Conditions: DLBCL Richter Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
This study evaluates the safety of acalabrutinib and vistusertib when taken in combination.

Detailed description:

Arms:
arm 1: acalabrutinib daily + vistusertib daily arm 2: acalabrutinib daily + vistusertib 5 days on and 2 days off

Interventions: intervention 1: acalabrutinib intervention 2: vistusertib
Intervention descriptions: intervention 1: Acalabrutinib is a selective, irreversible small molecule Bruton's tyrosine kinase (BTK) inhibitor. intervention 2: Vistusertib is an inhibitor of mechanistic target of rapamycin (mTOR) kinase

Protocol document:
Prot_000.pdf: 
 
Product: Acalabrutinib and vistusertib 
Protocol: ACE-LY-110 
 
 
 
Acerta Pharma 
Confidential 
Page 1 of 159 
 
 
PROTOCOL 
TITLE: 
A Phase 1/2 Proof-of-Concept Study of the Combination 
of Acalabrutinib and Vistusertib in Subjects with 
Relapsed/Refractory B-Cell Malignancies 
PROTOCOL NUMBER: 
ACE-LY-110 
STUDY DRUGS: 
Acalabrutinib (ACP-196) and vistusertib (AZD2014) 
IND NUMBER: 
133812 
EUDRACT NUMBER: 
2016-003736-21 
SPONSOR MEDICAL 
MONITOR: 
 
 
 
 
SPONSOR: 
Acerta Pharma BV 
Kloosterstraat 9 
5349 AB Oss 
The Netherlands 
ORIGINAL PROTOCOL: 
Version 0.0 – 02 February 2017 
AMENDMENT 1: 
Version 1.0 – 26 March 2017 
AMENDMENT 2: 
Version 2.0 – 06 February 2018 
AMENDMENT 3: 
Version 3.0 – 29 March 2019 
 
 
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV that 
must not be disclosed to anyone other than the recipient study staff and members of the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Acerta Pharma BV. 
  
PPD


 
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Protocol: ACE-LY-110 
 
 
 
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Page 2 of 159 
 
PROTOCOL APPROVAL PAGE 
I have carefully read Protocol ACE-LY-110 entitled “A Phase 1/2 Proof-of-Concept Study 
of the Combination of Acalabrutinib and Vistusertib in Subjects with Relapsed/Refractory 
B-cell Malignancies”.  I agree to conduct this study as outlined herein and in compliance 
with Good Clinical Practices (GCP) and all applicable regulatory requirements.  
Furthermore, I understand that the sponsor, Acerta Pharma, and the IRB/IEC must 
approve any changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or 
methods of Acerta Pharma.  All data pertaining to this study will be provided to Acerta 
Pharma.  The policy of Acerta Pharma requires that any presentation or publication of 
study data by clinical investigators be reviewed by Acerta Pharma, before release, as 
specified in the protocol. 
 
Principal Investigator’s Signature 
Date 
 
 
Print Name 
 
 


 
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SUMMARY OF AMENDMENT 3 
The primary reason for amending the study protocol is to provide information about the 
closure of the study before initiation of Part 2 and to allow subjects who are deriving 
clinical benefit to remain on study treatment.  On 21 May 2018, a decision was made by 
the sponsor to stop enrollment and close this study after evaluating the safety, efficacy, 
pharmacokinetics (PK), and pharmacodynamics (PD) of acalabrutinib in combination 
with vistusertib at Dose Level -1 and Dose Level 0.  In general, the acalabrutinib and 
vistusertib (an mTOR1 and mTOR2 dual inhibitor) combination was well tolerated in 
subjects with relapsed/refractory diffuse large B-cell lymphoma enrolled in Dose Level -1 
and Dose Level 0.  However, modest clinical efficacy was observed at both dose levels.  
 
 
  PK modeling indicated 
that increasing dose levels and/or changing dosing schedules would not improve target 
engagement.  A total of 25 subjects have enrolled in the study; 23 subjects have been 
treated and are no longer participating in the study.  The protocol is being amended to 
allow 2 subjects who are still receiving study treatment and deriving clinical benefit to 
remain on study treatment beyond the first 12 cycles and until disease progression. 
The schedule of the computed tomography scans was changed from occurring every 
8 weeks to every 12 weeks.  The frequency of follow-up visits was changed from every 
4 weeks to every 12 weeks.  Updates were made to the appendix that provides 
investigators with information to identify and report cases of severe liver toxicity 
(Potential Hy’s law and Hy’s law cases), for consistency across the sponsor’s clinical 
development program.  Changes have been made to the inclusion criteria, reproductive 
toxicity section, and pregnancy section to align with the Clinical Trial Facilitation Group 
recommendations related to contraception and pregnancy testing in clinical studies and 
for consistency across the sponsor’s clinical development program. 
Minor clarification edits and typographical corrections have been made throughout the 
protocol and are not highlighted below.  The following substantive changes or edits were 
made as part of this amendment: 
CCI


 
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Change 
Rationale 
Synopsis 
Updated to reflect changes made throughout the protocol. 
To ensure 
consistency between 
the body of the 
protocol and the 
synopsis 
Section 1.1 Acalabrutinib (ACP-196) 
Revised text as shown (bold indicates new text): 
 
Acalabrutinib (CALQUENCE®) was recentlyhas been approved in the 
United States and other markets for the treatment of adult patients with 
MCL who have hadreceived at least 1 prior therapy (CALQUENCE 
package insert).   
To provide updated 
information about 
acalabrutinib 
approvals 
Section 3.0 STUDY DESIGN 
Revised text as shown (bold indicates new text): 
 
This study is a multicenter, open-label, randomized (Part 1 only) parallel 
group study to be conducted at approximately 15 to 20 sites.  The study 
iswas originally designed to be divided into 2 parts. The Phase 1 
portion of the study (Part 1) evaluateds the safety, PK, and PD of 
combining acalabrutinib 100 mg twice a day (bid) and vistusertib (various 
doses and schedules).  Part 1 willwas to be used to select the vistusertib 
dose and schedule for Phase 2.  The Phase 2 portion of the study (Part 
2) allowswas to allow for expansion groups in select B-cell histologies to 
further evaluate safety, efficacy, and PKPD of the combination treatment; 
however, the sponsor has decided to close the study prior to 
initiating Part 2. 
… 
Part 1 will enroll approximately 12 to 36 subjects depending on safety.  
The safety results (eg, DLTs, discontinuation due to adverse events and 
tolerability) of Part 1 willwere to be used to select the vistusertib 
dose/schedule for Part 2.  Any DLTs attributed to the combination after 
cycle 1 willwere also to be taken into consideration when determining the 
vistusertib dose and schedule for Part 2.  Enrollment into Part 2 will 
proceed if a dose and schedule has been successfully selected for 
vistusertib from Part 1. 
Enrollment into Dose Level 1 and beyond (Part 2) was discontinued 
by the sponsor.  The primary reason for discontinuation of Part 2 
was that inhibition of the Torc-2 protein, which is a target of 
vistusertib, was not adequate as determined by PD studies.  In 
addition, PK data from subjects at vistusertib Dose Level 0 
suggested that increasing the dose to Level 1 would only increase 
exposure by approximately 20%, which is not expected to provide 
sufficient Torc-2 coverage to differentiate from approved Torc-1 
inhibitors and could increase risk for toxicity. 
 
