥200 mg/24 
hours) and/or 
c) 
Only in subjects without a measurable serum and urine M protein level: the 
difference between involved and uninvolved free light chain (FLC) levels 
(absolute increase) must be >10 mg/dL 
d) Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 

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plasmacytomas 
e) 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that 
can be attributed solely to the plasma cell proliferative disorder. 
 
3.1.4. Subjects with one to three lines of therapy for their disease with a line of therapy 
defined as one or more cycles of a planned treatment program.  Using this 
definition, treatment with induction therapy, followed by high dose chemotherapy 
and autologous stem cell transplantation, and finally by maintenance therapy, 
would constitute one line, provided that multiple myeloma did not meet criteria 
for progression at any time during this period.   
 
3.1.5. Subjects must have completed their most recent drug therapy directed at multiple 
myeloma in the following timeframes: 
a) Antitumor therapy (chemotherapy, antibody therapy, molecular targeted 
therapy, retinoid therapy, hormonal therapy, or investigational agent) at least 
21 days prior to C1D1 KRT-232 (AMG 232) + KRd. 
b) Corticosteroids at least 3 weeks prior to starting KRT-232 (AMG 232) + KRd, 
except for a dose equivalent to dexamethasone of ≤4 mg/day 
c) Autologous stem cell transplantation at least 12 weeks prior to starting KRT-
232 (AMG 232) + KRd 
d) Allogeneic stem cell transplantation at least 24 weeks prior to starting KRT-
232 (AMG 232) + KRd, and these subjects must also NOT have moderate to 
severe active acute or chronic graft versus host disease (GVHD). 
 
3.1.6. Subjects must be ≥ 18 years old.   Because no dosing or adverse event data are 
currently available on the use of KRT-232 (AMG 232) in combination with KRd, 
subjects < 18 years of age are excluded from this study. 
 
3.1.7. Subjects must have ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see 
Appendix A). 
 
3.1.8. 
Subjects must have normal organ and marrow function as defined below: 
a) Absolute neutrophil count (ANC) ≥ 1,000/mcL without growth factors within 
2 week of initiation of treatment 
b) Platelets ≥50,000 cells/mm3 if marrow plasmacytosis < 50% OR platelet count  
≥30,000 cells/mm3 if marrow plasmacytosis ≥ 50%. 
c) Hemoglobin ≥8 g/dL within 2 weeks of the initiation of treatment 
d) Total bilirubin < 1.5 × institutional upper limit of normal (ULN) (< 2.0 × 
ULN for subjects with documented Gilbert’s syndrome or < 3.0 × ULN for 
subjects for whom the indirect bilirubin level suggests an extrahepatic source 
of elevation) 
e) AST(SGOT)/ALT(SGPT) ≤ 2.5 × ULN 
f) Alkaline phosphatase < 2.0 × ULN (if liver or bone disease are present, < 3.0 
× ULN) 
g) Creatinine clearance (eGFR) ≥ 50 mL/min/1.73 m²  
 

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3.1.9.  Subjects must have adequate coagulation laboratory assessments, as follows: 
 
Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 × upper limit of 
normal (ULN), OR International normalized ratio (INR) < 1.5. 
 
3.1.10. Subjects who have received radiation therapy targeting > 10% of the bone marrow 
space must have completed this at least 2 weeks prior to starting therapy with 
KRT-232 (AMG 232) + KRd. 
 
3.1.11. Subjects must be able and willing to provide bone marrow biopsies/aspirates and 
buccal swab as requested by the protocol. 
 
3.1.12. Subjects must be willing to undergo myeloma genotyping for TP53 mutation, 
insertion, or deletion at screening.  
 
3.1.13. Subjects must have an estimated life expectancy of at least 3 months. 
 
3.1.14. The effects of KRT-232 (AMG 232) on the developing human fetus are unknown.  
For this reason and because lenalidomide is known to be teratogenic, women of 
child-bearing potential must commit to either abstaining continuously from 
heterosexual sexual intercourse or agree to use 2 forms of adequate contraception 
or continuously abstain from the time of informed consent for the duration of 
study participation through 5 weeks (women) after receiving the last dose of 
KRT-232 (AMG 232), lenalidomide, or carfilzomib.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately.  Men treated or 
enrolled on this protocol must also agree to use adequate contraception prior to 
the study, for the duration of study participation, and 3 months after completion of 
KRT-232 (AMG 232) administration.  This includes one highly effective form of 
contraception (e.g. intrauterine device [IUD], hormonal [birth control pills, 
injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) 
and one additional effective contraceptive method (e.g. male latex or synthetic 
condom, diaphragm, or cervical cap).  
 
3.1.15. Subjects must be able to swallow medication 
 
3.1.16. Ability to understand and the willingness to sign a written informed consent 
document. 
 
 
3.2. Exclusion Criteria 
 
3.2.1. 
Subjects with myeloma that is relapsed and/or refractory to KRd when used in 
combination defined as progression of disease while on therapy or within 60 days 
of completing therapy. 
  

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33 
3.2.2. 
Subjects must show evidence of wild-type (WT) p53 status on somatic tissue 
specimens as assessed by DNA sequencing. Note that since patients with relapsed 
myeloma have a rapidly proliferating disease, patient can be enrolled and begin 
treatment prior to obtaining the results of this test. Patients who are discovered to 
have a TP53 mutation will be removed from study after cycle one and can 
continue on carfilzomib, lenalidomide, and dexamethasone (KRd). All enrolled 
patients will be followed for toxicity.    
                                      
3.2.3. 
Subjects who have not recovered from toxicities from prior anti-tumor therapy, 
defined as not having resolved to Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility 
criteria with the exception of alopecia (Grade 2 or 3 toxicities from prior 
antitumor therapy that are considered irreversible [defined as having been present 
and stable for > 6 months], such as grade 2 chemotherapy-induced peripheral 
neuropathy, may be allowed if they are not otherwise described in the exclusion 
criteria AND there is agreement to allow by both the investigator and sponsor). 
 
3.2.4. 
Subjects who are receiving any other investigational agents. 
 
3.2.5. 
Subjects who have undergone major surgery within 28 days of study day 1. 
Vertebroplasty and/or kyphoplasty, which must have been performed at least 1 
week prior to starting KRT-232 (AMG 232) + KRd 
 
3.2.6. 
Subjects with known central nervous system involvement of myeloma should be 
excluded from this clinical trial because of their poor prognosis and because they 
often develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events. 
 
3.2.7. 
Subjects with history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to KRT-232 (AMG 232) or carfilzomib, 
lenalidomide, or dexamethasone.   
 
3.2.8. 
Subjects’ medication list such a herbal medicines (e.g., St. John’s wort), vitamins, 
and supplements will be reviewed before starting first dose of KRT-232 (AMG 
232) and at each clinic visit.  Any potential drug interactions will be brought and 
discussed with the Principle Investigator.  Use of any known CYP3A4 substrates 
with narrow therapeutic window (such as alfentanil, astemizole, cisapride, 
dihydroergotamine, pimozide, quinidine, sirolimus, or terfanide) within the 14 
days prior to receiving the first dose of KRT-232 (AMG 232) is not permitted.  
Other medications (such as fentanyl and oxycodone) may be allowed per 
investigator’s assessment/evaluation. 
 
3.2.9. 
Treatment with medications known to cause QTc interval prolongation within 7 
days of study day 1 is not permitted unless approved by the sponsor.  Use of 
ondansetron is permitted for treatment of nausea and vomiting. 
 

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34 
3.2.10. Current use of warfarin, factor Xa inhibitors and direct thrombin inhibitors. 
 
Note: Low molecular weight heparin and prophylactic low dose warfarin are 
permitted. PT/PTT must meet the inclusion criteria.  Subjects taking warfarin 
must have their INR followed closely. 
 
3.2.11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.2.12. Subjects with myocardial infarction within 6 months of study day 1, symptomatic 
congestive heart failure (New York Heart Association (NYHA) Class III and 
higher), unstable angina, or cardiac arrhythmia requiring medication are excluded. 
 
3.2.13. Subjects with GI tract disease causing the inability to take oral medication, 
malabsorption syndrome, requirement for intravenous alimentation, prior surgical 
procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., 
Crohn’s disease, ulcerative colitis). 
 
3.2.14. Subjects with history of bleeding diathesis. 
 
3.2.15. Subjects with active infection requiring IV antibiotics within 2 weeks of study 
enrollment (day 1) are excluded. 
 
3.2.16. Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic Hepatitis 
B), positive Hepatitis total core antibody with negative HBsAG (suggestive of 
occult hepatitis B), or detectable Hepatitis C virus RNA by a polymerase-chain 
reaction (PCR) assay (indicative of active Hepatitis C – screening is generally 
done by Hepatitis C Antibody (HepCAb), followed by Hepatitis C virus RNA by 
PCR if HepCAb is positive). Subjects with hepatitis B virus suppressed on 
therapy, and previously treated/eradicated hepatitis C virus are eligible for study.   
 
3.2.17. HIV-positive subjects positive for human immunodeficiency virus (HIV) are 
NOT excluded from this study, but HIV-positive subjects must have:  
a) 
A stable regimen of highly active anti-retroviral therapy (HAART)  
b) 
No requirement for concurrent antibiotics or antifungal agents for the 
prevention of opportunistic infections.   
c) 
CD4 count above 250 cells/mcL and an undetectable HIV viral load on 
standard PCR-based test 
 

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35 
3.2.18. Pregnant women are excluded from this study because KRT-232 (AMG 232) is an 
agent with the potential for teratogenic or abortifacient effects.  Because there is 
an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with KRT-232 (AMG 232), breastfeeding should be 
discontinued if the mother is treated with KRT-232 (AMG 232).  These potential 
risks may also apply to other agents used in this study. 
 
3.2.19. Women who are lactating/breast feeding or who plan to breastfeed while on study 
through 1 week after receiving the last dose of study drug. 
 
3.2.20. Subjects with prior treatment with an MDM2 inhibitor. 
 
3.3. Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1. Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr. 
 
RCR utilizes five person registration types. 
• IVR: MD, DO, or international equivalent, 
• NPIVR: advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., PhD), 
• AP: clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications such as 
the Roster Update Management System (RUMS), OPEN, Rave, acting as a primary site contact, 
or with consenting privileges, (e.g., Roster Update Management System [RUMS], OPEN, 
Rave,), 

NCI Protocol #: 10076  
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37 
 
IRB Approval 
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network. Site preferences can be set at the network 
or protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and on at 
least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile, and 
• Holds the appropriate CTEP registration type for the protocol. 
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO), and 
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1. 
Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Participating 
Organization (PO) on the protocol.  One way to search for a protocol is listed below. 
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-TX035, and protocol 
number 10076, 
• Click on Documents, select Site Registration, and download and complete the forms provided. 
(Note: For sites under the CIRB initiative, IRB data will load automatically to the CTSU.) 

NCI Protocol #: 10076  
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38 
 
Protocol Specific Requirements For 10076 Site Registration 
 
• Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site will need to 
complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to the 
CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual. If an individual has previously 
completed the training for another ETCTN study, the training does not need to be completed 
again nor does the certificate of completion need to be resubmitted to the CTSU. However, new 
versions of the Specimen Tracking System may require new training. 
o This training will need to be completed before the first patient enrollment at a given site. 
o Please contact STS Support at Theradex for the training (STS.Support@theradex.com, 
Theradex phone: 609-799-7580). 
 
4.2.2. 
Submitting Regulatory Documents 
 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to the 
Regulatory section, and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support.  
 
Checking Site Registration Status 
Site’s registration status may be verified on the CTSU website.  
• Click on Regulatory at the top of the screen, 
• Click on Site Registration, and  
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol.  It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
4.3. Subject Registration 
 

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4.3.1. 
OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment.  OPEN or IWRS will populate the 
patient enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Must be on an LPO roster, ETCTN 
corresponding roster, or PO roster with the role of Registrar.  Registrars must hold a 
minimum of an Associate Plus (AP) registration type. 
• If a DTL is required for the study, the registrar must hold the OPEN Registrar task on the 
DTL for the site. 
• Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  IWRS system also sends an email confirmation of the registration.  You 
may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System or the IWRS Slot 
Reservation System to ensure that a slot on the protocol is available to the patient.  Once a slot 
reservation confirmation is obtained, site staff may then proceed to CTSU OPEN Step 1 to enroll 
the patient to this study.  
This Study will use the ETCTN Specimen Tracking System (STS).  
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   
• The system is accessed through Rave user roles:  “Rave CRA” and “Rave CRA 

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40 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the NCI Early-
Phase and Experimental Clinical Trials Biospecimen Bank (EET Biobank, formerly 
known as the ETCTN Biorepository).   
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section  under the Rave Home tab and then 
under Rave Resource Materials. 
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
Detailed instructions on use of the STS can be found in Section Error! Reference source not f
ound.. 
 
4.3.2. 
Subject Enrollment Instructions   
 
• Sites must reserve a slot in Theradex IWRS. Each site is allowed 1 slot 
reservations at a time with a 5 day guaranteed hold for each slot.  
 
• Next, fax the following redacted documents for review:  
1. Latest clinic note  
2. Pathology report showing histologically confirmed diagnosis of multiple 
myeloma 
3. Documentation of measurable disease (defined by at least one of the 
following): 
a. Serum monoclonal protein M-protein level ≥0.5 g/dL  
b. Urinary M-protein excretion of ≥200 mg over a 24-hour period 
c. Involved free light chain level ≥10 mg/dL, along with an abnormal free light 
chain ratio 
  
• Fax to: Astrid Murga/Hans Lee, MD at 713-794-5656. Include your contact 
information in the fax cover sheet.  
 
• Each reservation will need to be authorized and approved by an MD Anderson 
designee prior to registering the patient in OPEN. Once the slot is approved in 
IWRS, you may proceed with registering your patient in OPEN. 
 
There is a two-step process to enrollment in CTSU OPEN. The subject cannot be  
fully registered in CTSU OPEN without knowledge of the TP53 mutation status which is part of 
the eligibility criteria 3.2.2. However, a patient may begin Cycle 1 of therapy provided they meet 
all other eligibility criteria aside from criteria 3.2.2. 
 
The two-step enrollment process is as follows: 
(1) Register in CTSU OPEN Step 1 once slot is approved through Theradex IWRS to 
obtain patient’s unique study ID 
(2) Subject may begin Cycle 1 therapy after eligibility is established even if TP53 mutation 

NCI Protocol #: 10076  
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41 
status is not yet known as per eligibility criteria 3.2.2            
(3) Study site receives TP53 results during Cycle 1 therapy (or before) with 
2 possibilities below: 
a) If non-wild-type (WT) TP53 results, the patient is withdrawn from protocol for not 
meeting eligibility criteria prior to cycle 2 therapy. The site will need to complete step 
2 of OPEN to indicate the patient has failed eligibility. 
b) If wild-type (WT) TP53 results meeting eligibility criteria, the patient can 
continue on protocol. The site will complete step 2 of OPEN to indicate that patient 
has met eligibility prior to commencing cycle 2 therapy. 
 
 
4.3.3. 
OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website: http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11 This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
609-619-7802 or Theradex main number 855-828-6113; CTMSSupport@theradex.com. 
 
4.4. General Guidelines 
 
Following registration, subjects should begin protocol treatment within 14 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a subject 
does not receive protocol therapy following registration, the subject’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
5. TREATMENT PLAN 
 
5.1. KRT-232 (AMG 232) + Carfilzomib, Lenalidomide, and Dexamethasone (KRd) 
 
This will be a two-part Phase 1 dose-escalation and exploratory dose-expansion study of KRT-
232 (AMG 232) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in 
relapsed and/or refractory TP53 WT myeloma subjects with 1-3 lines of prior therapy.  Part A 
will consist of a dose-escalation phase of KRT-232 (AMG 232) to assess its safety and 
tolerability and identify an MTD/tentative RP2D in combination with KRd. KRT-232 (AMG 
232) dose will be assigned according to the dose level stated in Section 5.4.  Please refer to 
Section 5.4 to KRT-232 (AMG 232) dose escalation After the MTD has been established, Part B 
of the study will involve an exploratory-dose expansion study of a goal of 10 additional subjects 
with relapsed and/or refractory myeloma who will be enrolled at the tentative RP2D.  
 

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42 
Due to the timely need to initiate treatment in relapsed myeloma, TP53 mutation status at 
screening is NOT required prior to KRT-232 (AMG 232) dosing.  However, subjects found to 
have TP53 mutation and/or deletion from screening bone marrow biopsy will be removed from 
study after C1 and continue on standard-of-care KRd alone.  Toxicity monitoring of such 
subjects removed from active therapy with KRT-232 (AMG 232) will continue as described in 
the Treatment Plan.  During the dose-expansion phase, subjects removed from study after Cycle 
1 based on the TP53 mutation and/or deletion status will be replaced to ensure that a goal of 10 
subjects with TP53 wild-type status are enrolled in the dose-expansion cohort.   
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the subject's malignancy. 
 