Part 2 
Part 2 was designed to consists of expansion groups of 15 or 20 
subjects per histology (N≤35 total for Part 2) provided the safety results 
from Part 1 of the study indicated that further evaluation of the 
combination iswas warranted.  As mentioned above, the study was 
 
To reflect the 
decision made by 
the sponsor to stop 
enrollment and close 
the study after 
evaluating the 
safety, efficacy, PK, 
and PD of 
acalabrutinib in 
combination with 
vistusertib at Dose 
Level -1 and Dose 
Level 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Protocol: ACE-LY-110 
 
 
 
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Change 
Rationale 
closed before initiating Part 2. The possible expansion groups for Part 
2 may include adult subjects with the following relapsed/refractory 
disease types: 
• 
De novo non-GCB DLBCL (n≤20) 
• 
De novo GCB DLBCL (n≤15) 
Treatment with acalabrutinib and vistusertib, in Part 1 and Part 2, may be 
continued until disease progression or an unacceptable drug-related 
toxicity occurs as defined in the protocol.  Subjects who do not tolerate 
vistusertib may continue to receive acalabrutinib monotherapy provided 
they are deriving clinical benefit.  Dose modification provisions are 
provided in Section 3.8.  All subjects who discontinue study treatment (ie, 
both drugs) will have an SFU visit 30 (+ 7) days after the last dose of 
study drug(s).  In addition, any subjects who discontinue study treatment 
(ie, both drugs) before documentation of disease progression will be 
followed according to standard of care to collect information on when 
documented disease progression occurs and whether a new anticancer 
therapy is started.  All subjects will be followed for survival. 
Subjects showing clinical benefit (ie, no disease progression) and who 
are tolerating study treatment may remain on study for up to a total of 12 
cycles of treatment.  Subjects who have received 12 cycles of treatment 
(ie, been on study for approximately 12 months) and are deriving clinical 
benefit from acalabrutinib monotherapy or the combination of 
acalabrutinib and vistusertib may remain on study treatment beyond 
the first 12 months until disease progression occurs or be eligible to 
enroll in either a rollover study of acalabrutinib monotherapy or a rollover 
study of the combination of acalabrutinib and vistusertib, respectively. 
… 
Figure 2.  Study Schema 
The following footnote was added to Figure 2: 
Note:  On 21 May 2018, a decision was made by the sponsor to stop 
enrollment and close the study before initiating Dose Level 1 and 
Part 2. 
Revised to allow 
subjects who are 
deriving clinical 
benefit from study 
treatment to remain 
on study treatment 
beyond the first 12 
months of treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study schema was 
revised to include a 
footnote clarifying 
the revision to the 
study design. 
Section 3.1.1 Safety Parameters 
Revised text as shown (bold indicates new text): 
For consistency of interpretation, AEs and laboratory results will be coded 
using MedDRA, and the severity of AEs will be graded using the CTCAE, 
Version 4.035.0 or higher.   
Updated Common 
Terminology Criteria 
for Adverse Events 
(CTCAE) version 
number 


 
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Change 
Rationale 
Section 3.1.2 Pharmacodynamic, Pharmacokinetic, and Biomarker 
Parameters 
Revised text as shown (bold indicates new text): 
 
The following PK parameters will be calculated, whenever possible, from 
plasma concentrations of acalabrutinib and vistusertib (Note: These will 
not be collected or assessed for subjects whose study participation 
extends past the first 12 cycles.): 
x 
AUC0-last: Area under the plasma concentration-time curve 
calculated using linear trapezoidal summation from time 0 to time 
last, where “last” is the time of the last measurable concentration 
x 
AUC0-inf: Area under the plasma concentration-time curve from 0 
to infinity, calculated using the formula: AUC0-inf=AUC0-last + Clast / 
Ȝz, where Ȝz is the apparent terminal elimination rate constant 
(whenever possible) 
x 
Cmax: Maximum observed plasma concentration 
x 
Tmax: Time of the maximum plasma concentration (obtained 
without interpolation) 
x 
t½: Terminal elimination half-life  
x 
Ȝz: Terminal elimination rate constant 
x 
CL/F: Oral clearance 
x 
Vz/F: Oral volume of distribution 
Revised to note that 
PK, PD, and 
biomarker 
parameters would 
not be assessed for 
the subjects who 
continue study 
treatment beyond 
12 cycles 
Section 3.1.3 Efficacy Parameters 
Revised text as shown (bold indicates new text): 
Analysis of efficacy parameters is provided in Section 5.5.4.  The 
efficacy evaluations will not be assessed for subjects whose study 
participation extends past the first 12 cycles.   
Efficacy will not be 
assessed for the 
subjects who 
continue study 
treatment beyond 
12 cycles. 
Section 3.2.1 Rationale for Combining mTOR and BTK Inhibition 
Revised text as shown (bold indicates new text): 
As is typical of dose-finding studies, …  Therefore, the purpose of Part 2 
iswas to evaluate the combination therapy in both subtypes to determine 
whether the combination therapy is active across subtypes or shows 
preferential activity for a particular subtype.  On 21 May 2018, a decision 
was made by the sponsor to stop enrollment and close this study 
after evaluating the safety, efficacy, PK, and PD of acalabrutinib in 
combination with vistusertib at Dose Level -1 and Dose Level 0.  In 
general, the acalabrutinib and vistusertib (an mTOR1 and mTOR2 
dual inhibitor) combination was well tolerated in subjects with 
relapsed/refractory DLBCL enrolled in Dose Level -1 and Dose Level 
0.  However, modest clinical efficacy was observed at both dose 
levels. 
 
  
PK modeling indicated that increasing dose levels and/or changing 
dosing schedules would not improve target engagement.  
Information from this study will be used to guide the design of future 
studies with the combination.  
 
Revisions made to 
reflect the decision 
made by the sponsor 
to stop enrollment 
and close the study 
after evaluating the 
safety, efficacy, PK, 
and PD of 
acalabrutinib in 
combination with 
vistusertib at Dose 
Level -1 and Dose 
Level 0. 
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Change 
Rationale 
Section 3.2.2 Dose Selection Rationale 
Revised text as shown (bold indicates new text): 
Vistusertib has been evaluated at several doses and schedules.  
Monotherapy vistusertib 50 mg bid continuous and 125 mg bid 2 days on 
and 5 days off has been well tolerated.  However, to reduce the potential 
for overlapping toxicities, the vistusertib dosages being evaluated have 
been reduced to 35 mg bid continuous (Level -1 for continuous dosing 
schedule) and 100 mg bid 2 days on and 5 days off (Level -1 for 
intermittent dosing schedule).  Amendment 2 of this protocol adds higher 
levels (Level +1) for vistusertib in Part 1 should the target level(s) be well 
tolerated with acalabrutinib.  As the target levels were derived from 
experience of vistusertib in subjects with solid tumors, the higher levels of 
vistusertib may be more efficacious in subjects with lymphoma and, 
therefore, warrant evaluating for potential toxicity.  The proposed higher 
dose levels for vistusertib are within the range of doses previously 
evaluated in subjects with solid tumors (refer to the Investigator Brochure 
for detailed information).  As described previously, this study incorporates 
a formal DLT review to select the most tolerated vistusertib 
dosage/schedule for the expansion portion of the study.  Amendment 2 
of this protocol added a higher dose level of vistusertib (Level +1) to 
Part 1 of the protocol.  However, as mentioned previously, the 
sponsor stopped the study after evaluating the efficacy, safety, PD, 
and PK data from the subjects treated with the lower dose levels of 
vistusertib. 
Revisions made to 
reflect the decision 
made by the sponsor 
to stop enrollment 
and close the study 
after evaluating the 
safety, efficacy, PK, 
and PD of 
acalabrutinib in 
combination with 
vistusertib at Dose 
Level -1 and Dose 
Level 0. 
Section 3.3.1 Inclusion Criteria 
Revised text as shown (bold indicates new text): 
Inclusion criterion #12 was modified as follows: 
12. Men should be willing towho are sexually active must use 
barrier contraception (ie, condoms) in addition to the highly 
effective contraception and refrain from sperm donation during the 
study and for a washout period of 120 until 2 days after discontinuing 
study drug(s)the subject’s last dose of acalabrutinib or 16 weeks 
after the subject’s last dose of vistusertib, whichever is longer.  
If not done previously, storage of sperm before receiving vistusertib 
will be advised to male subjects with a desire to have children. 
Revised to align with 
current acalabrutinib 
and vistusertib 
contraception 
information 
Section 3.3.2 Exclusion Criteria 
Revised text as shown (bold indicates new text): 
Exclusion criterion #15 was modified as follows: 
15. Unresolved toxicities from prior anticancer therapy, defined as 
having not resolved to CTCAE, Version 4.035.0 Grade 0 or 1, or to 
the levels dictated in the inclusion/exclusion criteria, with the 
exception of alopecia. 
Updated CTCAE 
version number 


 
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Change 
Rationale 
Section 3.5 Study Treatment Schedule 
Revised text as shown: 
 
Vistusertib Dose Levels and Schedules 
 
Dose Level 
Schedule Type 
Dose Schedule 
Weekly 
Dose 
SCHEDULE 1 
Starting dose 
(Level -1) 
Continuous  
35 mg twice 
daily continuous 
490 mg 
Target dose 
(Level 0) 
Continuous  
50 mg twice 
daily continuous 
700 mg 
Level +1 
dose 
Continuous 
75 mg twice 
daily continuous 
1050 mg 
SCHEDULE 2 
Level -2 dose 
Intermittent 
75 mg twice 
daily 2 days 
on/5 days off 
300 mg 
Starting dose 
(Level -1) 
Intermittent 
100 mg twice 
daily 2 days 
on/5 days off 
400 mg 
Target dose 
(Level 0) 
Intermittent 
125 mg twice 
daily 2 days 
on/5 days off 
500 mg 
Level +1 
dose 
Intermittent 
150 mg twice 
daily 2 days 
on/5 days off 
600 mg 
 
Revised to remove 
the dose-level 
information for the 
discontinued Level 
+1 dose 
Section 3.6 Duration of Therapy 
Revised text as shown (bold indicates new text): 
Treatment with acalabrutinib and vistusertib, in Part 1 and Part 2, may be 
continued until disease progression or an unacceptable drug-related 
toxicity occurs as defined in the protocol.  Subjects who do not tolerate 
vistusertib may continue to receive acalabrutinib monotherapy provided 
they are deriving clinical benefit. 
Subjects showing clinical benefit and who are tolerating study treatment 
may remain on study for up to 12 cycles of treatment.  Subjects who have 
received 12 cycles of treatment (ie, been on study for approximately 12 
months) and are deriving clinical benefit from acalabrutinib monotherapy 
or the combination of acalabrutinib and vistusertib may remain on study 
treatment beyond the first 12 months until disease progression 
occurs or be eligible to enroll in either a rollover study of acalabrutinib 
monotherapy or a rollover study of the combination of acalabrutinib and 
vistusertib, respectively. 
Revised to allow 
subjects who are 
deriving clinical 
benefit from study 
treatment to remain 
on study treatment 
beyond the first 12 
months of treatment 


 
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Change 
Rationale 
Section 3.8 Dosing Delays and Modifications 
Starting dose of 150 mg vistusertib deleted from dose reduction table. 
Table 5  Vistusertib dose reduction options 
Starting dose 
1st dose 
reduction 
2nd dose 
reduction 
3rd dos
reductio
35 mg 
25 mg 
discontinue 
not applic
50 mg 
35 mg  
25 mg 
discontin
75 mg 
50 mg 
25 mg 
discontin
100 mg 
75 mg 
50 mg 
25 mg
125 mg 
100 mg 
75 mg 
50 mg
150 mg 
125 mg 
100 mg 
75 mg
a 
If allowed after consultation with medical monitor 
 
Revised to remove 
the dose-level 
information for the 
discontinued dose 
Section 3.11.7 Reproductive Toxicity 
Revised text as shown (bold indicates new text): 
Definition of contraception: 
(1) Practice abstinence† from heterosexual intercourse;  
OR  
(2) Use (or have their partner use) highly effective contraception during 
heterosexual intercourse.   
Highly effective methods of contraception are‡: 
Combination method:  Use of a male condom is required and one of the 
following: 
• 
Use of medroxyprogesterone acetate depot injection (Depo-
Provera™). (Please note: use of any other oral, injected, or 
implanted hormonal methods of contraception cannot be 
considered highly effective as it is currently unknown whether 
vistusertib may reduce their effectiveness.) 
• 
Vasectomized partner (condom use in male subjects is 
recommended to prevent possible direct exposure in case of a 
pregnant female partner) 
• 
Diaphragm with spermicide  
• 
Cervical cap with spermicide (nulliparous women only) 
• 
Contraceptive sponge (nulliparous women only) 
• 
Intrauterine device (IUD) 
• 
Bilateral tubal ligation 
†Abstinence (relative to heterosexual activity) can only be used as the 
sole method of contraception if it is consistently employed as the 
subject’s preferred and usual lifestyle and if considered acceptable by 
local regulatory agencies and IECs/IRBs.  Periodic abstinence (eg, 
calendar, ovulation, sympto-thermal, and post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable method 
of contraception for subjects participating at sites in this country/region.   
 