5.2. KRT-232 (AMG 232) Administration  
 
KRT-232 (AMG 232) will be administered QD for 7 days every 28 days (i.e., 7 consecutive days 
of dosing followed by 21 consecutive days off treatment). 
 
For QD dosing, subjects should self-administer KRT-232 (AMG 232) with or without food.with 
a full glass of water.  KRT-232 (AMG 232) should not be crushed, chewed, or dissolved in water.  
Subjects should not be re-dosed with KRT-232 (AMG 232) after vomited doses.  
 
The subject will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each course (APPENDIX E). 
 
 
5.3. Carfilzomib, Lenalidomide, and Dexamethasone Administration 
 
  
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Carfilzomib 
IV Hydration: 250 
mL to 500 mL 
normal saline (250 
mL/hr) prior to each 
dose for Cycle 1 
(optional for 
subsequent cycles). 
 
Dexamethasone:  
4 mg PO or IV 
administered 30 
minutes to 4 hours 
prior to Days 1-2, 
Days 8-9, and Days 
15-16 dose 
20 mg/m2 on 
Cycle 1, Day 1 
and Cycle 1, 
Day 2 in 50 mL 
D5Wb 
 
27 mg/m2 
starting on Cycle 
1, Day 8 and all 
subsequent 
doses in 50 mL 
D5Wb 
IV over 10-
30 minutes 
(allowable 
window of 
+10 
minutes) 
Cycles 1-12: 
Days 1-2, 8-9, 
15-16 for Cycles 
1-12. 
 
Cycles 13-18: 
Days 1-2, 15-16. 
28 days  
(4 weeks) 
 
 
 

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43 
 
Ondansetron 
(optional) 8 mg IV 
or PO 30 minutes 
prior to each dose 
Lenalidomide 
Can be taken with 
or without food.  
capsules should be  
swallowed  
whole with water 
and capsules should 
not be opened, 
broken, or chewed. 
25 mg 
Oral 
Days 1-21 
Dexamethasone 
None 
40 mg 
Oral or IV  
Days 1, 8, 15, 
and 22  
aPremedication with dexamethasone 4 mg is required before each carfilzomib dose during Cycle 1 and is optional 
for subsequent cycles.  During Cycle 1 and if pretreatment dexamethasone is necessary beyond Cycle 1, the 
treatment dose of dexamethasone 40 mg IV or PO will be given 30 minutes to 4 hours prior to each carfilzomib 
dose on Days 1, 8, and 15 which will serve as both the pretreatment and treatment dose of dexamethasone.   
bCalculate carfilzomib dose using the patient’s actual body surface area at baseline.  In patients with a body 
surface area greater than 2.2 m2, calculate the dose based upon a body surface area of 2.2 m2. 
 
   Doses of lenalidomide or oral dexamethasone that are skipped or vomited will not be made up. 
 
5.4. KRT-232 (AMG 232) + Carfilzomib, Lenalidomide, and Dexamethasone Treatment 
Plan 
 
Dose Regimen 
 
KRT-232 (AMG 232) + carfilzomib, lenalidomide, and dexamethasone will be administered per 
the following schedule: 
 
Cycles 1-12 (28 day cycle) 
• KRT-232 (AMG 232) once daily by mouth 7 out of 28 days 
• Carfilzomib 20 mg/m2 IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m2 IV on 
Days 8, 9, 15, 16 of Cycle 1 and continuing on Days 1, 2, 8, 9, 15, 16 of Cycles 2 
through Cycle 12 
• Lenalidomide 25 mg PO on Days 1-21 
• Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
 
Cycles 13-18 (28 days each) 
• KRT-232 (AMG 232) once daily by mouth 7 out of 28 days 
• Carfilzomib 27 mg/m2 IV on Days 1, 2, 15, and 16  
• Lenalidomide 25 mg PO on Days 1-21 
• Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
 
Cycles 19+ (28 days each) 

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44 
• KRT-232 (AMG 232) once daily by mouth 7 out of 28 days 
• Lenalidomide 25 mg PO on Days 1-21 
• Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
 
Part A (Dose-escalation scheme) 
The MTD is defined as the highest dose at which six subjects have been treated and less than two 
subjects experienced DLT within the first cycle of treatment in Phase I of the trial. To determine 
the MTD, escalation for KRT-232 (AMG 232) will be conducted following the “3+3” design 
with de-escalation.  A cohort of three subjects will be treated at the starting dose level and 
observed until the end of the first cycle (subjects non-evaluable for DLT will be replaced).  The 
dose level will be escalated with each new cohort until at least one out of three subjects of a 
cohort experiences DLT.  If one subject experiences a DLT, then three additional subjects will be 
treated at the same dose level; if none of the three additional subjects experiences a DLT, then 
the dose escalation will be continued by treating the next cohort of three subjects at the next 
higher dose level.  If at least two out of up to six subjects at a dose level experience a DLT, the 
MTD will be considered to have been exceeded, and up to 3 more subjects will be treated at the 
next lower dose if there are less than 6 subjects already treated at that dose.  The dose steps for 
escalation are displayed below: 
 
 
Dose Escalation Schedule 
Dose Level 
Dose of KRT-232 (AMG 232)* 
- 1 
30 mg/day PO x 7 days out of 28 day cycle 
+ 1 
60 mg/day PO x 7 days out of 28 day cycle 
+ 2 
90 mg/day PO x 7 days out of 28 day cycle 
+ 3 
120 mg/day PO x 7 days out of 28 day cycle 
+ 4 
180 mg/day PO x 7 days out of 28 day cycle 
+ 5 
240 mg/day PO x 7 days out of 28 day cycle 
 
If dose-de-escalation is needed for Dose level 1, Dose level -1 is defined as 30 mg/day x 7 days 
out of 28 day cycle. 
 
There should be no dose modifications of KRT-232 (AMG 232) and KRd during the DLT-
evaluable period (Cycle 1).  Subjects requiring dose-reductions during the DLT-evaluable period 
will be considered a DLT. 
 
Part B (Dose-expansion scheme) 
After determination of the KRT-232 (AMG 232) MTD or proven tolerability of the highest 
planned dose, and a goal of 10 additional subjects will be treated in the Part 2 dose expansion in 
combination with KRd.  The primary objective of this dose-expansion phase is to confirm the 
safety and tolerability of KRT-232 (AMG 232) + KRd at the MTD and tentative RP2D in a goal 

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of 10 subjects with relapsed and/or refractory multiple myeloma.  The tentative RP2D will be 
determined based on the review of safety data at the MTD. 
 
During the dose-expansion phase, subjects removed from study after Cycle 1 based on the TP53 
mutation and/or deletion status will be replaced to ensure that a goal of 10 subjects with TP53 
wild-type status are enrolled in the dose-expansion cohort.   
 
The subject will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each course. 
 
KRT-232 (AMG 232) 
 
The following medications and/or therapies should not be administered within the timeframes 
specified prior to enrollment and during the study (unless otherwise specified below): 
 
• Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid 
therapy, hormonal therapy, or investigational agent) within 21 days of study day 1; 
concurrent use of hormone deprivation therapy for hormone-refractory prostate cancer or 
breast cancer and continuation of previous hormone therapy in breast cancer subjects are 
permitted. 
• Treatment with immune modulators including, but not limited to, corticosteroids, 
cyclosporine and tacrolimus within 3 weeks prior to enrollment, except for a 
corticosteroid dose equivalent to dexamethasone of ≤4 mg/day 
• Therapeutic or palliative radiation therapy within 4 weeks of KRT-232 (AMG 232) day 
1. 
• All herbal medicines (e.g., St. John’s wort), vitamins, and supplements consumed by the 
subject within the 30 days prior to receiving the first dose of KRT-232 (AMG 232), and 
continuing use, if applicable, will be reviewed by the Principal Investigator and the 
sponsor. 
• Use of any known CYP3A4 substrates with narrow therapeutic window (such as 
alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus, or 
terfanide) within the 14 days prior to receiving the first dose of KRT-232 (AMG 232).  
Other medications (such as fentanyl and oxycodone) may be allowed per investigator’s 
assessment/evaluation. 
• Use of any known CYP2C8 substrates with a narrow therapeutic window within the 14 
days prior to receiving the first dose of KRT-232 (AMG 232) 
• Treatment with medications known to cause QTc interval prolongation within 7 days of 
study day 1 unless approved by the sponsor.  Use of ondansetron is permitted for 
treatment of nausea and vomiting.  Systemic anticoagulation therapy, with warfarin, 
direct thrombin inhibitors, indirect thrombin inhibitors and direct factor Xa inhibitors, 
within 14 days or 5 half-lives (whichever is longer) of day 1.  Low molecular weight 
heparin and prophylactic low-dose warfarin are permitted. 
• Autologous stem cell transplantation at least 12 weeks prior to starting KRT-232 (AMG 
232) + KRd 
• Allogeneic stem cell transplantation at least 24 weeks prior to starting KRT-232 (AMG 
232) + KRd, and these subjects must also NOT have moderate to severe active acute or 

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chronic graft versus host disease (GVHD). 
 
5.5. Prophylactic and Supportive Medications 
 
At least 24 hours prior to Cycle 1 Day 1, the following treatments should be started: 
 
• Valacyclovir 500 mg PO daily (or equivalent antiviral), continuing for the duration of 
treatment (additional prophylaxis is at the Investigator’s discretion) for varicella zoster 
prevention while on carfilzomib-based therapy  
• Pantoprazole 40mg PO daily, or other oral proton-pump inhibitor to prevent peptic 
disease for the duration of treatment with dexamethasone 
• Aspirin (enteric-coated) PO daily at the standard prophylactic dose continuing for the 
duration of treatment with lenalidomide and dexamethasone.  Other antiplatelet or 
anticoagulation medications may be used in cases of intolerance to aspirin at the 
Investigator’s discretion.   
 
 
5.6. Definition of Dose-Limiting Toxicity 
A DLT is defined as any treatment emergent adverse event (TEAE) during the first treatment 
cycle that does not have a clear alternative cause (e.g., disease under study, concomitant therapy) 
based on the following criteria using NCI-CTCAE v5.0: 
 
• Hematological toxicity 
o Grade 3 or 4 neutropenia with fever ≥ 380 C lasting > 48 hours   
o Grade 4 neutropenia lasting > 7 days 
o Grade 3 or 4 thrombocytopenia associated with > grade 1 bleeding.  Grade 4 
thrombocytopenia that persists for > 14 days, despite holding treatment 
o Grade 4 anemia, unexplained by underlying disease 
o Any other grade 4 hematologic toxicity that does not resolve to subject’s pre-
treatment baseline level within 72 hours 
 
• Non-hematological toxicity 
o Grade ≥ 3 nausea, vomiting or diarrhea lasting longer than 72 hours despite 
optimal medical support 
o Grade ≥ 3 non-hematological toxicity (excluding increased serum creatinine, or 
electrolyte abnormalities that are not clinically significant and require no 
treatment) 
o Any grade 3 electrolyte abnormalities that do not resolve to grade ≤ 2 within 72 
hours 
o Grade 3 fatigue persisting > 7 days 
o Grade ≥ 3 acute kidney injury (creatinine > 3 × baseline or > 4.0 mg/dL) lasting 
> 72 hours 
o Any other grade 3 or 4 non-hematologic toxicities not predefined above will be 
considered a DLT. 
o A delay of ≥ 14 days in commencing Cycle 2 Day 1 due to lack of adequate 

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recovery of KRT-232 (AMG 232) +KRd-related toxicities will be considered a 
DLT. 
 
Subjects who receive < 75% of the planned study drug doses during the first cycle of  (i.e. ≤ 5/7 
daily doses of KRT-232 (AMG 232) will considered nonevaluable for purposes of determining 
the MTD (unless due to a DLT) and will be replaced.  Subjects who experience a DLT during the 
DLT-evaluable period will be considered evaluable for the purposes of determining the MTD as 
per Section 13.1.4 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.  
 
Number of Subjects with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 subjects at the next dose level. 
≥ 2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional subjects will be 
entered at the next lowest dose level if only 3 subjects 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more subjects at this dose level. 
If 0 of these 3 subjects experience DLT, proceed to the 
next dose level. 
If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
subjects will be entered at the next lowest dose level if 
only 3 subjects were treated previously at that dose. 
≤ 1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At 
least 6 subjects must be entered at the recommended 
phase 2 dose. 
 
 
5.7. Dose Expansion Cohorts: 
 
Once the RP2D is reached, a goal of 10 additional subjects will be treated at this dose.  For the 
expansion cohort, subjects will continue to be monitored for occurrence of DLT.  If 2 of the first 
5 subjects or if ≥ 4 of 10 subjects experience DLT, the Principal Investigator will discuss with all 
study investigators and with CTEP whether further addition of subjects is needed to re-assess the 
RP2D. When the first 5 additional patients are enrolled in the expansion phase, with a total of 11 
patients including the 6 patients who had been already treated at the RP2D, the probabilities of 
observing 3 or more patients with DLT are 22.1%, 68.7% and 96.7% if the true toxicity rate are 
15%, 30%, and 50%. When all 10 additional patients are enrolled in the expansion phase, with a 

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total of 16 patients including the 6 patients who had been already treated at the RP2D, the 
probabilities of observing 5 or more patients with DLT are 7.9%, 55%, and 96.2% if the true 
toxicity rate are 15%, 30%, and 50%. Monitoring of all safety and toxicity data is done by the 
Principal Investigator and the Corresponding Organization on a real-time basis as data are 
entered into Medidata Rave using the Web Reporting Module.  All participating sites are 
expected to notify the Principal Investigator when a DLT has occurred. 
 
5.8. General Concomitant Medication and Supportive Care Guidelines 
 
5.8.1. 
Concomitant Medications  
 
Because there is a potential for interaction of KRT-232 (AMG 232) with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies.  The Principal Investigator should be alerted if 
the subject is taking any agent known to affect or with the potential for drug interactions. The 
principal investigator should be notified if the subject is taking CYP3A4 substrates with narrow 
therapeutic window (such as alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, 
quinidine, sirolimus, or terfanide) or any known CYP2C8 substrates with a narrow therapeutic 
window while receiving AMG232.  
 
A patient drug information leaflet and wallet card for the potential drug-interactions will be 
provided to each subject as referenced in Appendix B. 
 
As noted in section 3.2.9, for treating emesis, other medications (such as fentanyl and 
oxycodone) may be allowed per investigator’s assessment/evaluation.   The study team should 
check a frequently-updated medical reference for a list of drugs to avoid or minimize use of.  
  
5.8.2. 
Hydration 
Adequate hydration is required prior to dosing of carfilzomib in Cycle 1, especially in patients at 
high risk of tumor lysis syndrome or renal toxicity. The recommended hydration includes both 
oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 
mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an 
additional 250 mL to 500 mL of intravenous fluids following carfilzomib administration. 
Continue oral and/or intravenous hydration, as needed, in subsequent cycles. Monitor patients for 
evidence of volume overload and adjust hydration to individual patient needs, especially in 
patients with or at risk for cardiac failure. 
 
5.8.3. 
Infusion Reactions 
Infusion reactions, including life-threatening reactions, have occurred in patients receiving 
carfilzomib. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, 
vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These 
reactions can occur immediately following or up to 24 hours after administration of carfilzomib. 
Dexamethasone will be administered will be required as a premedication during Cycle 1 prior to 
carfilzomib infusion to reduce the incidence and severity of infusion reactions (See Section 5.7). 
Subjects will be informed about risk and of symptoms and to contact a physician immediately if 
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5.8.4. 
Blood Pressure Monitoring 
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with 
carfilzomib.  Some of these events have been fatal. Monitor blood pressure regularly in all 
patients. If hypertension cannot be adequately controlled, withhold carfilzomib and evaluate. 
Consider whether to restart carfilzomib based on a benefit/risk assessment. 
 
5.9. Treatment Duration 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• Disease progression by IMWG criteria (Appendix 15.6). 
 
• Unacceptable adverse event(s) defined as: 
o Occurrence of an AE that is related to treatment with the study drug which, 
in the judgment of the investigator, compromises the subject's ability to 
continue study-specific procedures, or is considered to not be in the subject's 
best interest. 
o Persistent AE requiring a delay of therapy for more than 4 weeks (28 
days) 
 
• Subject decides to withdraw from the study 
 
• Pregnancy 
 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a subject participating in the study. 
 