Revised to correct 
the definition of 
highly effective 
contraception to 
align with the Clinical 
Trial Facilitation 
Group guidance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Change 
Rationale 
Highly effective methods of contraception (to be used during 
heterosexual activity) are defined as methods that can achieve a 
failure rate of <1% per year when used consistently and correctly.  
Such methods include the following: 
• 
Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation, which 
may be oral, intravaginal, or transdermal 
• 
Progestogen-only hormonal contraception associated with 
inhibition of ovulation, which may be oral, injectable, or 
implantable 
• 
Intrauterine device (IUD) or intrauterine hormone-releasing 
system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomy of a female subject’s male partner (with medical 
assessment and confirmation of vasectomy surgical 
success) 
• 
Sexual abstinence (only if refraining from heterosexual 
intercourse during the entire period of risk associated with 
the study treatments) 
Hormonal contraception may be susceptible to interaction with 
study or other drugs, which may reduce the efficacy of the 
contraception method. 
Abstinence (relative to heterosexual activity) can only be used as 
the sole method of contraception if it is consistently employed 
during the entire period of risk associated with the study treatments 
as the subject’s preferred and usual lifestyle.  Periodic abstinence 
(eg, calendar, ovulation, sympto-thermal, and post-ovulation 
methods) and withdrawal are not acceptable methods of 
contraception. 
If a contraceptive method is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable 
highly effective method of contraception for subjects participating 
at sites in the relevant country/region. 
… 
Men who have a partner who is a womanshould be asked to avoid 
unprotected sex (ie, always use a condom) with women of childbearing 
potential must use highly effective contraception with the additional 
use of a condom during the study and for a washout period of 120 days 
after discontinuing study drug(s)16 weeks after the subject’s last dose 
of vistusertib.  Male subjects should refrain from donating sperm from 
the start of dosing until 120 days16 weeks after discontinuing the study 
drug(s) subject’s last dose of vistusertib.  If male subjects wish to 
father children, they should be advised to arrange for freezing of sperm 
samples before receiving the first dose of study drug(s)vistusertib. 
Subjects should promptly notify the investigator if they or their partners 
become pregnant during this study or within 1202 days after their last 
dose of study drug(s)acalabrutinib or 16 weeks after the subject’s last 
dose of vistusertib, whichever is longer.  If a woman becomes 
pregnant during the treatment period, she must discontinue acalabrutinib 
and vistusertib.  Pregnancy must be reported as outlined in Section 6.2.3.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised to align with 
current acalabrutinib 
and vistusertib 
contraception 
information 


 
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Change 
Rationale 
Section 4.1.22 Pharmacokinetics 
Revised text as shown: 
Vistusertib PK blood sampling (2 mL per sample) will be collected at 
predose and at approximately 1, 2, 4, and 6 hours postdose on Cycle 1 
Day 1 and Cycle 1 Day 22 for all subjects in Part 1 and approximately 9 
selected subjects in Part 2.  The same 9 subjects from Part 2 will have 
samples collected for acalabrutinib PK as described below. 
Acalabrutinib PK blood sampling (2 mL per sample) will be collected.  For 
Part 1, samples will be collected from all subjects on Cycle 1 Day 1 and 
Cycle 1 Day 22 predose and at approximately 1, 2, 4 and 6 hours 
postdose.For Part 2, 9 selected subjects will have acalabrutinib PK 
samples taken on Cycle 0 Day -1 and Cycle 1 Day 22 predose and 
approximately 1, 2, 4 and 6 hours postdose. 
Revised to reflect the 
decision made by 
the sponsor to stop 
enrollment and close 
the study before 
proceeding to Part 2 
Section 4.1.25 Pharmacodynamic Samples 
Revised text as shown: 
 
 
Revised to reflect the 
decision made by 
the sponsor to stop 
enrollment and close 
the study before 
proceeding to Part 2 
Section 4.1.27 Whole Blood Immunophenotyping 
Section has been deleted 
Whole blood immunophenotyping will be done in Part 2 of the study 
only.  Whole blood samples (a 4-mL and 5-mL sample for 9 mL total of 
whole blood) will be collected for flow cytometry-based 
immunophenotyping.  Samples will be collected at screening and predose 
on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1.   Populations 
monitored may include, but are not limited to, leukocyte or lymphocyte 
subsets (eg, T, B and NK cells) and their respective activation states.  
The results of this exploratory research will be reported separately and 
will not form part of the CSR.   
Refer to the laboratory manual for instructions on collection and shipment 
of the whole blood immunophenotyping samples.  All testing will be done 
by the sponsor or designee.   
Revised to reflect the 
decision made by 
the sponsor to stop 
enrollment and close 
the study before 
proceeding to Part 2 
Section 4.1.30 Tumor Assessments 
Revised text as shown (bold indicates new text): 
For all histologies: 
Baseline tumor assessments will be performed using radiologic imaging 
by CT with contrast and PET-CT covering neck, chest, abdomen, and 
pelvis within 30 days before the first dose of study drug.  Radiologic 
scans (ie, contrast CT) will be repeated every 23 cycles (ie, 
approximately every 812 weeks ± 7 days).  PET-CT also will be repeated 
on the same schedule, when required, per Section 4.3 of the protocol.  
For subjects with baseline hepatosplenomegaly, the cranial-caudal 
measurement of the spleen and longest diameter of the liver will be 
assessed at screening and subsequent response evaluations. 
Revised to extend 
the CT scans to 
every 3 cycles for 
the subjects who 
remain on study 
treatment beyond 
12 cycles 
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Section 5.2 Rationale for Sample Size 
Revised text as shown (bold indicates new text): 
Depending on dose escalation/de-escalation and enrollment in the 
expansion groups up to 71 subjects will be enrolled in this study.  
In Part 1 (dose selection), enrollment of 6 subjects per dose level limits 
the number of subjects exposed consistent with the expected safety 
profiles of the study drugs, but includes sufficient subjects to explore 
effects on PD biomarkers of BTK and mTOR inhibition.  The trial 
employsed the standard NCI definition of MTD (dose associated with DLT 
in <33.3% of subjects assessed during cycle 1).  
A maximum of 3 dose levels will bewere to have been explored in each 
of the two schedules (continuous/intermittent vistusertib dosing). The 
maximum number of subjects in Part 1 iswas therefore 36.  The sponsor 
stopped the study in Part 1 after treating 25 subjects with the first 2 
dose levels of vistusertib. 
 
The recommended vistusertib dose and schedule from Part 1 will be 
evaluated further in two cohorts in Part 2: a de novo non-GCB cohort with 
target sample size 20, and a de novo GCB cohort with target sample size 
15.  Wherever possible, subjects with the same subtype of DLBCL, who 
have received the recommended dose/schedule of vistusertib in Part 1, 
will be pooled for analysis.  Note:  Local DLBCL subgroup classifications 
will be centrally confirmed for analysis purposes (details provided in the 
Statistical Analysis Plan). The total number of subjects enrolled into Part 
2 will be up to 35.  This sample size is large enough to evaluate further 
the safety and PKPD of the chosen dose/schedule for vistusertib from 
Part 1, and gives a reasonable chance of detecting an efficacy signal, 
should one exist. 
 
The primary analysis will be conducted after all ongoing subjects have 
had the opportunity to complete at least 3 scheduled post-baseline scans.  
No formal statistical testing will be performed.  Confidence intervals will 
be constructed around the objective response rate observed, and this will 
enable decisions to be made around the likely success of future studies.  
Historical response rates in relapsed/refractory DLBCL are in the region 
of 30% to 55%, with some evidence that response rates are higher for the 
non-GCB subtype (Hernandez‐Ilizaliturri et al 2011; Morschhauser et al 
2014; Van Den Neste et al 2016a; Van Den Neste et al 2016b; Wilson et 
al 2015; Witzig et al 2011). The following examples give an indication of 
the level of precision that will be achieved in this study: 
In the non-GCB subgroup 
• 
If the observed response rate is 35% (7/20), the 2-sided 80% 
confidence interval will be (21%, 52%). 
• 
If the observed response rate is 60% (12/20), the 2-sided 80% 
confidence interval will be (43%, 75%). 
In the GCB subgroup 
• 
If the observed response rate is 20% (3/15), the 2-sided 80% 
confidence interval will be (8%, 39%). 
• 
If the observed response rate is 33% (5/15), the 2-sided 80% 
confidence interval will be (17%, 53%). 
In addition to ORR, the criteria for success will take into account the 
observed safety and tolerability data, and the other efficacy endpoints, in 
particular the DRR. 
Subjects will continue to be followed for survival after objective disease 
progression.  A final analysis will be performed after the earlier of 12 
Revised to reflect the 
decision made by 
the sponsor to stop 
enrollment and close 
the study before 
proceeding to Part 2 


 
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Change 
Rationale 
months after the last subject is recruited to Part 2 or when 50% of the 
subjects in Part 2 have died due to any cause. 
Interim analysis 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.5.1 Safety 
Revised text as shown (bold indicates new text): 
Verbatim descriptions of AEs will be mapped according to the MedDRA 
thesaurus terms and graded according to NCI CTCAE, v4.035.0 or 
higher. 
Updated CTCAE 
version number 
Section 5.5.5 Pharmacokinetic Analyses 
Revised text as shown (bold indicates new text): 
The plasma PK of acalabrutinib and vistusertib will be characterized using 
noncompartmental analysis. The following PK parameters will be 
calculated, whenever possible, from plasma concentrations of analytes 
(Note: These will not be collected or assessed for subjects whose 
study participation extends past the first 12 cycles.): 
x 
AUC0-last:  Area under the plasma concentration-time curve 
calculated using linear trapezoidal summation from 
time 0 to time last, where “last” is the time of the last 
measurable concentration 
x 
AUC0-inf:  Area under the plasma concentration-time curve 
from 0 to infinity, calculated using the formula: 
AUC0-inf = AUC0-last + Clast / ȜzZKHUHȜz is the apparent 
terminal elimination rate constant 
x 
Cmax:  Maximum observed plasma concentration 
x 
Tmax:  Time of the maximum plasma concentration 
(obtained without interpolation) 
x 
t½:  Terminal elimination half-life (whenever possible) 
x 
Ȝz:  Terminal elimination rate constant (whenever possible) 
x 
CL/F:  Oral clearance 
x 
Vz/F:  Oral volume of distribution 
Revised to note that 
PK parameters 
would not be 
assessed for the 
subjects who 
continue study 
treatment beyond 
12 cycles 
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Change 
Rationale 
Section 6.1.3 Severity 
Revised text as shown (bold indicates new text): 
Definitions found in the CTCAE version 4.035.0 or higher will be 
used for grading the severity (intensity) of AEs.  The CTCAE 
displays Grades 1 through 5 with unique clinical descriptions of 
severity for each referenced AE.   
Updated CTCAE 
version number 
Section 6.2.3 Pregnancy 
Revised text as shown (bold indicates new text): 
Any uncomplicated pregnancy that occurs during this study will be 
reported.  All pregnancies that are identified during or after this study, 
wherein the estimated date of conception is determined to have occurred 
from the time of consent to 1202 days after the last dose of study drug(s) 
acalabrutinib or 16 weeks after the last dose of vistusertib, 
whichever is longer, will be reported, followed to conclusion, and the 
outcome reported, as long as the subject or subject’s partner is willing to 
participate in follow up.  Upon completion of the pregnancy, additional 
information on the mother, pregnancy, and baby will be collected and 
sent to 
. 
Revised to align with 
current acalabrutinib 
and vistusertib 
pregnancy 
information 
Appendix 1 Schedule of Assessments (Acalabrutinib + Vistusertib) 
The Schedule of Assessments was revised to remove Part 2 
assessments and long-term follow up and to add an assessment column 
for extended study treatment (ie, for subjects continuing study 
participation >12 cycles).  The frequency of the CT scan was also revised 
to occur every 3 cycles instead of every 2 cycles. 
Revised to reflect 
changes in the 
protocol 
Appendix 2 Schedule of Assessments (Acalabrutinib Monotherapy) 
The Schedule of Assessments was revised to remove long-term follow up 
and to add an assessment column for extended study treatment (ie, for 
subjects continuing study participation >12 cycles).   
Revised to reflect 
changes in the 
protocol 
Appendix 5 Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
Revised text in this appendix 
Revised to reflect 
standard practice 
concerning Hy’s law 
across the sponsor’s 
clinical development 
program 
 
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TABLE OF CONTENTS 
1.0 
BACKGROUND INFORMATION ............................................................. 43 
1.1 
Acalabrutinib (ACP-196) .......................................................................... 43 
1.1.1 
Safety Pharmacology and Toxicology ........................................ 44 
1.1.2 
Drug-drug Interaction Potential................................................... 44 
1.1.3 
Clinical Experience ..................................................................... 44 
1.2 
Vistusertib (AZD2014).............................................................................. 45 
1.2.1 
Safety Pharmacology and Toxicology ........................................ 47 
1.2.2 
Drug-drug Interaction Potential................................................... 47 
1.2.3 
Clinical Experience ..................................................................... 47 
1.3 
Benefit/Risk .............................................................................................. 51 
2.0 
STUDY OBJECTIVES ............................................................................. 52 
2.1 
Primary Objective: ................................................................................... 52 
2.2 
Secondary Objectives: ............................................................................. 53 
2.3 
Exploratory Objectives: ............................................................................ 53 
3.0 
STUDY DESIGN ...................................................................................... 53 
3.1 
Study Parameters .................................................................................... 56 
3.1.1 
Safety Parameters ...................................................................... 56 
3.1.2 
Pharmacodynamic, Pharmacokinetic and Biomarker Parameters
 ................................................................................................... 57 
3.1.3 
Efficacy Parameters ................................................................... 57 
3.2 
Rationale for Study Design and Dosing Regimen .................................... 58 
3.2.1 
Rationale for Combining mTOR and BTK Inhibition ................... 58 
3.2.2 
Dose Selection Rationale ........................................................... 60 
3.3 
Selection of Study Population .................................................................. 61 
3.3.1 
Inclusion Criteria ......................................................................... 61 
3.3.2 
Exclusion Criteria ....................................................................... 63 
3.3.3 
Replacement of Subjects ........................................................... 65 
3.3.4 
Enrollment and Randomization Procedures ............................... 65 
3.4 
Study Drug ............................................................................................... 66 
3.4.1 
Premedications ........................................................................... 66 
3.4.2 
Formulation, Packaging, and Storage ........................................ 66 
3.4.3 
Administration of Study Drug ...................................................... 66 
3.4.4 
Assuring Subject Compliance..................................................... 67 
3.5 
Study Treatment Schedule ...................................................................... 68 
3.6 
Duration of Therapy ................................................................................. 68 
3.7 
Assessment of Dose-Limiting Toxicity (DLT) ........................................... 69 
3.8 
Dosing Delays and Modifications ............................................................. 70 