• Termination of the study by sponsor 
 
• The drug manufacturer can no longer provide the study agent 
 
• Subject achieves complete remission (CR), and the subject and investigator feel that 
discontinuation of KRT-232 (AMG 232) + KRd is in the subject’s best interests, or 
 
• Subject achieves a level of response that qualifies him or her for another therapy, such as 
high dose therapy with autologous stem cell transplantation, and the subject and 
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best interests 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
5.10. 
Duration of Follow Up 
 
Subjects will be followed for 30 days after removal from study or until death, whichever occurs 
first.  Subjects removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
 
 
This section provides guidelines for dose modification guidelines and holding parameters for 
KRT-232 (AMG 232), carfilzomib, lenalidomide, and dexamethasone to manage possible 
toxicity.  There should be no dose modifications of KRT-232 (AMG 232) and KRd during the 
DLT-evaluable period (Cycle 1).  Subjects requiring dose-reductions during the DLT-evaluable 
period (Cycle 1) will be considered a DLT. 
 
Guidelines on dose-reductions for carfilzomib were based on the Carfilzomib Prescribing 
Information 2016 (Amgen Inc, 2016).  
 
Guidelines on dose-reduction for lenalidomide were based on the Lenalidomide Prescribing 
Information 2015 (Celgene Inc, 2015). 
 
6.1. Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
 
The criteria for toxicity recovery before the subject can begin the next cycle of treatment are 
as follows: 
 
• ANC ≥ 1000/mm3. 
• Platelet count ≥ 50,000/mm3  
• All non-hematologic toxicity considered to be related to treatment with study therapy 
must have resolved to ≤ Grade 2, to the subject’s baseline values, or to a severity level 
considered stable and tolerable by the investigator/subject (eg, Grade 2 chronic kidney 
disease due to underlying MM). 
 
If the subject does not meet the above-cited criteria for retreatment, initiation of the next 
cycle of KRT-232 (AMG 232) + KRd should be delayed for 1 week. After 1 week, the 
subject should be re-evaluated to determine whether the criteria for retreatment have been 
met. If the subject continues not to meet the previously cited criteria, delay KRT-232 (AMG 
232) + KRd and continue to re-evaluate.  
 

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The maximum delay before treatment regimen of KRT-232 (AMG 232) + KRd should be 
discontinued will be 4 weeks (28 days) or at the discretion of the Principal Investigator, with 
the exception of C2D1 for which a delay ≥or, with in initiating C2D1 will be considered a 
DLT and subject will be removed from study (Section 5.6). 
 
 
 
6.2. Dose Reductions 
 
KRT-232 (AMG 232) 
 
Dose Level 
KRT-232 (AMG 232) Dose 
- 1 
30 mg/day PO x 7 days out of 28 day cycle 
+ 1 
60 mg/day PO x 7 days out of 28 day cycle 
+ 2 
90 mg/day PO x 7 days out of 28 day cycle 
+ 3 
120 mg/day PO x 7 days out of 28 day cycle 
+ 4 
180 mg/day PO x 7 days out of 28 day cycle 
+5 
240 mg/day PO x 7 days out of 28 day cycle 
 
Carfilzomib 
Dose Level 
Carfilzomib Dose 
- 2 
15 mg/m2  
- 1 
20 mg/m2   
+1 
27 mg/m2 
 
Lenalidomide 
Dose Level 
Lenalidomide Dose 
- 3 
5 mg  
- 2 
10 mg 
- 1 
15 mg 
+1 
25 mg 
 
Dexamethasone 
Dose Level 
Dexamethasone Dose 
- 2 
12 mg  
- 1 
20 mg   
+ 1 
40 mg 
 
6.3. Non-Hematologic Toxicity Dose Delay/Dose Modification Guidelines. 
 
 
 
 
 
 
 
 

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Management/Next Dose for KRT-232 (AMG 232) 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Management/Next Dose for KRT-232 (AMG 232) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Management/Next Dose for KRT-232 (AMG 232) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Management/Next Dose for KRT-232 (AMG 232) 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Acute Renal Injury Management/Next Dose for Carfilzomib 
≤ Grade 1 
No change in dose. 
≥ Grade 2  or 
Creatinine clearance 
< 15 mL/min, or 
creatinine clearance 
decreases to less than 
or equal to 50% of 
baseline, or need for 
dialysis 
Withhold dose and continue monitoring renal function (serum 
creatinine or creatinine clearance) 
If attributable to carfilzomib, resume when renal function has 
recovered to within 25% of baseline; start at 1 dose level 
reduction 
If not attributable to carfilzomib, dosing may be resumed at the 
discretion of the physician 
For subjects on dialysis receiving carfilzomib, the dose is to be 
administered after the dialysis procedure 
*Subjects requiring a delay of > 4 weeks should go off protocol therapy. 
**Subjects requiring > two dose reductions should go off protocol therapy. 
 
Hepatic Impairment 
 
Grade 3 or 4 elevation of 
transaminases, bilirubin or 
other liver abnormalities 
25% dose reduction in case of baseline or treatment 
emergent mild or moderate hepatic impairment. 
-Withhold carfilzomib until resolved or returned to baseline. 
-After resolution, consider if restarting carfilzomib appropriate; may be 
reinitiated at a reduced dose with frequent monitoring of liver 
function. 
-If tolerated, the reduced dose may be escalated to previous dose at the 
discretion of the physician. 
-Monitor liver enzymes regularly, regardless of baseline values, and modify 
dose based on toxicity. 
Posterior Reversible 
Encephalopathy Syndrome 
(PRES) 
-If PRES is suspected, hold carfilzomib. Consider 
evaluation with MRI for onset of symptoms suggest PRES. 
-If PRES is confirmed, permanently discontinue carfilzomib. 
-If PRES is excluded, may resume carfilzomib at same dose if clinically 
appropriate. 
-If PRES recurs, permanently discontinue carfilzomib 
Thrombotic Microangiopathy 
(TMA) 
-If TMA is suspected, hold carfilzomib and manage as per standard of care. 
-If TMS is confirmed and related to carfilzomib, permanently discontinue 
carfilzomib. 
-If TMA is excluded, may restart carfilzomib. 
 
 

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• For other ≥ 3 non-hematologic toxicity assessed as KRT-232 (AMG 232)-related, KRT-
232 (AMG 232) will be held until toxicity resolves to ≤ Grade 1 or baseline.  KRT-232 
(AMG 232) will be restarted at 1 dose decrement. 
 
• For other ≥ 3 non-hematologic toxicity assessed as carfilzomib-related, carfilzomib will 
be held until toxicity resolves to ≤ Grade 1 or baseline.  Consider restarting carfilzomib at 
1 dose decrement at physician’s discretion. 
 
• For other ≥ 3 non-hematologic toxicity assessed as lenalidomide-related, lenalidomide 
will be held until toxicity resolves to ≤ Grade 2 or baseline.  Consider restarting 
lenalidomide at 1 dose decrement at physician’s discretion. 
 
 
6.4. Hematologic Toxicity Dose Delay/Dose Modification Guidelines. 
 
Neutropenia 
Management/Next Dose for 
KRT-232 (AMG 232) 
Management/Next Dose for 
Carfilzomib 
≤ Grade 2 
No change in dose. 
No change in dose. 
Grade 3 
Hold treatment. 
Add colony stimulating factor.a 
Check weekly CBC. 
Resume at same dose level when 
until ≤ Grade 2. 
For subsequent grade 3 or 4 
neutropenia, restart at 1 dose 
decrement.   
No change in dose.   
Grade 4 
 
 
 
 
 
 
 
   
Hold treatment. 
Add colony stimulating factor. 
Check weekly CBC. 
Resume at same dose level when ≤ 
Grade 3. 
For subsequent grade 4 
neutropenia, restart at 1 dose 
decrement.   
*Subjects requiring a delay of > 4 weeks should go off protocol therapy. 
**Subjects requiring > two dose reductions should go off protocol therapy. 
aColony stimulating factors such as filgrastim or sargramostim as examples. 
 
 
Neutropenia 
Management/Next Dose for Lenalidomide 
≤ Grade 2 
No change in dose 
Grade 3 or 4 
Hold treatment. 
Add colony stimulating factor.a 
Check weekly CBC. 
Resume at same dose level when ≤ Grade 2. 

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Neutropenia 
Management/Next Dose for Lenalidomide 
For subsequent grade 3 or 4 neutropenia, restart at 1 dose decrement.   
*Subjects requiring a delay of > 4 weeks should go off protocol therapy. 
**Subjects requiring > two dose reductions should go off protocol therapy. 
aColony stimulating factors such as filgrastim or sargramostim as examples. 
 
 
 
Management/Next Dose for KRT-232 (AMG 232) 
 
 
 
 
 
 
   
 
 
 
Thrombocytopenia 
Management/Next Dose for Carfilzomib 
 ≥ 10,000 cells/mm3 
No change in dose 
< 10,000 cells/mm3 
or bleeding 
Hold treatment. 
Check weekly CBC 
Resume at same dose level when ≥ 10,000 cells/mm3 
For subsequent thrombocytopenia < 10,000 cells/mm3, restart at 1 dose 
decrement.   
*Subjects requiring a delay of > 4 weeks should go off protocol therapy. 
**Subjects requiring > two dose reductions should go off protocol therapy. 
 
Thrombocytopenia 
Management/Next Dose for Lenalidomide 
≥ 30,000 cells/mm3 
No change in dose 
< 30,000 cells/mm3 
Hold until treatment. 
Check weekly CBC. 
Hold prophylactic anticoagulation. 
Restart at 1 dose decrement ≥ 30,000 cells/mm3 
*Subjects requiring a delay of > 4 weeks should go off protocol therapy. 
**Subjects requiring > two dose reductions should go off protocol therapy. 
 
 
6.5. Dexamethasone Toxicity Dose Delay/Dose Modification Guidelines.  
 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1–2 
(requiring medical management) 
Treat with H2 blockers, sucralfate, or omeprazole.  
If symptoms persist despite above measures, 
decrease dexamethasone dose by 1 dose level. 
Gastrointestinal 
> Grade 3 (requiring 
hospitalization or surgery) 
Hold dexamethasone until symptoms adequately 
controlled.  Restart dexamethasone at 1 dose 
decrement along with concurrent therapy with H2 
blockers, sucralfate, or omeprazole. 
If symptoms persist despite above measures, 

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discontinue dexamethasone permanently. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone permanently. 
Cardiovascular 
Edema > Grade 3 (limiting 
function and unresponsive to 
therapy or anasarca) 
Diuretics as needed, and restart dexamethasone at 1 
dose decrement; if edema persists despite above 
measures, decrease dose another level.  
Discontinue dexamethasone permanently if 
symptoms persist despite second reduction. 
Neurology 
Confusion or mood alteration > 
Grade 2 (interfering with function 
+/– interfering with activities of 
daily living) 
Hold dexamethasone until symptoms resolve.  
Restart dexamethasone at 1 dose decrement. If 
symptoms persist despite above measures, reduce 
by another dose decrement. 
Musculoskeletal 
Muscle weakness > Grade 2 
(symptomatic and interfering 
with function +/– interfering with 
activities of daily living) 
Decrease dexamethasone by 1 dose level.  If 
weakness persists, decrease dose by 1 more dose 
level.  Discontinue dexamethasone permanently if 
symptoms persist. 
Metabolic 
Hyperglycemia ≥ Grade 3 
Treatment with insulin or other hypoglycemic 
agents as needed.  If uncontrolled despite above 
measures, decrease dose by 1 dose level until levels 
are satisfactory. 
All Other 
Other nonhematologic toxicity ≥ 
Grade 3 felt related to 
dexamethasone 
Hold dexamethasone dose.  Resume at 1 dose 
decrement when toxicity has resolved to Grade 2 or 
less or to baseline.  If toxicity recurs, discontinue 
dexamethasone permanently. 
 
 
6.6. Hepatotoxicity Stopping and Rechallenge Rules 
 
Subjects with abnormal hepatic laboratory values (e.g., ALP, AST, ALT, total bilirubin, or INR) 
or signs/symptoms of hepatitis may meet the criteria for withholding of investigational product.  
Withholding is either permanent or conditional depending upon the clinical circumstances 
discussed below (as specified in the Guidance for Industry Drug-Induced Liver Injury:  
Premarketing Clinical Evaluation, July 2009). 
 
Criteria for Permanent Withholding of KRT-232 (AMG 232) Due to Potential Hepatotoxicity 
 
KRT-232 (AMG 232) should be permanently withheld and the subject should be followed 
according to the recommendations in APPENDIX C if ALL of the criteria below are met: 
 
• Increased AST or ALT from the relevant baseline value as specified below:  
 
o Baseline AST/ALT level is < 1 × ULN and AST/ALT is elevated > 3 × ULN 
AND 
o Total bilirubin level is > 2 × ULN or INR is > 1.5 
AND 
o No other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
elevated total bilirubin values include, but are not limited to:  
 
➢ Hepatobiliary tract disease 
➢ Viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr virus (EBV), 

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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 6.1) and the characteristics of an observed AE (Section 6.2 and 
6.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
7.1. Comprehensive Adverse Events and Potential Risks List (CAEPR) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm for further clarification.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
CAEPRs for CTEP IND Agent 
 
7.1.1. 
CAEPR for KRT-232 (AMG 232) 
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
KRT-232 (AMG 232, NSC 789723) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 379 patients. Below is the CAEPR for KRT-232 (AMG 232). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in 
the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has 
an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
 
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Note: KRT-232 (AMG 232) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
7.1.2. Adverse Event List(s) for [Other Investigational Agent(s)] 
 
7.1.3. 
CAEPR for Lenalidomide 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Lenalidomide (CC-5013, NSC 703813) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf  for further clarification. 
Frequency is provided based on 4081 patients. Below is the CAEPR for Lenalidomide (CC-5013). 

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11Gastrointestinal obstruction includes:  Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal 
obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal obstruction under the 
GASTROINTESTINAL DISORDERS SOC. 
 
12Osteonecrosis of the jaw has been seen with increased frequency when lenalidomide is used in combination with 
bevacizumab, docetaxel (Taxotere®), prednisone, and zolendronic acid (Zometa®). 
 
NOTE:  While not observed in human subjects, lenalidomide, a thalidomide analogue, caused limb abnormalities in 
a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used 
during pregnancy, it may cause birth defects or embryo-fetal death. Pregnancy must be excluded before start of 
treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. 
 
NOTE: In a trial of first line treatment of patients with chronic lymphocytic leukemia (CLL), single agent 
lenalidomide (CC-5013) increased the risk of death as compared to control arm (chlorambucil). 
 
NOTE: In two randomized trials of patients with multiple myeloma (MM), the addition of MK-3475 
(pembrolizumab) to a thalidomide analog plus dexamethasone, resulted in increased mortality.  Treatment of 
patients with MM with a PD-1 or PD-L1 blocking antibody, such as MK-3475 (pembrolizumab), in combination 
with a thalidomide analog, such as lenalidomide, is not recommended outside of controlled clinical trials. 
 
NOTE:  In a clinical trial in patients with Mantle cell lymphoma (MCL), there was an increase in early deaths 
(within 20 weeks); 12.9% in the lenalidomide (CC-5013) arm vs. 7.1% in the control arm. 
 
 
Adverse events reported on lenalidomide (CC-5013) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that lenalidomide (CC-5013) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(monocytosis); Disseminated intravascular coagulation; Eosinophilia 
CARDIAC DISORDERS - Atrial flutter; Atrioventricular block first degree; Cardiac arrest; Cardiac disorders - 
Other (cardiovascular edema); Cardiac disorders - Other (ECG abnormalities); Chest pain - cardiac; Left ventricular 
systolic dysfunction; Palpitations; Pericarditis; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia; 
Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Cushingoid 
EYE DISORDERS - Dry eye; Flashing lights; Retinopathy 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal mucositis; Ascites; Colonic perforation; 
Dysphagia; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (Crohn's disease 
aggravated); Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other (pale feces); 
Gastrointestinal hemorrhage10; Gastrointestinal obstruction11; Ileus; Mucositis oral; Pancreatitis; Rectal mucositis; 
Small intestinal mucositis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS - Cholecystitis 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Infections and infestations - Other (opportunistic infection 
associated with >=Grade 2 Lymphopenia); Myelitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Hip fracture; Vascular access 
complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Cholesterol high; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; INR increased; Investigations - Other (hemochromatosis) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; Hypoglycemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; Joint 
effusion; Muscle weakness lower limb; Neck pain; Osteonecrosis of jaw12 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 

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NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dysphasia; Edema cerebral; 
Encephalopathy; Intracranial hemorrhage; Ischemia cerebrovascular; Leukoencephalopathy; Memory impairment; 
Nervous system disorders - Other (hyporeflexia); Spinal cord compression; Seizure; Somnolence; Transient 
ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Psychosis 
RENAL AND URINARY DISORDERS - Urinary frequency; Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - Other 
(hypogonadism); Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Atelectasis; Bronchopulmonary hemorrhage; Hypoxia; Laryngeal mucositis; Pharyngeal mucositis; 
Pleural effusion; Pulmonary hypertension; Respiratory failure; Tracheal mucositis; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Nail loss; Photosensitivity; Rash acneiform; 
Skin and subcutaneous tissue disorders - Other (Sweet’s Syndrome); Urticaria 
VASCULAR DISORDERS - Hot flashes; Phlebitis; Vascular disorders - Other (hemorrhage NOS) 
 
 
Note: Lenalidomide (CC-5013) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
 
Adverse Event List(s) for other Commercial Agent(s) 
 
In the Phase 3 randomized ASPIRE (Stewart et al., 2015) trial of carfilzomib, lenalidomide, and 
dexamethasone (KRd) vs. lenalidomide and dexamethasone (Rd), the following adverse 
reactions occurred in ≥ 10% of subjects in the KRd arm during cycles 1-12. 
 