 
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3.8.1 
Dose modifications for hematologic toxicities ............................. 72 
3.8.2 
Dose modifications for nonhematologic toxicities ....................... 74 
3.9 
Management of Toxicites ......................................................................... 75 
3.9.1 
Recommendations for Evaluation and Treatment of Severe 
Fatigue ....................................................................................... 75 
3.9.2 
Recommendations for Treatment of Diarrhea ............................ 76 
3.9.3 
Recommendations for the Treatment of Nausea and Vomiting .. 76 
3.9.4 
Recommendations for Treatment of Decreased Appetite ........... 77 
3.9.5 
Recommendations for Treatment of Rash/Skin Toxicity ............. 77 
3.9.6 
Recommendations for treatment of Stomatitis/Oral 
Mucositis/Mouth Ulcers .............................................................. 78 
3.9.7 
Recommendations for Treatment of Hyperglycemia .................. 79 
3.9.8 
Recommendations for Evaluation and Treatment of Electrolyte 
Changes Including Hypokalemia and Hypophosphatemia ......... 79 
3.9.9 
Recommendations for Evaluation and Treatment of Interstitial 
Lung Disease ............................................................................. 79 
3.9.10 Recommendations for Evaluation and Management of 
Electrocardiogram (ECG) Changes ............................................ 80 
3.9.11 Recommendations for Evaluation and Treatment of Renal Effects
 ................................................................................................... 80 
3.9.12 Recommendations for Evaluation and Treatment of Liver Function 
Test Abnormalities (Risk for Vistusertib and/or Acalabrutinib) .... 81 
3.9.13 Recommendations for Evaluation and Treatment of Infections .. 83 
3.9.14 Recommendations for Other Nonhematologic Toxicities ............ 83 
3.9.15 Recommendations for Treatment of Hematologic Findings and 
Associated Dose Modifications................................................... 83 
3.9.16 Recommendations for Tumor Lysis Syndrome (TLS) ................. 83 
3.10 
Concomitant Therapy............................................................................... 84 
3.10.1 Permitted Concomitant Therapy ................................................. 84 
3.10.2 Prohibited or Restricted Concomitant Therapy ........................... 85 
3.11 
Precautions .............................................................................................. 86 
3.11.1 Hepatitis B Reactivation ............................................................. 86 
3.11.2 Progressive multifocal leukoencephalopathy (PML) ................... 86 
3.11.3 Phototoxicity ............................................................................... 87 
3.11.4 Dietary Restrictions .................................................................... 87 
3.11.5 Drug-drug Interactions ................................................................ 87 
3.11.6 Surgery ....................................................................................... 89 
3.11.7 Reproductive Toxicity ................................................................. 89 
3.11.8 Overdose Instructions ................................................................ 90 
3.12 
Withdrawal of Subjects From Study Treatment ........................................ 91 


 
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3.13 
Reasons for Study Exit/Termination ........................................................ 92 
3.14 
Data and Safety Monitoring ..................................................................... 92 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ............................................ 93 
4.1 
Description of Procedures ........................................................................ 93 
4.1.1 
Informed Consent ....................................................................... 93 
4.1.2 
Confirmation of Eligibility ............................................................ 93 
4.1.3 
Medical History ........................................................................... 93 
4.1.4 
Adverse Events .......................................................................... 94 
4.1.5 
Concomitant Medications and Therapy ...................................... 94 
4.1.6 
ECOG Performance Status ........................................................ 94 
4.1.7 
Cumulative Illness Rating Scale-Geriatric (CIRS-G) .................. 94 
4.1.8 
Physical Examination, Vital Signs, Height & Weight ................... 94 
4.1.9 
Electrocardiogram ...................................................................... 95 
4.1.10 ECHO/MUGA ............................................................................. 95 
4.1.11 CT Scan of Thorax ..................................................................... 95 
4.1.12 Hematology ................................................................................ 95 
4.1.13 Serum Chemistry ........................................................................ 95 
4.1.14 Pregnancy Testing ..................................................................... 96 
4.1.15 Cardiac Troponin ........................................................................ 96 
4.1.16 Coagulation ................................................................................ 96 
4.1.17 Hepatitis B and C Testing ........................................................... 96 
4.1.18 CMV Testing............................................................................... 97 
4.1.19 Urinalysis .................................................................................... 97 
4.1.20 T/B/NK Cell Count ...................................................................... 97 
4.1.21 Serum Immunoglobulin .............................................................. 97 
4.1.22 Pharmacokinetics ....................................................................... 97 
4.1.23 Archival Tumor Sample (Required for Study Entry) .................... 97 
4.1.24 Optional Fresh Tumor Biopsy Sample ........................................ 98 
4.1.25 Pharmacodynamic Samples ....................................................... 99 
4.1.26 ctDNA Samples .......................................................................... 99 
4.1.27 Exploratory Blood Biomarker Samples ....................................... 99 
4.1.28 Optional Pharmacogenetics Sample ........................................ 100 
4.1.29 Bone Marrow Biopsy/Aspirate .................................................. 100 
4.1.30 Tumor Assessments ................................................................. 100 
4.1.31 Study Drug Accountability ........................................................ 100 
4.2 
Biologic Sampling Procedures ............................................................... 101 
4.2.1 
Handling, Storage, and Destruction of Biologic Samples ......... 101 
4.2.2 
Pharmacokinetic Samples ........................................................ 101 
4.2.3 
Samples for Exploratory Research ........................................... 101 


 
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4.2.4 
Chain of Custody of Biologic Samples ..................................... 102 
4.2.5 
Withdrawal of Informed Consent for Donated Biological Samples
 ................................................................................................. 102 
4.3 
Investigator’s Assessment of Response to Treatment ........................... 103 
4.4 
Safety Follow-up (SFU) Visits ................................................................ 107 
4.5 
Follow-up for Progression and Survival ................................................. 107 
4.6 
Missed Evaluations ................................................................................ 108 
5.0 
STATISTICAL METHODS OF ANALYSIS ............................................. 108 
5.1 
General Considerations ......................................................................... 108 
5.2 
Rationale for Sample Size ..................................................................... 108 
5.3 
Definition of Analysis Sets ..................................................................... 109 
5.4 
Missing Data Handling ........................................................................... 109 
5.5 
Outcome Data Analysis ......................................................................... 109 
5.5.1 
Safety ....................................................................................... 109 
5.5.2 
Demographics and Baseline Characteristics ............................ 110 
5.5.3 
Exposure to Study Drug(s) ....................................................... 110 
5.5.4 
Analysis of Efficacy Parameters ............................................... 110 
5.5.4.1 
Overall Response Rate (ORR) and Complete Response 
(CR) Rate .........................................................................110 
5.5.4.2 
Progression-Free Survival (PFS) ....................................110 
5.5.4.3 
Duration of Response (DOR) ...........................................110 
5.5.4.4 
Durable Response Rate (DRR) .......................................111 
5.5.4.5 
Overall Survival (OS) ........................................................111 
5.5.5 
Pharmacokinetic Analyses ....................................................... 111 
5.5.6 
Additional PK and PD Analyses ............................................... 112 
6.0 
ASSESSMENT OF SAFETY ................................................................. 112 
6.1 
Definitions .............................................................................................. 112 
6.1.1 
Adverse Events ........................................................................ 112 
6.1.2 
Serious Adverse Event ............................................................. 113 
6.1.3 
Severity .................................................................................... 114 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events .. 115 
6.2.1 
Adverse Event Reporting Period .............................................. 115 
6.2.2 
Assessment of Adverse Events ................................................ 115 
6.2.3 
Pregnancy ................................................................................ 116 
6.2.4 
Expedited Reporting Requirements for Serious Adverse Events
 ................................................................................................. 116 
6.2.5 
Type and Duration of Follow-up of Subjects after Adverse Events
 ................................................................................................. 117 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...... 117 