KRd Arm (N = 392) n (%) 
Adverse Reactions by Body System 
Any Grade 
≥ Grade 3 
Blood and Lymphatic System Disorders 
Anemia 
138 (35) 
53 (14) 
Neutropenia 
124 (32) 
104 (27) 
Thrombocytopenia 
100 (26) 
58 (15) 
Gastrointestinal Disorders 
Diarrhea 
115 (29) 
7 (2) 
Constipation 
68 (17) 
0 
Nausea 
60 (15) 
1 (0) 
General Disorders and Administration Site Conditions 
Fatigue 
109 (28) 
21 (5) 
Pyrexia 
93 (24) 
5 (1) 
Edema peripheral 
63 (16) 
2 (1) 
Asthenia 
53 (14) 
11 (3) 
Infections and Infestations 
Upper respiratory tract infection 
85 (22) 
7 (2) 
Nasopharyngitis 
63 (16) 
0 
Bronchitis 
54 (14) 
5 (1) 

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Pneumoniaa 
54 (14) 
35 (9) 
Metabolism and Nutrition Disorders 
Hypokalemia 
78 (20) 
22 (6) 
Hypocalcemia 
55 (14) 
10 (3) 
Hyperglycemia 
43 (11) 
18 (5) 
Musculoskeletal and Connective Tissue Disorders 
Muscle spasms 
88 (22) 
3 (1) 
Nervous System Disorders 
Peripheral neuropathiesb 
43 (11) 
7 (2) 
Psychiatric Disorders 
Insomnia 
63 (16) 
6 (2) 
Respiratory, Thoracic, and Mediastinal Disorders 
Coughc 
91 (23) 
2 (1) 
Dyspnead 
70 (18) 
9 (2) 
Skin and Subcutaneous Tissue Disorders 
Rash 
45 (12) 
5 (1) 
Vascular Disorders 
Embolic and thrombotic events venouse 
49 (13) 
16 (4) 
Hypertensionf 
41 (11) 
12 (3) 
 
KRd = Carfilzomib, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone 
aPneumonia includes pneumonia and bronchopneumonia. 
bPeripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral 
motor neuropathy. 
cCough includes cough and productive cough. 
dDyspnea includes dyspnea and dyspnea exertional. 
eEmbolic and thrombotic events, venous include deep vein thrombosis, pulmonary embolism, 
thrombophlebitis superficial, thrombophlebitis, venous thrombosis limb, post thrombotic syndrome, 
venous thrombosis. 
fHypertension includes hypertension, hypertensive crisis. 
  
• For complete information on potential adverse events for carfilzomib, please refer to 
Carfilzomib Prescribing Information 2016 (Amgen Inc, 2016).  
 
• For complete information on potential adverse events for lenalidomide, please refer to 
Lenalidomide Prescribing Information 2015 (Celgene Inc, 2015). 
 
 
7.2. Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 

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to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3. Expedited Adverse Event Reporting 
 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP Web site (https://eapps-ctep.nci.nih.gov/ctepaers).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” 
which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm).  
These requirements are briefly outlined in the tables below (Section 6.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
 
Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific subject ID assigned during trial 
registration on all reports. 
 

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1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
 
 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
Not Applicable. 
 
7.4. Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5. Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 

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7.6. Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
7.7. Pregnancy, Contraception, and Risk of Embryo-Fetal Toxicity 
 
Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey 
study.  Thalidomide is a known human teratogen that causes severe life-threatening human birth 
defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal 
death.  Carfilzomib can cause fetal harm based on findings from animal studies and the drug’s 
mechanism of action.  There are no adequate and well-controlled studies in pregnant women 
using carfilzomib.  It is not known what effects KRT-232 (AMG 232) has on human pregnancy 
or development of the embryo or fetus.  Therefore, female patients participating in this study 
should avoid becoming pregnant, and male patients should avoid impregnating a female partner.   
Nonsterilized female patients of reproductive potential must agree to one of the following 
through defined periods during and after study treatment as specified below.  Non-reproductive 
potential is defined as female subjects who are permanently sterile or are post-menopausal (no 
menses in 12 consecutive months without an alternative medical cause). 
• Agree to practice 2 effective methods of contraception from the time of signing of the 
informed consent form through 5 weeks after the last dose of study drug.  This includes 
one highly effective form of contraception and one additional effective contraceptive 
method (see examples below).  
 
Highly effective methods:  
o Intra-uterine devices (IUD) 
o Hormonal (birth control pills/oral contraceptives, injectable contraceptives, 
contraceptive patches, or contraceptive implants) 
 
Other effective methods (barrier methods): 
o Latex or non latex condom  with or without a spermicidal agent 
o Diaphragm with spermicide; Cervical cap with a spermicide; Sponge with a 
spermicide OR 
 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of contraception.) 
 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following defined periods during and after study treatment as specified below. 

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• Agree to practice effective barrier contraception during the entire study treatment period 
and through 90 days after the last dose of study drug, OR 
 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner] and withdrawal are not acceptable methods 
of contraception.) 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
 
8.1. CTEP IND Agent(s) 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB Online Agent Order Processing (OAOP) application.  Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password.  Questions about IB access 
may be directed to the PMB IB coordinator via email. 
 
KRT-232 (AMG 232) (NSC 789723) 
 
Chemical Name: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-
(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl) acetic acid 
 
International Non-Proprietary Name (INN):  Navtemadlin 
 
Classification: MDM2 inhibitor 
 
Molecular Formula: C28H35Cl2NO5S  
 
M.W.: 568.55 
 
Mode of Action:  AMG 232 (KRT 232) is a small molecule, cytotoxic chemotherapeutic agent that 
binds to murine double minute chromosome 2 (MDM2) and inhibits the MDM2/tumor protein 53 
protein-protein interaction.  
 
Description: Is a slightly hygroscopic, anhydrous, and crystalline white to off-white powder. 
 
How Supplied: Kartos Therapeutics supplies, and the Pharmaceutical Management Branch 
distributes       AMG 232 (KRT 232) as an immediate release tablet formulated as either an uncoated 
tablet with a low drug load (LDL tablet) or a film-coated tablet with a high drug load (HDL tablet). 
 
The current supply is uncoated tablet with a low drug load (LDL tablet):  
• 15 mg tablet: white to off-white round  
• 60 mg tablet: white to off-white oval 

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Future supply is film-coated tablet with a high drug load or HDL tablet.  The HDL tablet drug label 
has a blue bar to differentiate from the LDL tablet bottle: 
• 15 mg tablet:  green round 
• 30 mg tablet:  light orange round 
• 60 mg tablet: blue oval 
• 120 mg tablet: purple oval 
 
AMG 232 (KRT 232) supply is packaged as 30 tablets per high-density polyethylene bottle and closed 
with aluminum foil lined heat induction seals and polypropylene child-resistance closures.  Inactive 
ingredients of the tablets are lactose monohydrate, microcrystalline cellulose, hydroxylpropyl 
cellulose, croscarmellose sodium, and magnesium stearate. 
 
Preparation:  AMG 232 (KRT 232) uncoated tablets (LDL tablet) can be dispensed in the original 
container or in pharmacy dispensing bottles.  The film-coated tablets (HDL tablet) must be 
dispensed in the original bottle.  There are no data to support the re-packaging of HDL tablets in 
containers other than the original bottle. 
 
Storage: Store intact bottles according to the drug label. 
 
Uncoated tablet (LDL tablet): 
• AMG 232 (KRT 232) 15 mg Tablets: below 250C (770F), protect from light. 
• AMG 232 (KRT-232) 60 mg Tablets: 150C – 300C (590F - 860F), protect from light 
 
Film-coated tablet (HDL tablet): 150C – 300C (590F - 860F), protect from light. 
 
If a storage temperature excursion is identified, promptly return AMG 232 (KRT 232) to the 
proper storage temperature and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and duration of the excursion) 
to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Shelf-life stability studies of AMG 232 (KRT 232) tablets are ongoing.  
 
Route(s) of Administration: Oral.   
 
Method of Administration: AMG 232 (KRT 232), uncoated (LDL) or coated (HDL) tablet, can be 
taken with a glass of water with or without food. 
 
Potential Drug Interactions: 
AMG 232 (KRT 232) is metabolized by three uridine diphosphoglucuronosyl transferases 
(UGT1A1, UGT1A3, and UGT1A4) to an acyl glucuronide (M1). In vitro, M1 is not impacted 
by UGT1A1 polymorphic genotypes UGT1A1*1/*1, UGT1A1*1/*28 or UGT1A1*28/*28.  
 
AMG 232 (KRT 232) is not metabolized by CYP450 isozymes. In-vitro study suggests that 
AMG 232 is a substrate for P-glycoprotein, a competitive moderate inhibitor of CYP2C8, and a 
time-dependent moderate inhibitor of CYP3A4.  M1 is a weak inhibitor of CYP2B6. KRT-232 

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has the potential to cause a minor drug-drug interaction (DDI) with drugs cleared predominantly 
by CYP3A4 (inhibition and induction). There is no identified DDI potential for other CYP 
enzymes. Use caution in patients taking CYP3A4 substrates with narrow therapeutic ranges.  
 
Since AMG 232 (KRT 232) absorption was not impacted in the presence of high pH as 
demonstrated in a PK simulation, KRT-232 is not likely to be affected by proton pump inhibitor-
mediated increase in gastric pH.   
 
In pooled human liver microsomes, AMG 232 (KRT 232) and M1 are moderate inhibitors of 
UGT1A1.  In human hepatocytes, UGT1A1/3/4 enzymatic activities were increased by AMG 
232(KRT 232) at concentration > 5 µm and the mRNA transcripts were minimally increased by 
AMG 232 (KRT 232) at concentration ≥10 µm. Since the exposure of AMG 232 is expected to 
be low (unbound Cmax = 0.161 µm at 480 mg), an increase in metabolism and CL via auto-
induction are not expected. 
 
AMG 232 (KRT 232) is not a BCRP substrate.  Although AMG 232 (KRT 232) is an inhibitor of 
OAT3 (moderate to potent), OATP1B1 (moderate to potent), OATP1B3 (moderate to potent), 
OAT1 (moderate), BCRP (very weak), OCT2 (very weak), and P-glycoprotein (moderate), the 
ratios of unbound Cmax to the in vitro IC50 is low (<0.03) at the proposed doses; thus, the 
potential for AMG 232 (KRT 232) to cause transporter-mediated DDIs due to inhibition of the 
transporter is low.  
 
Patient Care Implications 
Advise women study participants of reproductive potential to use effective contraception while 
receiving AMG 232 (KRT 232) and 1 month + 1 week (or 5 weeks) after the last dose of AMG 
232 (KRT 232). Men study participants must continue to use contraception for 3 months and 1 
week (or 13 weeks) after the last dose of AMG 232 (KRT 232).  Refer to the protocol document 
for specific guidance. 
 
Availability 
 
KRT-232 (AMG 232) is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
KRT-232 (AMG 232) is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
Agent Ordering and Agent Accountability 
 
NCI-supplied agents may be requested by the responsible investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the subject is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained).  The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 

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Investigator), Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there 
are several participating investigators at one institution, CTEP-supplied investigational agents for 
the study should be ordered under the name of one lead investigator at that institution. 
 
No starter supplies.  Sites may order agent supplies when subject enrollment is confirmed.  
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status and a “current” 
password.  For questions about drug orders, transfers, returns, or accountability, call or email 
PMB any time.  Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final disposition of all 
agents received from the PMB using the appropriate NCI Investigational Agent (Drug) 
Accountability Record (DARF) available on the CTEP forms page.  Store and maintain separate 
NCI Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
8.2. Other Investigational Agent(s) 
 
N/A 
 
8.3. Commercial Agent(s) 
 
8.3.1. 
Carfilzomib 
 
Product description:  Carfilzomib is an antineoplastic agent available for intravenous use only. 
Carfilzomib is a sterile, white to off-white lyophilized powder and is available as a single-dose 
30 mg or 60 mg vial. Each 30 mg vial contains 30 mg of carfilzomib, 1500 mg sulfobutylether 

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beta-cyclodextrin, and 28.9 mg anhydrous citric acid and sodium hydroxide for pH adjustment 
(target pH 3.5). Each 60 mg vial contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-
cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5). 
Carfilzomib is a modified tetrapeptidyl epoxide, isolated as the crystalline free base. 
The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran- 2-yl)-
1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)- 
4-phenylbutanamido)-4-methylpentanamide. Carfilzomib has the following structure:  
 
 
 
Carfilzomib is a crystalline substance with a molecular weight of 719.9. The molecular 
formula is C40H57N5O7. Carfilzomib is practically insoluble in water and very slightly 
soluble in acidic conditions. 
 
Solution preparation (how the dose is to be prepared): Please refer to please refer to the FDA 
approved package insert for additional information.  
 
Route of administration:  Carfilzomib is infused over 10 or 30 minutes.  Do not administer as a 
bolus. Flush the intravenous administration line with normal saline or 5% dextrose injection, 
USP immediately before and after carfilzomib administration. Do not mix carfilzomib with or 
administer as an infusion with other medicinal products. 
 
Administration Precautions: 
• Dose Calculation - Calculate the carfilzomi dose [see Dosage and Administration 
(2.2)] using the subject’s actual body surface area at baseline. In subjects with a body 
surface area greater than 2.2 m2, calculate the dose based upon a capped body surface 
area of 2.2 m2. 
• Hydration - Adequate hydration is required prior to dosing in Cycle 1, especially in 
subjects at high risk of tumor lysis syndrome or renal toxicity. The recommended 
hydration includes both oral fluids (30 mL per kg at least 48 hours before Cycle 1, 
Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid 
prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of 
intravenous fluids following carfilzomib administration. Continue oral and/or 
intravenous hydration, as needed, in subsequent cycles. Monitor subjects for evidence 
of volume overload and adjust hydration to individual subject needs, especially in 
subjects with or at risk for cardiac failure. 
• Electrolyte Monitoring - Monitor serum potassium levels regularly during treatment 
with carfilzomib. 
• Premedications - Premedicate with the recommended dose of dexamethasone for 
monotherapy or the recommended dexamethasone dose if on combination therapy.  
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than 4 hours prior to all doses of Carfilzomib during Cycle 1 to reduce the incidence 
and severity of infusion reactions.  Reinstate dexamethasone premedication if these 
symptoms occur during subsequent cycles. 
• Thromboprophylaxis - Thromboprophylaxis is recommended for subjects being 
treated with the combination of carfilzomib with dexamethasone or with lenalidomide 
plus dexamethasone. The thromboprophylaxis regimen should be based on an 
assessment of the subject’s underlying risks. 
• Infection Prophylaxis - Consider antiviral prophylaxis for subjects being treated with 
carfilzomib to decrease the risk of herpes zoster reactivation. 
 
Agent Ordering: Carfilzomib is commercially available.    
 
Please refer to the FDA approved package insert for additional information. 
 
8.3.2. 
Lenalidomide 
 
Product description: Lenalidomide, a thalidomide analogue, is an immunomodulatory agent 
with antiangiogenic and antineoplastic properties. The chemical name is 3- (4-amino-1-oxo 1,3-
dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure: 
 
 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3.   Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic 
solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging 
from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the 
optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical 
rotation of zero. 
 
Solution preparation:  Lenalidomide is available in 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 
mg capsules for oral administration. Each capsule contains lenalidomide as the active ingredient 
and the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, 
croscarmellose sodium, and magnesium stearate. The 5 mg and 25 mg capsule shell contains 
gelatin, titanium dioxide and black ink. The 2.5 mg and 10 mg capsule shell contains gelatin, 
FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. The 15 mg capsule shell 
contains gelatin, FD&C blue #2, titanium dioxide and black ink. The 20 mg capsule shell 
contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. 
 

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Route of administration:  Lenalidomide should be taken orally at about the same time each day, 
either with or without food. REVLIMID capsules should be swallowed whole with water. The 
capsules should not be opened, broken, or chewed.  
 
Agent Ordering: Lenalidomide is commercially available.    
 
Please refer to the FDA approved package insert for additional information. 
Dexamethasone 
 
In this study, dexamethasone may be administered intravenously or by mouth.   
 
8.3.3. 
Dexamethasone sodium phosphate (intravenous) 
 
Product Description: Dexamethasone sodium phosphate, a synthetic adrenocortical steroid, is a 
white or slightly yellow, crystalline powder . It is freely soluble in water and is exceedingly 
hygroscopic. The molecular weight is 516.41 . It is designated chemically as 9-fluoro-110,17-
dihydroxy-16amethyl-21-(phosphonooxy) pregna-l,4-diene-3,20-dione disodium salt. The 
empirical formula is C22H28FNa2O8P. 
 
 
 
Solution Preparation:  Please refer to the FDA approved package insert for information on 
solution preparation. 
 
Route of Administration:  In this study, dexamethasone sodium phosphate formulation will be 
administered intravenously.   
 
Agent Ordering: Dexamethasone sodium phosphate is commercially available.   
 
Please refer to the FDA approved package insert for additional information. 
 
8.3.4. 
Dexamethasone (oral) 
Product Description:  Dexamethasone, a synthetic adrenocortical steroid, is a white to 
practically white, odorless, crystalline powder. It is stable in air. It is practically insoluble in 
water. The molecular formula is C22H29FO5. The molecular weight is 392.47. It is designated 
chemically as 9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene,3,20-dione and the 
structural formula is: 

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Solution Preparation: Dexamethasone tablets are available for oral administration containing 
either 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg or 6 mg of Dexamethasone USP. Each tablet 
contains the following inactive ingredients: lactose monohydrate, magnesium stearate, starch, 
sugar, D&C Yellow #10 (0.5 mg and 4 mg), FD&C Blue #1 (0.75 mg and 1.5 mg), FD&C Green 
#3 (4 mg and 6 mg), FD&C Red #3 (1.5 mg), FD&C Red #40 (1.5 mg), FD&C Yellow #6 (0.5 
mg and 4 mg) and Yellow Iron Oxide (1 mg). 
 
Route of administration:  Dexamethasone will be administered by mouth. 
 
Agent Ordering: Dexamethasone is commercially available. 
 
Please refer to the FDA approved package insert for additional information. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1. Integral Laboratory or Imaging Studies 
 
9.1.1. 
TP53 DNA Sequencing 
 
Background:   In the two largest sequencing studies to-date in myeloma, TP53 mutations occur 
in only 3-8% of myeloma subjects (Lohr et al., 2014; Walker et al., 2015).  A number of 
preclinical studies have suggested that wild-type TP53 may be a biomarker for response with the 
use of MDM2 inhibitors, including studies performed in myeloma (Gu et al., 2014).   In the 
clinical setting, several studies have been reported to-date evaluating the use of MDM2 
inhibition in various malignancies.  In a phase 1 trial of RG7112, a small molecule inhibitor 
MDM2, in relapsed leukemias, TP53 mutations were identified in 19 of 96 subjects tested, and 
all but two subjects failed to show any clinical response, suggesting that the presence of at least 
one wild-type TP53 allele is necessary for response.  However, wild-type TP53 alone was not 
sufficient to predict response to treatment in this study (Andreeff et al., 2016).  
  
Method: The test will be performed by the  NCI Molecular Characterization Laboratory 
(MoCha) or by an outside CLIA-certified laboratory.  The MoCha laboratory will use human 
reference genome GRCh37 (hg19) as a reference sequence to determine mutational status of the 
TP53 gene in the patient’s tumor samples.  
 
A minimum of 5% plasma cells on either the bone marrow biopsy or bone marrow aspirate is 
required to ensure sufficient plasma cells were present in the bone marrow to prevent from 
reporting false negative results on TP53 mutational status. 

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If testing is performed by a CLIA-certified laboratory outside of MoCHa, the coordinating 
molecular pathologist listed on the protocol face page will be responsible for confirming and 
signing a clinical report on TP53-wild type status for purposes of trial eligibility and treatment 
assignment.  A copy of a CLIA laboratory or the MoCHA laboratory report (Appendix 15.4) 
must be captured in the patient’s trial record.  
 
 
Analysis: Due to the timely need to initiate treatment in relapsed myeloma, TP53 mutation status 
at screening is NOT required prior to KRT-232 (AMG 232) dosing.  However, subjects found to 
have TP53 mutation and/or deletion from screening bone marrow biopsy as assessed by a CLIA-
certified laboratory or the NCI Molecular Characterization Laboratory (MoCha) will be removed 
from study after C1 and continue on standard-of-care KRd alone.  
 
9.1.1.1. 
Specimen Tracking System Instructions 
 
Bone marrow aspirate specimens (Section 9.1.1.2. and Section 9.4.1.1.), blood specimens 
(Section 9.5), and nucleic acids (Section 9.1.1.3. and Section 9.4.1.2.) for biobanking for this 
trial must be submitted using the ETCTN Rave Specimen Tracking System (STS) unless 
otherwise noted.  The system is accessed through special Rave user roles: “CRA Specimen 
Tracking” for data entry at the treating institutions and “Biorepository” for users receiving the 
specimens for processing and storage at reference labs and the Biorepository.  Please refer to the 
Medidata Account Activation and Study Invitation Acceptance link on the CTSU website under 
the Rave/DQP tab. 
 
Important:  Failure to complete required fields in STS may result in a delay in sample 
processing.  Any case reimbursements associated with sample submissions will not be credited 
if samples requiring STS submission are not logged into STS. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact the Theradex Help Desk 
at CTMSSupport@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
Specimen Labeling 
 
Blood Specimen Labels 
 
Include the following on blood specimens for optional blood samples for biobanking as per 
Section 9.5: 
Patient Study ID 
Specimen ID (automatically generated by Rave) 
Time point 

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Specimen type (e.g., blood, serum) 
Collection date  
 
Tissue Specimen Labels 
Include the following on all tissue specimens or containers (e.g., bone marrow aspirate tube):  
Patient Study ID 
Specimen ID (automatically generated by Rave) 
Time point 
Specimen type (e.g., bone marrow aspirate, buccal mucosal swab) 
Collection date 
 
Nucleic Acid Specimen Labels 
Include the following on nucleic acids  (e.g., DNA, RNA, cDNA):  
Patient Study ID 
Specimen ID (automatically generated by Rave) 
Time point 
Specimen category (e.g. bone marrow) 
Specimen type (e.g., DNA, RNA, cDNA) 
Collection date 
 
 
Example of Specimen Label 
 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide. 
 
  
 
The QR code in the above example is for the Specimen ID shown on the second line.   
NOTE:  The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the beginning of the 
specimen ID; this field is blank if not relevant (e.g., for blood) 
Block ID or blank if not relevant 
SPID (Surgical Pathology ID) or blank if none 

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The last alpha-numeric code is protocol specific and is only included if the protocol requires an 
additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 
 
 
9.1.1.2. 
Collection of Specimen (s) 
Bone marrow biopsy and aspiration will be performed at screening and at the end of study at the 
local study site.  An optional bone marrow biopsy and aspiration will be performed pre-Cycle 2, 
Day 1.   Immediately after marrow is aspirated, place 3-5 mL of bone marrow aspirate into 
sterile EDTA (lavender top tube). Mix well by inversion.  Bone marrow aspirate specimen 
should be labeled as per the Specimen Tracking Instructions (Section 9.1.1.1.) 
 
A bilateral bone marrow biopsy and aspiration will be performed at screening to ensure a high 
quality specimen for integral biomarker testing.  Standard-of-care testing (e.g. flow cytometry, 
FISH) should be performed on the bone marrow aspirate from one side, and the bone marrow 
aspirate for integral biomarker testing should taken from “first pull” on the contralateral side. 
 
9.1.1.3. 
Handling and Processing of Specimens(s) 
After bone marrow aspirate collection, specimen will be processed at the MD Anderson Tissue 
Qualification Laboratory (TQL) where it will be logged into the PowerPath database.  
Subsequently, the MD Anderson Molecular Diagnostics Laboratory (MDL) will perform CD138 
bead enrichment from the bone marrow sample, followed by DNA and RNA extraction in a 
CLIA-certified environment.  The MD Anderson TQL and MDL will serve as a central site for 
myeloma tissue processing for the study. 
 
For study sites outside of MD Anderson, bone marrow aspirates should be kept at room 
temperature until same-day overnight shipping at ambient temperature to the MD Anderson TQL 
where it will logged prior to further processing.    
 
The bone marrow aspirate tube and 3-5 unstained slides should shipped to the following address: 
 
MD Anderson Department of Pathology 
Tissue Qualification Laboratory 
Unit 0085 
1515 Holcombe Blvd 
Room G1.3598, 
Houston, Texas 77030  
 
An email should be sent to the MD Anderson TQL at path-tql@mdanderson.org prior to sending 
the specimen alerting the laboratory that the specimen is being shipped.    
 
9.1.1.4. 
Shipping of Specimen(s) 
After tissue processing by the MD Anderson MDL, DNA for TP53-wild type status 
determination will be shipped according the CLIA laboratory test manufacturer’s instructions (if 
this method is used), or follow the laboratory manual for shipping specimens from the MD 

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Anderson TQL to the NCI MoCha laboratory.  Nucleic acids shipped to the MoCha laboratory 
should be labeled as per the Specimen Tracking Instructions (Section 9.1.1.1.). 
 
9.1.1.5. 
Site(s) Performing Correlative Study. 
NCI Molecular Characterization Laboratory (MoCha) or any CLIA laboratory test.   
 
9.2. Investigational Device Information 
 
N/A 
 
9.3. Integrated Correlative Studies 
 
9.3.1. 
KRT-232 (AMG 232) Pharmacokinetic Profile 
 
Background: This assay will be utilized to determine KRT-232 (AMG 232) concentrations and 
ultimately the drug exposure.  There was an exposure-response correlation observed between 
changes in serum MIC-1 levels and KRT-232 (AMG 232) exposure (both maximal (Cmax) and 
total exposure (AUC) (Amgen Inc., 2015). 
 
Method: KRT-232 (AMG 232) blood levels will be measured by LC-MS/MS. The bioanalytical 
method for determining KRT-232 (AMG 232) in human plasma will be developed and validated 
utilizing liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) 
techniques.  The analytical method will be validated as recommended by the FDA Guidance for 
Industry: Bioanalytical Method Validation, May 2001 (REF: Guidance for Industry: 
Bioanalytical Method Validation. U.S. Department of Health and Human Services Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary 
Medicine (CVM). Draft Guidance, September 2013. U.S. Food and Drug Administration). 
 
Analysis: The PK profile of KRT-232 (AMG 232) will be compared. The plasma concentration-
time data will be will be analyzed by standard noncompartmental analysis as implemented in the 
program Phoenix WinNonlin (Pharsight, A CertaraTM Company, Cary, NC).  Pharmacokinetic 
parameters such as Cmax, Tmax, AUC, Cl/F, Vd/F andT1/2 will be calculated and reported.  
Additional compartmental and/or pharmacometric analyses may be explored to elucidate inter- 
and intra-subject variability. 
 
9.3.1.1. 
Collection of Specimen(s) 
Blood samples (~6 mL) will be taken into K3EDTA tubes at designated time points, and 
immediately placed on ice. C1D1: pre KRT-232 (AMG 232), 1, 3, 5, 8, and 24 hours post (24 hr 
post is C1D2). 
 
9.3.1.2. 
Handling of Specimens(s)  
At each time point, ~6 mL of peripheral blood will be collected in a purple-top EDTA vacutainer 
(Becton Dickinson Catalog # 367863 or 367899, Franklin Lakes, NJ).  
 
Obtain venous blood by standard phlebotomy technique from a peripheral access point.  NOTE:  
Suggest using a minimum 18G needle to avoid sample hemolysis.   

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Fill-up the tubes as much as possible until blood flow stops. 
GENTLY invert each tube several times (8-10 times) immediately after collection to avoid 
sample hemolysis. 
Place samples immediately on ice after collection; samples must be processed within 30 
minutes. 
 
9.3.1.3. 
Processing instructions: 
1) Invert sample 8-10 times immediately before processing.   
2) Centrifuge at 2500-3000 rpm for 10 minutes in swinging bucket (SW) or 15 minutes in a 
fixed angel (FA) rotor at 4ºC in a refrigerated centrifuge.  Make sure that the centrifuge 
reaches speed and is maintained throughout the entire spin. 
3) Carefully remove tube from centrifuge.  
4) Using a pipette, transfer equal aliquots of plasma into 2-3 labeled 2 mL cryovials, not 
exceeding 1.5 mL per cryovial.   
5) Label samples as KRT-232 (AMG 232) PK, including study number (NCI10076 ), 
unique subject ID (assigned by OPEN), initials, date of collection, draw time, and time 
point. 
6) Store plasma samples at -70oC or below until shipment or transfer to Johns Hopkins. 
 
9.3.1.4. 
Shipping of Specimen(s) 
 
Specimens should be stored through the duration of KRT-232 (AMG 232) correlative studies 
(through C1D2) and shipped as a batch by participant (more than one participant/shipment is 
acceptable if the site has >1 participant on-study). A participant's samples should be shipped to 
the APC lab within 1 month of the last sample's collection date. (i.e., if C1D1 sample is collected 
on 1/1/2017, all of that participant's samples should be at the APC lab by 2/1/2017). The APC 
lab may contact the study team to request shipment off-schedule.  The MIC-1 and KRT-232 
(AMG 232) pharmacokinetic specimens can be shipped in the same shipment. 
 
Please ship 1-2 aliquots to the APC laboratory. Once receipt is confirmed, the back-up 
aliquot may be shipped.  The back-up can be shipped later 
 
Preparing the shipment  
*Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH).  
*Please organize the samples by Subject and Time point in the box.  
*Do not store in plastic bags (they break on dry-ice and labels will detach).  
*A copy of each of the pharmacokinetic sample collection forms for the respective 
subjects or a sample list should be included with each shipment. To prevent problems 
with illegible writing on tubes, consider numbering them (in addition to sample label) 
and numbering samples on the sample sheet.  
*Note the study number, PI, and the drugs used/to be measured.  
*A name, phone number and email address should be included with samples so that 
receipt can be acknowledged.  
 
      *Please notify the lab by e-mail onc-pharmacology@lists.johnshopkins.edu   
 
 
(preferable) or telephone (410-502-7192 or 410-955-1129) or fax (410- 
 
 
 
502-0895) at least 24 hours prior to shipment.  

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Shipping  
*All samples should be shipped via overnight express courier in insulated containers 
with enough dry ice to maintain the samples in a frozen state.  
*Overnight shipments should occur on Monday through Wednesday (Tuesday is the 
preferred day) except when the following day is a holiday. 
 
Analytical Pharmacology Core Laboratory* 
Attn: NCI10076 KRT-232 (AMG 232) Study Samples 
1650 Orleans St. CRB1 Rm 184 
Baltimore, MD 21231-1000 
Phone: 410-502-7192 or 410-955-1129 
Fax: 410-502-0895 
 
Site(s) Performing Correlative Study 
ETCTN Central Laboratory: Dr. Michelle Rudek, The Analytical Pharmacology Core Laboratory 
at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (SKCCC) 
 
9.3.2. 
MIC-1 
 
Background: MIC-1, a secreted protein that is strongly induced by activated p53, can be 
detected in the peripheral blood following MDM2 inhibition (64). Therefore, MIC-1 could have 
utility as a pharmacodynamic biomarker for KRT-232 (AMG 232). MIC-1 level can be 
determined by a sensitive ELISA test and if correlated with dose or other pharmacodynamic 
effects can serve as a serum biomarker for p53 activation. We anticipate that most subjects 
treated with KRT-232 (AMG 232) will have an induction in MIC-1 and the level MIC-1 
induction will be correlated with the dose of KRT-232 (AMG 232) and the combination with 
KRd..  A commercially available ELISA kit (e.g., Biovendor, LLC, Asheville, NC) will be 
utilized to measure serum MIC-1 levels. This is for an integrated assay aimed at assessing drug 
response in subjects on the clinical trial and will be utilized to determine serum MIC-1 
concentrations and ultimately the drug response.    
 
Method: A commercially available ELISA kit (e.g., Biovendor, LLC, Asheville, NC) will be 
utilized to measure serum MIC-1 levels. 
 