 
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7.1 
Institutional Review Board and Independent Ethics Committee ............. 118 
7.2 
Informed Consent and Protected Subject Health Information Authorization
 ............................................................................................................... 118 
7.3 
Subject Screening Log ........................................................................... 119 
7.4 
Case Report Forms ............................................................................... 119 
7.5 
Study Monitoring Requirements ............................................................. 119 
7.6 
Investigational Study Drug Accountability .............................................. 120 
7.7 
Record Retention ................................................................................... 120 
7.8 
Protocol Amendments............................................................................ 121 
7.9 
Publication of Study Results .................................................................. 121 
7.10 
Clinical Trial Insurance........................................................................... 121 
7.11 
General Investigator Responsibilities ..................................................... 121 
8.0 
REFERENCES ...................................................................................... 123 
9.0 
APPENDICES ........................................................................................ 127 
 
IN-TEXT TABLES 
Table 1.  Vistusertib monotherapy (D2270C00001) .......................................................48 
Table 2.  Vistusertib in combination with fulvestrant (D2270C00005) ............................48 
Table 3.  Howard definition of clinical tumor lysis syndrome ..........................................70 
Table 4.  Howard definition of laboratory tumor lysis syndrome .....................................70 
Table 5.  Vistusertib dose reduction options ..................................................................71 
Table 6.  Acalabrutinib dose reduction options ..............................................................71 
Table 7.  Dose modifications for hematologic toxicities ..................................................73 
Table 8.  Dose modification guidance in the event of Grade 3 nonhematologic 
toxicities except liver dysfunction* ..........................................................................75 
Table 9.  Recommendations for acalabrutinib and vistusertib dose modifications for 
abnormal liver function results ...............................................................................82 
Table 10.  Recommended TLS prophylaxis based on risk .............................................84 
Table 11.  Revised criteria for response assessment for non-Hodgkin lymphoma 
(NHL) ................................................................................................................... 104 
Table 12.  Analysis sets ............................................................................................... 109 
Table 13.  Cytochrome P450 enzyme inhibitors/inducers and transporters 
restrictions ........................................................................................................... 137 
Table 14.  Transporter substrate restrictions................................................................ 138 
 
IN-TEXT FIGURES 
Figure 1.  PI3K/AKT/mTOR pathway .............................................................................46 
Figure 2.  Study Schema ...............................................................................................56 
Figure 3.  Tumor Volume Over Time .............................................................................59 
 


 
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LIST OF APPENDICES 
Appendix 1.  Schedule of Assessments (Acalabrutinib + Vistusertib) ........................... 128 
Appendix 2.  Schedule of Assessments (Acalabrutinib Monotherapy) ......................... 133 
Appendix 3.  Performance Status Scores .................................................................... 135 
Appendix 4.  Restricted CYP and Transporter-Related Comedications........................ 136 
Appendix 5.  Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ......................................................................................... 139 
 
Appendix 7.  Cumulative Illness Rating Scale-Geriatric (CIRS-G) Calculator ............... 147 
Appendix 8.  Adverse Event Assessment of Causality ................................................. 148 
Appendix 9.  Response Criteria for NHL ...................................................................... 149 
 
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ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
λz  
Terminal elimination rate constant 
4EBP1 
Eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 
5PS 
5-point scale 
ABC 
Activated B cell-like subtype of diffuse large B-cell lymphoma 
AE 
Adverse event 
ACP-196 
Acalabrutinib 
AKT 
Protein kinase B 
ALC 
Absolute lymphocyte count 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
AMPK, AMP 
Activated protein kinase 
ANC 
Absolute neutrophil count  
anti-HBc 
Hepatitis B core antibody  
anti-HBs 
Hepatitis B surface antibody  
aPTT 
Activated partial thromboplastin time  
ASCT 
Autologous stem cell transplant  
AST 
Aspartate aminotransferase  
AUC0-inf 
Area under the plasma concentration-time curve from 0 to infinity, 
calculated using the formula: AUC0-inf = AUC0-last + Clast / λz, where λz 
is the apparent terminal elimination rate constant 
AUC0-last 
Area under the plasma concentration-time curve calculated using 
linear trapezoidal summation from time 0 to time last, where “last” is 
the time of the last measurable concentration 


 
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Abbreviation or 
special term 
Explanation 
AZD2014 
Vistusertib 
BAD Bcl-2 
Associated death promoter 
B-ALL 
Burkitt acute lymphoblastic leukemia 
BCR 
B-cell receptor 
BCRP 
Breast cancer resistance protein  
bid/BID 
Twice per day 
BTK 
Bruton tyrosine kinase  
BUN 
Blood urea nitrogen  
C 
Cycle 
CBC 
Complete blood count  
cGMP 
Current Good Manufacturing Practices  
CIRS-G 
Cumulative Illness Rating Scale-Geriatric 
CIs 
Confidence intervals 
CL/F 
Oral clearance 
CLL 
Chronic lymphocytic leukemia  
Cmax 
Maximum observed plasma concentration 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete remission/response 
CFR 
Code of Federal Regulations  
CSR 
Clinical Study Report  
CT 
Computed tomography  


 
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Abbreviation or 
special term 
Explanation 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CYP 
Cytochrome P450  
Cys  
Cysteine  
d or D 
Day(s) 
DFU 
Discontinuation follow-up;  
DILI 
Drug induced liver injury  
DLBCL 
Diffuse large B-cell lymphoma 
DLCO 
Carbon monoxide diffusing capacity 
DLT/DLTs 
Dose-limiting toxicities  
DOR 
Duration of response 
DRR 
Durable response rate 
ECG/ECGs 
Electrocardiogram(s) 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group;  
eCRF 
Electronic case report form  
EDC 
Electronic data capture  
Enrolled subject 
An enrolled subject is a subject who has signed informed consent 
and has received at least 1 dose of study drug(s) 
ESCR  
Externally sponsored collaborative research  
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FL 
Follicular lymphoma 


 
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Abbreviation or 
special term 
Explanation 
FOXO 
Forkhead box protein O1  
FSH 
Follicle-stimulating hormone 
GCB  
Germinal center B-cell subtype of diffuse large B-cell lymphoma 
GCP 
Good Clinical Practice  
G-CSF 
Granulocyte colony-stimulating factor 
GI 
Gastrointestinal  
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GSK3 
Glycogen synthase kinase 3 
HBsAg 
Hepatitis B surface antigen  
HCV 
Hepatitis C Virus 
HIV 
Human immunodeficiency Virus  
HL  
Hy’s law 
ICF  
Informed Consent Form  
Ig  
Immunoglobulin 
IHC  
Immunohistochemistry 
IMP  
Investigational Medicinal Product  
INR  
International normalization ratio 
Interm.  
Intermittent dosing 
IRB/IEC  
Institutional Review Board/Independent Ethics Committee 
IUD  
Intrauterine device  
IVIG  
Intravenous immunoglobulins  
IXRS 
Interactive Voice/Web Response System 