Analysis: For serum MIC-1 levels, each individual level will be normalized to the baseline level 
for that subject.  In preliminary analyses of clinical trial data, there was an exposure-response 
correlation observed between changes in serum MIC-1 levels and KRT-232 (AMG 232) 
exposure (both maximal (Cmax) and total exposure (AUC). 
 
9.3.2.1. 
Collection of Specimen(s) 
Blood samples (~6 mL) will collected be in red-topped vacutainer tube at designated time points. 
Serum samples from the peripheral blood will be collected for MIC-1 assay at screening, C1D1 
(pre-KRT-232 (AMG 232)), and C1D2 (~24 hour post KRT-232 (AMG 232)). 
 

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9.3.2.2. 
Handling of Specimens(s) 
At each time point, ~6 mL of peripheral blood will be collected in a red-topped vacutainer 
(Becton Dickinson Catalog #367815, Franklin Lakes, NJ).  
- 
Obtain venous blood by standard phlebotomy technique from a peripheral access 
point.  NOTE:  Suggest using a minimum 18G needle to avoid sample hemolysis.   
- 
Fill-up the tubes as much as possible until blood flow stops. 
- 
GENTLY invert each tube several times (8-10 times) immediately after collection 
to avoid sample hemolysis. 
- 
Transport the tube(s) as soon as possible to the laboratory. Allow the blood to clot 
in an upright position for at least 30 minutes but not longer than 1 hour before 
centrifugation.  
 
9.3.2.3. 
Processing instructions: 
1) Centrifuge at 2200-2500 rpm for 15 minutes in swinging bucket (SW) or 15 minutes in a 
fixed angel (FA) rotor.  Make sure that the centrifuge reaches speed and is maintained 
throughout the entire spin. 
2) Carefully remove tube from centrifuge.  
3) Using a pipette, transfer equal aliquots of plasma into ~4-6 labeled 2 mL cryovials, with a 
minimum volume of 0.5 mL per cryovial.   
4) Label samples as MIC-1, including study number (NCI10076), unique subject ID 
(assigned by the consortium), initials, date of collection, draw time, and time point. 
5) Store serum samples at -70oC or below until shipment or transfer to Johns Hopkins. 
 
 
9.3.2.4. 
Shipping of Specimen(s) 
Serum samples will be shipped frozen according to Section 9.3.1.4. 
 
9.3.2.5. 
Site(s) Performing Correlative Study  
ETCTN Central Laboratory: Dr. Michelle Rudek, The Analytical Pharmacology Core Laboratory 
at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (SKCCC) 
 
 
9.4. Exploratory/Ancillary Correlative Studies 
 
9.4.1. 
DNA and RNA sequencing of exploratory biomarkers 
9.4.1.1. 
Collection of Specimen(s) 
Bone marrow biopsy and aspiration will be performed at screening and at the end of study at the 
local study site.  An optional bone marrow biopsy and aspiration will be performed pre-Cycle 2, 
Day 1.  Immediately after marrow is aspirated, place 3-5 mL of bone marrow aspirate into sterile 
EDTA (lavender top) tube. Mix well by inversion. Bone marrow aspirate specimen should be 
labeled as per the Specimen Tracking Instructions (Section 9.1.1.1.).  Buccal mucosa collection 
will also be performed at screening which will serve as a germline control for whole exome 
sequencing. See Appendix G for details regarding details of performing buccal swabs for the 
collection of buccal mucosa. 
 
 

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9.4.1.2. 
Handling and Processing of Specimens(s) 
After bone marrow aspirate collection, specimen will be processed at the MD Anderson Tissue 
Qualification Laboratory (TQL) where it will be logged into the PowerPath database.  
Subsequently, the MD Anderson Molecular Diagnostics Laboratory (MDL) will perform CD138 
bead enrichment from the bone marrow sample, followed by DNA and RNA extraction in a 
CLIA-certified environment.  The MD Anderson MDL will also perform DNA extraction from 
the buccal mucosal swab which will serve as a germline control.  The MD Anderson TQL and 
MDL will serve as a central site for myeloma tissue processing for the study. 
 
For study sites outside of MD Anderson, bone marrow aspirates should be kept at room 
temperature until same-day overnight shipping at ambient temperature to the MD Anderson TQL 
where it will logged prior to further processing.  Buccal swab should be sent in the same 
specimen container as the bone marrow aspirate to the MD Anderson TQL. 
 
The bone marrow aspirate tube, 3-5 unstained slides, and buccal swab should shipped to the 
following address: 
 
MD Anderson Department of Pathology 
Tissue Qualification Laboratory 
Unit 0085 
1515 Holcombe Blvd 
Room G1.3598, 
Houston, Texas 77030  
 
An email should be sent to the MD Anderson TQL at path-tql@mdanderson.org prior to sending 
the specimen alerting the laboratory that the specimen is being shipped.    
 
 
9.4.1.3. 
Shipping of Specimen(s) 
After tissue processing by the MD Anderson MDL, DNA and cDNA will be shipped according 
to the laboratory manual for shipping specimens from the MD Anderson TQL to the NCI MoCha 
laboratory.  Nucleic acids shipped to the MoCha laboratory should be labeled as per the 
Specimen Tracking Instructions (Section 9.1.1.1.). 
 
9.4.1.4. 
Site(s) Performing Correlative Study 
The NCI Molecular Characterization (MoCha) Laboratory. 
 
9.5. Optional biobanking of blood and marrow samples 
 
Optional biobanking will be available for blood and left-over bone marrow aspirate samples 
collected during the study for future analyses.  These samples may be used for further 
exploratory studies, which include genomic sequencing, based on emerging scientific knowledge 
to better understand the target disease, the effects of study treatment, and potential mediators of 
primary and acquired resistance to therapy.  Consent will be obtained per the ICF from subjects 
who wish to participate in optional sample biobanking.   
 

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For optional serum banking, approximately 10 mL of blood will be collected in a heparin (green 
top) tube to bank viably frozen peripheral blood mononuclear cells, and approximately 7 mL of 
blood will be collected in a red top tube for serum banking.  Blood specimens should be labeled 
as per the Specimen Tracking Instructions (Section 9.1.1.1.)  Collection of optional blood sample 
for biobanking will occur at screening outlined in the Study Calendar (Section 10.).   
 
For study sites outside of MD Anderson, blood samples for biobanking should be kept at room 
temperature until same-day overnight shipping at ambient temperature to MD Anderson in same 
shipping container as bone marrow aspirate tubes and unstained slides as described in Section 
9.1.1.2.  
 
9.6. Other studies:  Minimal Residual Disease Testing  
 
Minimal residual disease (MRD) testing will be assessed as per standard of care per the updated 
2016 IMWG response guidelines (Appendix F).   In this study, MRD will be assessed using the 
CLIA-certified clonoSEQ® (Adaptive Biotechnologies) VDJ NGS assay. 
 
In subjects achieving a biochemical complete response (CR) defined as a negative SPEP, UPEP, 
serum IFE, and urine IFE, a bone marrow biopsy and aspiration will be performed to confirm CR 
and to assess for MRD using the clonoSEQ® assay.  In subjects achieving MRD negativity, a 
bone marrow biopsy and aspirate may subsequently be performed every 12 months (+/- 30 days) 
to evaluate for sustained MRD per IMWG response criteria (see Appendix F).   
 
Sample Collection: 
Immediately after marrow is aspirated, place 2 mL of bone marrow aspirate into sterile 
EDTA (lavender top) tube. Mix well by inversion.  
 
Handling of Specimens(s) 
Specimens should be stored at ambient room temperature until same day overnight 
shipping. 
 
Shipping of Specimen(s). 
 
Bone marrow aspirate specimen for in EDTA tube should be shipped at ambient 
temperature overnight to the following address: 
 
MD Anderson Department of Pathology 
Tissue Qualification Laboratory 
Unit 0085 
1515 Holcombe Blvd 
Room G1.3598, 
Houston, Texas 77030  
 
Archived DNA from the subject’s myeloma cells that was banked from the pretreatment 
screening bone marrow aspiration as per Section 9.1.1.2. will also be sent concurrently to 

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A: KRT-232 (AMG 232), dose as assigned, Day 1 through D7  
B1: Carfilzomib 20 mg/m2 IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m2 IV on Days 
8, 9, 15, 16 of Cycle 1 and continuing on Days 1, 2, 8, 9, 15, 16 of Cycles 2 through Cycle 12 
B2: Carfilzomib 27 mg/m2 IV on Days 1, 2, 15, and 16  
C: Lenalidomide 25 mg PO on Days 1-21 
D: Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
 
a. Each cycle will last 28 days.  Cohort safety assessment for DLTs will be performed after Day 28 of Cycle 1. 
b. End-of-Treatment Visit will occur 30 (± 5) days after the last administration of KRT-232 (AMG 232).  If the 
subject begins another form of anticancer therapy before the end of the 30 (± 5)-day period, every effort will 
be made to complete all the End-of-Treatment assessments prior to commencing the new therapy.  If there is 
an abnormality in need of monitoring beyond the End-of-Treatment Visit, subjects will be followed until 
resolution or confirmed stability of the abnormality.  
c. A complete history & physical examination should be performed at screening.  Thereafter, only a symptom-
directed physical exam is required.  
d. CBC and serum chemistries for Cycle 1/Day 1 pre-dose can be collected within 48 hours before the first dose.  
e. CBC are collected pretreatment (within 48 hours) on Days 8 and 15 during Cycles 2-12 and Day 15 during 
Cycles 13-18.  
f. Serum chemistries: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, 
magnesium.   
g. Basic Metabolic Panel (bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, sodium) are 
collected pretreatment (within 48 hours) on Days 8 and 15 during Cycles 2-12 and Day 15 during Cycles 13-
18.  
h. Hepatitis panel will include HAV Ab, qualitative HBsAb, HBsAg, HBcAb, and HCV Ab 
i. 
Two negative pregnancy tests must be obtained prior to initiating therapy in female subjects of childbearing 
potential during the screening period. The first test should be performed within 10-14 days and the second 
test within 24 hours prior to initiating therapy and then weekly during the first month, then monthly thereafter 
in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles as per 
the lenalidomide Risk Evaluation and Mitigation Strategy (REMS) program. 
j. 
Myeloma laboratory assessment includes serum free light-chain assay, serum protein electrophoresis (and 
immunofixation if needed to confirm CR if no M-protein detected on electrophoresis), serum quantitative 
immunoglobulins (IgG, IgA, IgM), 24-hour urine protein electrophoresis (and immunofixation if needed to 
confirm CR if no M-protein detected on electrophoresis), and β2-microglobulin.  Initial pretreatment 
assessment can be collected within 1 week of first dose. 
k. Initial pretreatment/screening bone assessment requires bilateral biopsy and aspirates.  Can occur within 4 
weeks of first dose date.  Bone marrow analysis should include morphologic review, quantification of 
percentage of plasma cells, flow cytometry, and myeloma fluorescence in situ hybridization (FISH) panel 
(performed locally) as per standard of care.    
l. 
Optional bone marrow biopsy and aspiration for Cycle 2/Day 1 may be performed anytime from Cycle 1/Day 
24 to Cycle 2/Day 5.  Mandatory bone marrow biopsy and aspiration at EOT would be performed within 30 
days following the last study treatment, preferably prior to initiating new therapy.  In patients achieving a 
biochemical CR (negative SPEP/UPEP and urine/serum IFE), an additional bone marrow should be 
performed to confirm a CR with MRD testing using the clonoSEQ® NGS assay (Adaptive Biotechnologies) 
with minimum sensitivity to 10-5 nucleated cells.  In patients achieving MRD negativity, a bone marrow 
biopsy and aspirate may subsequently be performed every 12 months (+/- 30 days) to evaluate for sustained 
MRD. 
m. Blood samples for drug exposure measurement will be collected Cycle 1/Day 1 pre-dose and post-dose at 1 
hr, 3 hr, 5 hr, 8 hr, and 24 hr (C1D2).  

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Cycle 12 
B2: Carfilzomib 27 mg/m2 IV on Days 1, 2, 15, and 16  
C: Lenalidomide 25 mg PO on Days 1-21 
D: Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 
 
 
a. Each cycle will last 28 days.  Cohort safety assessment for DLTs will be performed after Day 28 of Cycle 1. 
b. End-of-Treatment Visit will occur 30 (± 5) days after the last administration of KRT-232 (AMG 232).  If the 
subject begins another form of anticancer therapy before the end of the 30 (± 5)-day period, every effort will 
be made to complete all the End-of-Treatment assessments prior to commencing the new therapy.  If there is 
an abnormality in need of monitoring beyond the End-of-Treatment Visit, subjects will be followed until 
resolution or confirmed stability of the abnormality.  
c. A complete history & physical examination should be performed at screening.  Thereafter, only a symptom-
directed physical exam is required.  
d. CBC and serum chemistries for Cycle 1/Day 1 pre-dose can be collected within 48 hours before the first dose.  
e. CBC are collected pretreatment (within 48 hours) on Days 8 and 15 during Cycles 2-12 and Day 15 during 
Cycles 13-18.  
f. Serum chemistries: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, 
magnesium. 
g. Basic Metabolic Panel (bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, sodium) are 
collected pretreatment (within 48 hours) on Days 8 and 15 during Cycles 2-12 and Day 15 during Cycles 13-
18. 
h. Hepatitis panel will include HAV Ab, qualitative HBsAb, HBsAg, HBcAb, and HCV Ab 
i. 
Two negative pregnancy tests must be obtained prior to initiating therapy in female subjects of childbearing 
potential during the screening period. The first test should be performed within 10-14 days and the second 
test within 24 hours prior to initiating therapy and then weekly during the first month, then monthly thereafter 
in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles as per 
the lenalidomide Risk Evaluation and Mitigation Strategy (REMS) program. 
j. 
Myeloma laboratory assessment includes serum free light-chain assay, serum protein electrophoresis (and 
immunofixation if needed to confirm CR if no M-protein detected on electrophoresis), serum quantitative 
immunoglobulins (IgG, IgA, IgM), 24-hour urine protein electrophoresis (and immunofixation if needed to 
confirm CR if no M-protein detected on electrophoresis), and β2-microglobulin.  Initial pretreatment 
assessment can be collected within 1 week of first dose. 
k. Initial pretreatment/screening bone assessment requires bilateral biopsy and aspirates.  Can occur within 4 
weeks of first dose date.  Bone marrow analysis should include morphologic review, quantification of 
percentage of plasma cells, flow cytometry, and myeloma fluorescence in situ hybridization (FISH) panel 
(performed locally) as per standard of care.    
l. 
Optional bone marrow biopsy and aspiration for Cycle 2/Day 1 may be performed anytime from Cycle 1/Day 
24 to Cycle 2/Day 5.  Mandatory bone marrow biopsy and aspiration at EOT would be performed within 30 
days following the last study treatment, preferably prior to initiating new therapy.  In patients achieving a 
biochemical CR (negative SPEP/UPEP and urine/serum IFE), an additional bone marrow should be 
performed to confirm a CR with MRD testing using the clonoSEQ® NGS assay (Adaptive Biotechnologies) 
with minimum sensitivity to 10-5 nucleated cells.  In patients achieving MRD negativity, a bone marrow 
biopsy and aspirate may subsequently be performed every 12 months (+/- 30 days) to evaluate for sustained 
MRD. 
m. Blood samples for drug exposure measurement will be collected Cycle 1/Day 1 pre-dose and post-dose at 1 
hr, 3 hr, 5 hr, 8 hr, and 24 hr (C1D2).  
n. Blood samples for MIC-1 testing will be collected at screening, Cycle 1/Day 1 pre-dose, and post-dose at 24 
hr (C1D2) 

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o. Blood samples for optional biobanking will be collected at screening.  Approximately 10 mL of blood will be 
collected in a heparin (green top) tube and approximately 7 mL of blood will be collected in a red top tube. 
p. One additional bony survey may be performed solely to confirm a CR, if this is indicated by serum and urine 
immunofixation assays.  
 
ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; MIC-1 = macrophage inhibitory cytokine-
1; TBD = to be determined. 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1. 
Multiple Myeloma Response Assessment 
Although the clinical benefit of KRT-232 (AMG 232) has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit in combination with KRd, and 
thus the subject will be carefully monitored for tumor response and symptom relief in addition to 
safety and tolerability.  Subjects with measurable disease will be assessed by standard criteria.  
Responses levels, including MRD-negative, sCR, CR, VGPR, PR, MR, SD, and progressive 
disease will be determined by the IMWG Uniform Response Criteria as per Appendix F (Kumar 
et al., 2016).   For the purposes of this study, subjects should be re-evaluated for response every 4 
weeks.  In addition to a baseline myeloma laboratory testing, confirmatory myeloma laboratory 
assessment will also be obtained within 4 weeks following initial documentation of an objective 
response. 
 
11.2. 
Other Response Parameters 
 
N/A 
 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
 
12.1. 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, subject-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal. 
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 

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or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems. 
 
All Study Investigators at participating sites who register/enroll subjects on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
 
12.2. 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. To access Rave via iMedidata: 
• Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM account, 
and 
• Assigned one of the following Rave roles on the relevant Lead Protocol Organization (LPO) or 
Participating Organization roster at the enrolling site: Rave CRA, Rave Read Only, Rave CRA 
(LabAdmin), Rave SLA, or Rave Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a minimum of an AP 
registration type, 
o To hold Rave Investigator role, the individual must be registered as an NPIVR or IVR, and 
o To hold Rave Read Only role, site staff must hold an Associates (A) registration type. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff will not be able 
to access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name. 
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website in the Rave section under the Rave resource materials (Medidata Account Activation and 

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Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 799-7580 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
 
Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm)  and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials), the recommended 
phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 

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unique study requirements.  The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation.  CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
The study data manager listed on the protocol face page is responsible for logging the TP53-wild 
type status confirmation report regardless of test result into the routine reporting system used by 
Theradex Oncology. This confirmed eligibility report must be sent by email to the submitting 
physicians/Principal Investigators/Clinical Trials Operations Offices per normal routine and kept 
on file by the coordinating site per normal routine for audit. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics. 
 
The DQP is located on the CTSU members’ website under Data Management. The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries. 
DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are available to access 
details and reports of unanswered queries, delinquent forms, and timeliness reports. Review the 
DQP modules on a regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link on 
the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, and DQP Delinquent Forms modules.’ 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on the 
DQP. A protocol must have the Calendar functionality implemented in Rave by the Lead 
Protocol Organization (LPO) for delinquent form details and reports to be available on the DQP. 
Site staff should contact the LPO Data Manager for their protocol regarding questions about 
Rave Calendaring functionality. 
 

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12.3. 
CTEP Multicenter Guidelines 
 
N/A 
 
12.4. 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be 
maintained as such by the investigators.  The protocol documents for studies utilizing Agents 
contain confidential information and should not be shared or distributed without the permission 
of the NCI.  If a copy of this protocol is requested by a subject or subject’s family member 
participating on the study, the individual should sign a confidentiality agreement.  A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and use 
of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and 

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unless additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the date of 
receipt for review.  Collaborator shall have the right to request that publication be delayed for up 
to an additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, 
in addition to Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts 
must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as 
possible and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings.  Press releases and other media 
presentations must also be forwarded to CTEP prior to release.  Copies of any manuscript, 
abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
12.5. 
Genomic Data Sharing Plan 
 
N/A 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1. 
Analysis Sets 
 
13.1.1. 
Enrolled Analysis Set 
The enrolled analysis set will include all subjects who signed an ICF and were enrolled in either 
the Dose Escalation part or Dose Expansion part of the study. 

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13.1.2. 
Full Analysis Set 
The full analysis set will include all subjects enrolled in the Dose Escalation part or the 
Dose Expansion part who received any amount of KRT-232 (AMG 232) and who had at least 1 
post-baseline disease assessment. 
 
13.1.3. 
Primary Analysis Set 
The primary analysis set will include all subjects in the full analysis set who were biomarker 
positive. 
 
13.1.4. 
Dose-Limiting Toxicity Evaluable Set 
The DLT-evaluable set will include all subjects enrolled in the Dose Escalation part who had a 
DLT within the first 4 weeks (28 days) on study, or without DLT but received at least 75% of 
scheduled KRT-232 (AMG 232) doses during the first 3 weeks (21 days).  Subjects who 
complete C1 but are removed from study due to a TP53 mutation and/or deletion are still eligible 
to be included in the DLT-evaluable set.   
 
13.1.5. 
Safety Analysis Set 
The safety analysis set will include all subjects enrolled who received any amount of KRT-232 
(AMG 232). Subjects will be summarized according to treatment actually received. 
 
Three groups of subjects will be identified within the safety analysis set: (1) subjects in the 
Dose Escalation part, (2) subjects in the Dose Expansion part, and (3) all subjects in the study. 
 
13.1.6. 
Pharmacokinetic Analysis Set 
The PK analysis set will include all subjects in the enrolled analysis set who received any amount 
of KRT-232 (AMG 232) and had measurable plasma concentrations of KRT-232 (AMG 232). 
 
13.1.7. 
Pharmacodynamic/Biomarker Analysis Set 
The biomarker analysis set will include all subjects in the enrolled analysis set who received any 
amount of KRT-232 (AMG 232) and who had the baseline assessment and where applicable, at 
least 1 post-baseline assessment for biomarkers. 
 
 
13.2. 
Study Design/Endpoints 
 
The primary endpoint is to assess the safety and tolerability of KRT-232 (AMG 232) + KRd in 
subjects with relapsed and/or refractory myeloma and to determine the MTD/tentative RP2D of 
KRT-232 (AMG 232) + KRd. 
 
All subjects who receive any amount of the study drug will be evaluable for toxicity.   The DLT-
evaluable period will be during cycle 1, although toxicity will be monitored throughout the 
course of treatment.   The primary analysis will occur after all subjects in Part B have either 
discontinued the study or completed at least 6 months of treatment. 
 

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13.2.1. 
Safety Analyses 
Safety parameters will include SAEs, TEAEs, physical examination findings (including ECOG 
performance status), vital sign measurements, and standard clinical laboratory parameters (serum 
chemistry, hematology, urinalysis). Adverse events will be graded according to the NCI-CTCAE 
v5.0.  In the Dose Escalation part, the incidence of DLTs will also be evaluated. 
 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics.  In the Dose Escalation part, the number of DLTs identified 
among the DLT-evaluable subjects in the DLT-evaluable set will be listed and summarized for 
each dose of KRT-232 (AMG 232). 
 
13.2.2. 
 Adverse Event Analyses 
A TEAE is defined as an adverse event that emerges during the treatment period (from first dose 
date till 30 (± 5) days after the last dosing date), having been absent at pre-treatment; or 
reemerges during treatment, having been present at baseline but stopped prior to treatment; or 
worsens in severity after starting treatment relative to the pre-treatment state, when the adverse 
event is continuous.  The number and percentage of subjects reporting TEAEs will be tabulated 
by the worst NCI- CTCAE grade, system organ class (SOC), and preferred term. 
 
Similarly, the number and percentage of subjects reporting treatment-emergent SAEs will be 
tabulated, as well as TEAEs/SAEs considered related to KRT-232 (AMG 232) + KRd. 
 
A by-subject adverse event (including TEAE) data listing will be provided including, but not 
limited to, verbatim term, preferred term, SOC, NCI-CTCAE grade, and relationship to study 
drug. 
 
Deaths, other SAEs, and other significant adverse events, including those leading to permanent 
discontinuation from KRT-232 (AMG 232) + KRd, will be listed. 
 
13.2.3. 
 Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for selected clinical laboratory test results (hematology and 
blood chemistry) and changes from baseline by scheduled time of evaluation, including the End-
of-Treatment Visit, maximum post-treatment value, and minimum post-treatment value. 
 
Abnormal laboratory results will be graded according to NCI-CTCAE, v5.0, if applicable. A shift 
table, presenting the 2-way frequency tabulation for baseline and the worst post-treatment value 
according to the NCI-CTCAE grade, will be provided for selected clinical laboratory tests.  
Abnormal clinical laboratory test results that are deemed of clinical significance or of grade 3 or 
4 will be listed. 
 
13.2.4. 
Vital Signs Analyses 
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation, including the End-of-Treatment Visit and the 
maximum and minimum post-treatment values.  
 
 

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disease (MRD) negative, stringent complete response (sCR), complete response (CR), very good 
partial response (VGPR), and partial response (PR), minimal response (MR) and stable disease 
(SD) per IMWG Uniform Response criteria. In addition, overall response rate (defined as greater 
than or equal to PR across all cycles of treatment), response duration, time-to-response (TTR), 
PFS, and OS will be assessed. 
 
Best overall response categories will be tabulated by dose cohort and overall for the IMWG 
categories of MRD-negative, sCR, CR, VGPR, PR, MR, SD, progressive disease.  A two-sided 
95% exact binominal CI will be calculated for each category.  The myeloma response rate 
(responses ≥PR) will also be tabulated by dose cohort and overall. Time-to-event analyses will 
be done using Kaplan-Meier analyses and will include time to response, duration of response, 
progression-free survival (PFS), and overall survival (OS), as data allow. If there is not enough 
data to apply the Kaplan-Meier test, the data will be summarized by descriptive statistics. 
 
Time to response (for responders only) will be calculated as the time from the date of first study 
treatment dosing to the first date of documented response (PR or better) based on IMWG uniform 
response criteria.  Time to response will be summarized by descriptive statistics by dose cohorts. 
 
Duration of response (for responders only) is defined as the time from the earliest date of 
documented response (PR or better, based on IMWG uniform response criteria) to the earliest 
date when disease progression was confirmed. Subjects who are non-responders will be excluded 
from this analysis. Detailed censoring rules for duration of response will be specified in the SAP. 
 
PFS will be calculated as the time from the time of enrollment until documented disease 
progression, as determined by the Investigator using IMWG uniform response criteria, or death 
from any cause, whichever occurs first. Kaplan-Meier methods will be used to estimate PFS over 
time and the median duration of PFS. Subjects with no PFS event will be censored at the date of 
their last myeloma disease assessment. 
 
OS is defined as the time from the initial administration of KRT-232 (AMG 232) + KRd to death 
form 
any cause. Kaplan-Meier methods will be used to estimate the OS function. Subjects who do not 
die will be censored at the date that the subject was last known to be alive. 
 
 
 
13.7. 
Analysis of Exploratory Endpoint 
 
Exploratory analyses of RNA expression levels of relevant genes in the TP53 pathway that may 
predict response to therapy will be performed on pre- and post-treatment bone marrow biopsies.  
An optional post-treatment bone marrow biopsy will be pre Cycle 2 Day 1.  An estimated 75% of 
subjects are expected to consent to this optional post-treatment bone marrow biopsy; thus we 
expect 19-30 of the planned 25-40 subjects to provide an additional biopsy.  These exploratory 
analyses will potentially guide future studies with larger cohorts of patients.   
 
 
 

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14. REFERENCES 
 
Canon, J., T. Osgood, S.H. Olson, et al.  (2015).  The MDM2 Inhibitor KRT-232 (AMG 232) 
Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic 
Agents.  Mol Cancer Ther.  14:649-658. 
 
Investigator’s Brochure (2015).  KRT-232 (AMG 232).  Amgen, Inc.  Edition 4.0 (December 8, 
2015) 
 
Rew, Y., and D. Sun.  (2014).  Discovery of a small molecule MDM2 inhibitor (KRT-232 (AMG 
232)) for treating cancer.  J Med Chem.  57:6332-6341. 
 
Sun, D., Z. Li, Y. Rew, et al.  (2014).  Discovery of KRT-232 (AMG 232), a potent, selective, 
and orally bioavailable MDM2-p53 inhibitor in clinical development.  J Med Chem.  57:1454-
1472. 
 
Vazquez, A., E.E. Bond, A.J. Levine, and G.L. Bond.  (2008).  The genetics of the p53 pathway, 
apoptosis and cancer therapy.  Nat Rev Drug Discov.  7:979-987. 
 
Ye, Q., M. Jiang, W.T. Huang, et al.  (2015).  Pharmacokinetics and metabolism of KRT-232 
(AMG 232), a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and 
monkeys: in vitro-in vivo correlation.  Xenobiotica.  45:681-692. 
 
Amgen Inc. (2015). KRT-232 (AMG 232) Investigators Brochure  
 
Andreeff, M., Kelly, K.R., Yee, K., Assouline, S., Strair, R., Popplewell, L., Bowen, D., 
Martinelli, G., Drummond, M.W., Vyas, P., et al. (2016). Results of the Phase I Trial of 
RG7112, a Small-Molecule MDM2 Antagonist in Leukemia. Clin Cancer Res 22, 868-876. 
 
Dimopoulos, M.A., Moreau, P., Palumbo, A., Chng, W.J., and Feng, S. (2016). Carfilozomib 
versus bortezomib for relapsed or refractory myeloma - Authors' reply. Lancet Oncol 17, e126. 
 
Gu, D., Wang, S., Kuiatse, I., Wang, H., He, J., Dai, Y., Jones, R.J., Bjorklund, C.C., Yang, J., 
Grant, S., et al. (2014). Inhibition of the MDM2 E3 Ligase induces apoptosis and autophagy in 
wild-type and mutant p53 models of multiple myeloma, and acts synergistically with ABT-737. 
PloS one 9, e103015. 
 
Jakubowiak, A.J., Dytfeld, D., Griffith, K.A., Lebovic, D., Vesole, D.H., Jagannath, S., Al-
Zoubi, A., Anderson, T., Nordgren, B., Detweiler-Short, K., et al. (2012). A phase 1/2 study of 
carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline 
treatment for multiple myeloma. Blood 120, 1801-1809. 
 
Kumar, S., Paiva, B., Anderson, K.C., Durie, B., Landgren, O., Moreau, P., Munshi, N., Lonial, 
S., Blade, J., Mateos, M.V., et al. (2016). International Myeloma Working Group consensus 
criteria for response and minimal residual disease assessment in multiple myeloma. Lancet 
Oncol 17, e328-346. 

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Kumar, S.K., Rajkumar, S.V., Dispenzieri, A., Lacy, M.Q., Hayman, S.R., Buadi, F.K., 
Zeldenrust, S.R., Dingli, D., Russell, S.J., Lust, J.A., et al. (2008). Improved survival in multiple 
myeloma and the impact of novel therapies. Blood 111, 2516-2520. 
 
Lohr, J.G., Stojanov, P., Carter, S.L., Cruz-Gordillo, P., Lawrence, M.S., Auclair, D., Sougnez, 
C., Knoechel, B., Gould, J., Saksena, G., et al. (2014). Widespread genetic heterogeneity in 
multiple myeloma: implications for targeted therapy. Cancer cell 25, 91-101. 
 
Lonial, S., Dimopoulos, M., Palumbo, A., White, D., Grosicki, S., Spicka, I., Walter-Croneck, 
A., Moreau, P., Mateos, M.V., Magen, H., et al. (2015). Elotuzumab Therapy for Relapsed or 
Refractory Multiple Myeloma. N Engl J Med 373, 621-631. 
 
Moreau, P., Masszi, T., Grzasko, N., Bahlis, N.J., Hansson, M., Pour, L., Sandhu, I., Ganly, P., 
Baker, B.W., Jackson, S.R., et al. (2016). Oral Ixazomib, Lenalidomide, and Dexamethasone for 
Multiple Myeloma. N Engl J Med 374, 1621-1634. 
 
Mulligan, G., Lichter, D.I., Di Bacco, A., Blakemore, S.J., Berger, A., Koenig, E., Bernard, H., 
Trepicchio, W., Li, B., Neuwirth, R., et al. (2014). Mutation of NRAS but not KRAS 
significantly reduces myeloma sensitivity to single-agent bortezomib therapy. Blood 123, 632-
639. 
 
Niesvizky, R., Martin, T.G., 3rd, Bensinger, W.I., Alsina, M., Siegel, D.S., Kunkel, L.A., Wong, 
A.F., Lee, S., Orlowski, R.Z., and Wang, M. (2013). Phase Ib dose-escalation study (PX-171-
006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive 
multiple myeloma. Clin Cancer Res 19, 2248-2256. 
 
Rajkumar, S.V., Jacobus, S., Callander, N.S., Fonseca, R., Vesole, D.H., Williams, M.E., 
Abonour, R., Siegel, D.S., Katz, M., Greipp, P.R., et al. (2010). Lenalidomide plus high-dose 
dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly 
diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 11, 29-37. 
 
Ray-Coquard, I., Blay, J.Y., Italiano, A., Le Cesne, A., Penel, N., Zhi, J., Heil, F., Rueger, R., 
Graves, B., Ding, M., et al. (2012). Effect of the MDM2 antagonist RG7112 on the P53 pathway 
in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an 
exploratory proof-of-mechanism study. Lancet Oncol 13, 1133-1140. 
 
Shangary, S., and Wang, S. (2008). Targeting the MDM2-p53 interaction for cancer therapy. 
Clin Cancer Res 14, 5318-5324. 
 
Siegel, D.S., Martin, T., Wang, M., Vij, R., Jakubowiak, A.J., Lonial, S., Trudel, S., Kukreti, V., 
Bahlis, N., Alsina, M., et al. (2012). A phase 2 study of single-agent carfilzomib (PX-171-003-
A1) in patients with relapsed and refractory multiple myeloma. Blood 120, 2817-2825. 
Stewart, A.K. (2015). Carfilzomib for the treatment of patients with relapsed and/or refractory 
multiple myeloma. Future Oncol 11, 2121-2136. 
 

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Stewart, A.K., Rajkumar, S.V., Dimopoulos, M.A., Masszi, T., Spicka, I., Oriol, A., Hajek, R., 
Rosinol, L., Siegel, D.S., Mihaylov, G.G., et al. (2015). Carfilzomib, lenalidomide, and 
dexamethasone for relapsed multiple myeloma. N Engl J Med 372, 142-152. 
Teoh, P.J., Chung, T.H., Sebastian, S., Choo, S.N., Yan, J., Ng, S.B., Fonseca, R., and Chng, 
W.J. (2014). p53 haploinsufficiency and functional abnormalities in multiple myeloma. 
Leukemia 28, 2066-2074. 
 
Wade, M., Li, Y.C., and Wahl, G.M. (2013). MDM2, MDMX and p53 in oncogenesis and 
cancer therapy. Nature reviews Cancer 13, 83-96. 
 
Walker, B.A., Boyle, E.M., Wardell, C.P., Murison, A., Begum, D.B., Dahir, N.M., Proszek, 
P.Z., Johnson, D.C., Kaiser, M.F., Melchor, L., et al. (2015). Mutational Spectrum, Copy 
Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly 
Diagnosed Myeloma. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 33, 3911-3920. 
 
Wang, M., Martin, T., Bensinger, W., Alsina, M., Siegel, D.S., Kavalerchik, E., Huang, M., 
Orlowski, R.Z., and Niesvizky, R. (2013). Phase 2 dose-expansion study (PX-171-006) of 
carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple 
myeloma. Blood 122, 3122-3128. 
 
Weber, D.M., Chen, C., Niesvizky, R., Wang, M., Belch, A., Stadtmauer, E.A., Siegel, D., 
Borrello, I., Rajkumar, S.V., Chanan-Khan, A.A., et al. (2007). Lenalidomide plus 
dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357, 2133-2142. 
 
Yang, H., Filipovic, Z., Brown, D., Breit, S.N., and Vassilev, L.T. (2003). Macrophage 
inhibitory cytokine-1: a novel biomarker for p53 pathway activation. Mol Cancer Ther 2, 1023-
1029. 
 
 
 

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15. APPENDICES 
 
15.1. 
APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed < 50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed > 50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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15.2. 
APPENDIX B: PATIENT DRUG INTERACTIONS HANDOUT AND 
WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis:  
      
Trial #: 
      
Study 
Doctor: 
      
Study 
Doctor 
Phone #:  
      
Study 
Drug(s): 
AMG 232      (KRT 
232) 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse 
practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the 
National Cancer Institute.  
 
These are the things that your healthcare providers need to know: 
 
AMG 232 (KRT 232) interacts with certain specific liver enzymes and certain transport proteins 
that help move drugs in and out of cells.  
 
 
Explanation 
CYP 
Isoenzymes  
The enzymes in question are CYP3A4 and CYP2C8. AMG 232 (KRT 232) is 
a moderate inhibitor of CYP3A4 and CYP2C8 and also induces CYP3A4 and 
may effect other drugs that are metabolized by these enzymes. KRT-232 has 
the potential to cause a minor drug-drug interaction (DDI) with drugs cleared 
predominantly by CYP3A4 (inhibition and induction). Use caution in patients 
taking CYP3A4 substrates with narrow therapeutic ranges. 
 
Glucuronidation 
 
 
 
 
AMG 232 (KRT 232) is metabolized by UGT1A1, UGT1A3, and UGT1A4 and 
is a moderate inhibitor of UGT1A1. AMG 232 (KRT 232) may be affected by 
other drugs that inhibit or induce these enzymes and may affect other drugs 
that are metabolized by UGT1A1.  
  
Transport 
Proteins 
The protein in question is P-gp.  AMG 232 (KRT 232) is a substrate of P-gp and 
may be affected by other drugs that inhibit or induce this transport protein. 
 
These are the things that you need to know: 
 
The study drug AMG 232 (KRT 232), may interact with other drugs which can cause side effects. 
For this reason, it is very important to tell your doctors about all your medicines, including: (a) 
medicines you are taking before this clinical trial, (b) medicines you start or stop taking during this 
clinical trial, (c) medicines you buy without a prescription (over-the-counter remedy), (d) herbals 

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or supplements (e.g. St. John’s Wort). It is helpful to bring your medication bottles or an updated 
medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care 
providers to review any medicines and herbal supplements that are considered substrates of 
CYP3A4 and CYP2C8 or inhibitors or inducers of transport protein P-gp. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist 
to determine if there could be any side effects.  
   
• Make sure your doctor knows to avoid certain prescription medicines.  
o Avoid any medicines considered substrates of CYP3A4 and CYP2C8. 
o Avoid any medicines considered inhibitors or inducers of P-gp. 
o Avoid any medications considered inhibitors or substrates of UGT1A1. 
 
 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.   
 
 
 
Version: November 2021 
 
(Next page: Patient Drug Interaction Wallet Card) 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

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15.4. 
APPENDIX C: Drug-Induced Liver Injury (DILI) Reporting & Additional 
Assessments 
 
Reporting 
 
To facilitate appropriate monitoring for signals of drug-induced liver injury (DILI), cases of 
concurrent AST or ALT and TBL and/or INR elevation according to the criteria specified in 
Section 6.1 require the following: 
 
The event is to be reported to CTEP as a serious adverse event within 24 hours of discovery or 
notification of the event (i.e., before additional etiologic investigations have been concluded) 
The appropriate CRF (e.g., Adverse Event CRF) that captures information necessary to facilitate 
the evaluation of treatment-emergent liver abnormalities is to be completed and sent to CTEP. 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse events if 
they meet the criteria for a serious adverse event defined in Section 7. 
 
Additional Clinical Assessments and Observation 
 
All subjects in whom investigational product(s) or protocol-required therapies is/are withheld 
(either permanently or conditionally) due to potential DILI as specified in Section 6.1 or who 
experience AST or ALT elevations ≥ 3 × ULN are to undergo a period of “close observation” 
until abnormalities return to normal or to the subject’s baseline levels. Assessments that are to be 
performed during this period include: 
 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours 
In cases of TBL > 2 × ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), and INR 
is to be performed every 24 hours until laboratory abnormalities improve. 
 
Testing frequency of the above laboratory tests may decrease if the abnormalities stabilize or the 
investigational product(s) or protocol-required therapies has/have been discontinued AND the 
subject is asymptomatic. 
 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL: 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti Smooth Muscle 
Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for autoimmune hepatitis 
Obtain serum acetaminophen (paracetamol) levels 
Obtain a more detailed history of: 
Prior and/or concurrent diseases or illness 
Exposure to environmental and/or industrial chemical agents 
Symptoms (if applicable) including right upper quadrant pain, hypersensitivity-type reactions, 
fatigue, nausea, vomiting and fever 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
Concomitant use of medications (including non-prescription medicines and herbal and dietary 
supplements), plants, and mushrooms 
Obtain viral serologies 

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Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
Perform appropriate liver imaging if clinically indicated 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
Obtain hepatology consult (liver biopsy may be considered in consultation with an hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal. The “close observation period” is to continue for a 
minimum of 4 weeks after discontinuation of all investigational product(s) and protocol-required 
therapies. 
 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
 
 

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15.6. 
APPENDIX E: MEDICATION DIARY 
DOSING DIARY: KRT-232 (AMG 232) + Carfilzomib, Lenalidomide, and Dexamethasone 
 
Subject Identification Number _____________            
Subject Initials _______ 
 
Investigator _____________________             
 
Cycle ________ 
 
Subject Completion Instructions 
This is a “diary” that you will use to keep track of when you take your oral study medications including KRT-232 (AMG 
232), lenalidomide, and dexamethasone. 
 
Please avoid food for 2 hours before and 2 hours after KRT-232 (AMG 232) study drug administration.  KRT-232 
(AMG 232) should be taken with a full glass (240 mL) of water.  Lenalidomide and dexamethasone study drugs may 
be taken with or without food. 
 
It is important that you fill out this diary every day once you take your study medications. Record the date and if 
tablet(s) was taken for that day.  If Yes, record the time tablet(s) was taken in the next column.  
You must bring this diary and all unused medication to the clinic at each visit. Therefore, it is important that you keep 
them in a safe place where they will not be lost. 
If you have any questions about your treatment, or in case of overdose, contact your study doctor at the number 
below: 
 
_______________________________ 
 
______________________________ 
Investigator  
 
 
 
 
Phone Number 
 
Your assigned daily dose of KRT-232 (AMG 232) on Days 1 through Day 7 is ______ mg. 
____ 15 mg tablet     
____ 60 mg tablet 
  
 
 
What if I miss a dose of KRT-232 (AMG 232)? 
 
If you forget a dose of KRT-232 (AMG 232) and it has been less than 12 hours since your regular time, take 
 
it as soon as you remember.  Otherwise, skip the missed dose. Do not take a double dose (two doses at the 
 
same time) to make up for a forgotten dose. If you vomit after taking a dose, do not repeat the dose, and you 
 
should resume dosing at the time of your next scheduled dose. 
 
Your assigned daily dose of Lenalidomide on Days 1 through Day 21 is ______ mg. 
____ 5 mg capsule    
____ 10 mg capsule 
____ 15 mg capsule    
____ 25 mg capsule 
 
 
What if I miss a dose of lenalidomide? 
 
f you forget a dose of lenalidomide and it has been less than 12 hours since your regular time, take it as 
 
soon as you remember. Otherwise, skip the missed dose. Do not take a double dose (two doses at the same 
 
time) to make up for a forgotten dose. If you vomit after taking a dose, do not repeat the dose, and you 
 
should resume dosing at the time of your next scheduled dose. 
 
Your assigned daily dose of oral Dexamethasone on Days 1, 8, and 15 is ______ mg.   If you are receiving 
dexamethasone intravenously on these days with carfilzomib, you will be instructed to not take oral 
dexamethasone doses on these days. 
____ 4 mg tablet    
 
Your assigned daily dose of oral Dexamethasone on Day 22 is ______ mg.    
____ 4 mg tablet   
  
 
What if I miss a dose of dexamethasone? 
 
If you forget a dose of dexamethasone, take it as soon as you remember it as long as your next scheduled 
 
dose is at least 72 hours away. Otherwise, skip the missed dose. Do not take a double dose (two doses at 
 
the same time) to make up for a forgotten dose. If you vomit after taking a dose, do not repeat the dose, and 
 
you should resume dosing at the time of your next scheduled dose. 
 
Please take the specified number of tablets or capsules recorded below each study drug. 
 

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15.7. 
APPENDIX F: IMWG Response Criteria (Kumar et al., 2016) 
 
IMWG MRD criteria (requires a complete response as defined below)  
Sustained MRD-negative  
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined 
below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to 
further specify the duration of negativity (eg, MRD-negative at 5 years)  
Flow MRD-negative  
Absence of phenotypically aberrant clonal plasma cells by next generation flow (NGF) 
on bone marrow aspirates using the EuroFlow standard operation procedure for MRD 
detection in multiple myeloma (or validated equivalent method) with a minimum 
sensitivity of 1 in 105 nucleated cells or higher  
Sequencing MRD-
negative  
Absence of clonal plasma cells by next generation sequencing (NGS) on bone marrow 
aspirate in which presence of a clone is defined as less than two identical sequencing 
reads obtained after DNA sequencing of bone marrow aspirates using the 
LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 
1 in 105 nucleated cells or higher  
Imaging plus MRD-
negative  
MRD negativity as defined by NGF or NGS plus disappearance of every area of 
increased tracer uptake found at baseline or a preceding PET/CT or decrease to less 
mediastinal blood pool SUV or decrease to less than that of surrounding normal tissue  
Standard IMWG response criteria  
Stringent complete 
response  
Complete response as defined below plus normal FLC ratio and absence of clonal cells 
in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ 
patients, respectively, after counting ≥100 plasma cells)  
Complete response  
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and <5% plasma cells in bone marrow aspirates  
Very good partial 
response  
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 
≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 h  
Partial response  
≥50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by ≥90% 
or to <200 mg per 24 h; 
If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein 
criteria; 
If serum and urine M-protein are unmeasurable, and serum-free light assay is also 
unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to these 
criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue 
plasmacytomas is also required  
Minimal response  
≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 
50–89%. In addition to the above listed criteria, if present at baseline, a ≥50% reduction 
in the size (SPD) of soft tissue plasmacytomas is also required  
Stable disease  
Not meeting criteria for complete response, very good partial response, partial response, 
minimal response, or progressive disease  
Progressive disease 
Any one or more of the following criteria: 
Increase of 25% from lowest confirmed response value in one or more of the following 
criteria: 
Serum M-protein (absolute increase must be ≥0.5 g/dL); 
Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL; 
Urine M-protein (absolute increase must be ≥200 mg/24 h); 
In patients without measurable serum and urine M-protein levels, the difference between 
involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); In patients 
without measurable serum and urine M-protein levels and without measurable involved 
FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute 
increase must be ≥10%); 
Appearance of a new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or ≥50% 

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increase in the longest diameter of a previous lesion >1 cm in short axis; ≥50% increase 
in circulating plasma cells (minimum of 200 cells per μL) if this is the only measure of 
disease  
Clinical relapse  
Clinical relapse requires one or more of the following criteria: 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) 
related to the underlying clonal plasma-cell proliferative disorder. It is not used in 
calculation of time to progression or progression-free survival but is listed as something 
that can be reported optionally or for use in clinical practice; Development of new soft 
tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute 
progression); 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPD§§ of 
the measurable lesion; 
Hypercalcemia (>11 mg/dL); 
Decrease in hemoglobin of ≥2 g/dL not related to therapy or other non-myeloma-related 
conditions; 
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and 
attributable to myeloma; 
Hyperviscosity related to serum paraprotein  
Relapse from complete 
response (to be used only 
if the end point is 
disease-free survival)  
Any one or more of the following criteria: 
Reappearance of serum or urine M-protein by immunofixation or electrophoresis; 
Development of ≥5% plasma cells in the bone marrow; 
Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or 
hypercalcemia see above)  
Relapse from MRD 
negative (to be used only 
if the end point is 
disease-free survival)  
Any one or more of the following criteria: 
Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or 
positive imaging study for recurrence of myeloma); Reappearance of serum or urine M-
protein by immunofixation or electrophoresis; 
Development of ≥5% clonal plasma cells in the bone marrow; 
Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or 
hypercalcemia)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15.8. 
 APPENDIX G: COLLECTION OF BUCCAL SWAB AT SCREENING  
 
Materials: 

NCI Protocol #: 10076  
Version Date: 01/15/2024 
 
 
 
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IsoHelix SK-1S DNA Swab: 1 buccal swab with one 5ml tube and cap 
 
Patient Preparation 
 
Patient should not eat, drink, smoke, chew gum or brush teeth for 1 hour prior to buccal 
collection. 
 
Specimen Labeling and Identification 
 
• Specimen should be labeled as per the Specimen Tracking Instructions (Section 
9.1.1.1.) 
 
Collection of Buccal cells: 
 
Note:  The collector should wear gloves to prevent any DNA contamination. 
 
1) Check the seal of the buccal swab to make sure it has not been broken. 
2) Check the expiration date (if on the swab) to ensure it’s not expired. 
3) Thoroughly rinse out the patient’s mouth twice with water. 
4) Open pouch from end opposite swab, and use care not to touch swab. 
5) Collect tissue by rubbing the swab firmly on the inside of both cheeks, 
approximately 30 seconds on each side, making certain to move the brush over the 
entire cheek. 
6) Place head of swab into collection tube and snap off handle, leaving swab in tube. 
7) Carefully place the cap on the tube. 
8) Be sure to double check the patient identifiers. 
Specimen Shipping and Delivery  
 
Non-MDACC study sites will ship buccal swabs in the same specimen container as the 
bone marrow aspirate to the MD Anderson TQL.   
 
DNA will be extracted by the MD Anderson Molecular Diagnostics Laboratory (MDL) 
and shipped to the NCI MoCha laboratory for DNA sequencing. 
 
Please refer to Section 9.1.1.2 and 9.1.1.3 in the protocol for additional details.   
 
 
Unacceptable Specimens: 
 
1.  Unlabeled or mislabeled specimens. 
2.  Any buccal swab that has been subjected to possible DNA contamination  
3.  Any buccal swab that has been subjected to UV light. 
 

NCI Protocol #: 10076  
Version Date: 01/15/2024 
 
 
 
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