 
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Abbreviation or 
special term 
Explanation 
JC (virus) 
John Cunningham virus 
KM  
Kaplan-Meier  
LDH  
Lactate dehydrogenase  
LDi  
Longest transverse diameter of a lesion 
LH 
Luteinizing hormone 
LTF  
Long-term follow-up 
LV  
Left ventricular 
LVEF  
Left ventricular ejection fraction  
MCL  
Mantle cell lymphoma 
MedDRA  
Medical Dictionary for Regulatory Activities  
mos  
Months 
MRI  
Magnetic resonance imaging 
MTD/MTDs  
Maximum tolerated dose(s) 
mTOR 
Mammalian target of rapamycin 
MUGA  
Multigated acquisition 
MZL 
Marginal zone lymphoma 
NCCN  
National Comprehensive Cancer Network  
NCI  
National Cancer Institute  
NK  
Natural killer  
Non-GCB  
Non-germinal center B-cell subtype of diffuse large B-cell lymphoma 
NYHA  
New York Heart Association  
ORR  
Overall response rate  


 
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Abbreviation or 
special term 
Explanation 
OS  
Overall survival 
PBMCs  
Peripheral blood mononuclear cells 
PCR  
Polymerase chain reaction  
PD  
Pharmacodynamic  
PDK1  
Phosphoinositide-dependent protein kinase 1 
PE  
Physical exam  
PET  
Positron-emission tomography 
PFS  
Progression-free survival 
P-gp  
Permeability glycoprotein  
PHL  
Potential Hy’s law  
PHLPP  
PH domain and leucine rich repeat protein phosphatases 
PI3K  
Phosphoinositide 3 kinase  
PIP  
Phosphatidylinositol phosphate 
PK  
Pharmacokinetics 
PKC  
Protein kinase C  
PML 
Progressive multifocal leukoencephalopathy 
PMBCL  
Primary mediastinal large B-cell lymphoma 
PRAS40  
Proline-rich AKT substrate of 40 kDa  
PT  
Prothrombin time  
PT/INR  
Prothrombin time/international normalized ratio  
PTEN  
Phosphatase and tensin homologue 
PTT  
Partial thromboplastin time 


 
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Abbreviation or 
special term 
Explanation 
Q3M  
Every 3 months 
qd  
Once daily dosing 
QM  
Every month 
QTc  
QT interval 
QTcF  
QT interval corrected by Fridericia's formula  
R/R  
Relapsed/refractory 
Randomization 
Randomization applies only to Part 1 of this study and will be used 
to randomly assign subjects to either Schedule 1 or Schedule 2 of 
vistusertib. 
R-CHOP  
Rituximab + cyclophosphamide, doxorubicin, vincristine, and 
prednisone  
RECIST  
Response Evaluation Criteria In Solid Tumors  
Rheb  
Ras homolog enriched in brain 
RS  
Richter syndrome 
S6K  
S6 kinase 
SAE  
Serious adverse event 
Schedule 1 
Continuous (ie, daily) dosing schedule for vistusertib 
Schedule 2 
Intermittent (ie, 2 days on/5 days off) dosing schedule for vistusertib. 
SD  
Stable disease  
SDi  
Shortest axis perpendicular to the longest transverse diameter of a 
lesion 
SFU  
Safety follow-up 
SGK  
Serine/threonine-protein kinase  
SLL  
Small lymphocytic lymphoma  
SOC  
Standard of care 


 
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Abbreviation or 
special term 
Explanation 
SPD 
Sum of the product of the perpendicular diameters for multiple 
lesions. 
SREBP  
Sterol regulatory element-binding protein  
SUSAR 
Suspected unexpected serious adverse reaction 
SYK  
Spleen tyrosine kinase  
t½  
Half-life  
TBL  
Total bilirubin 
TEAEs  
Treatment-emergent adverse events  
Tmax  
Time of the maximum plasma concentration 
TSC  
Tuberous sclerosis protein 
ULN  
Upper limit of normal 
Vz/F  
Oral volume of distribution 
WHO  
World Health Organization 
WHODRUG  
World Health Organization Drug Dictionary 
WM  
Waldenström macroglobulinemia 
 


 
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STUDY SYNOPSIS 
Protocol Number: 
ACE-LY-110 
Study Drugs: 
Acalabrutinib (ACP-196) and vistusertib (AZD2014) 
Protocol Title: 
A Phase 1/2 Proof-of-Concept Study of the Combination of 
Acalabrutinib and Vistusertib in Subjects with Relapsed/Refractory 
B-cell Malignancies 
Phase: 
Phase 1/2 
Comparator: 
None 
Background and 
Rationale for Study 
Decades of research across various oncologic diseases support 
the fact that multidrug regimens (eg, polychemotherapy and 
chemoimmunotherapy) produce higher and more durable complete 
response (CR) rates than single-agent chemotherapy.  However, 
these benefits are often outweighed with the increased toxicity 
associated with multidrug regimens.  The high risk:benefit ratio of 
multidrug regimens means these regimens are less likely to be 
used in elderly patients or patients with comorbid conditions.  The 
advent of highly selective, targeted agents to treat B-cell 
malignancies, such as B-cell receptor (BCR) signaling antagonists, 
has changed the risk:benefit paradigm traditionally associated with 
chemotherapy agents.  When administered as single agents, BCR 
antagonists have produced high objective overall response rates 
(ORR) in some patients with B-cell malignancies.  For example, 
ibrutinib, a small molecule inhibitor of Bruton tyrosine kinase 
(BTK), has been approved for the treatment for chronic 
lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 
mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and 
Waldenström macroglobulinemia (WM).  In addition, ibrutinib has 
shown clinical efficacy in other B-cell malignancies including 
follicular lymphoma (FL); (Advani et al 2012) and transformed 
diffuse large B-cell lymphoma (DLBCL); (Wilson et al 2015, Ayers 
& Mato 2016).   
However, the proportion of patients with CRs, when treated with 
BCR signaling antagonists as monotherapy, is low compared with 
traditional polychemotherapy or chemoimmunotherapy (Advani et 
al 2012, Blum 2015).  Also, in more aggressive histologies the 
median duration of response (DOR) can be low (<12 months) 
(Blum 2015).  The question remains whether “targeted 
combination” therapy can produce more durable responses and 
potentially more CRs than single agents without an undue 
associated increase in toxicity.   
Acerta Pharma is developing acalabrutinib as an orally 
administered, small molecule inhibitor of BTK.  Preclinical data 
indicate that acalabrutinib may offer greater potency, improved 
selectivity, better pharmaceutical properties, and less potential for 


 
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drug-drug interactions than ibrutinib.  Acalabrutinib has shown 
clinical activity in an ongoing Phase 1 study in subjects with CLL 
(
; Byrd et al 2016) and Richter syndrome (RS) 
(Hillmen et al 2016) and in an ongoing Phase 2 study in subjects 
with relapsed/refractory MCL (Wang et al 2017). 
AstraZeneca is developing a novel, oral, mammalian target of 
rapamycin (mTOR) inhibitor, vistusertib, which has shown in vitro 
and in vivo activity across a range of preclinical human cancer 
models.  In contrast to everolimus, temsirolimus or other rapalogs, 
which are solely mTORC1 inhibitors, vistusertib has a distinct 
mechanism of action as a dual mTORC1 and mTORC2 inhibitor.  
mTOR is part of the multiprotein complexes mTORC1 and 
mTORC2, which have been shown to play critical yet functionally 
distinct roles in the regulation of cellular processes.  A first-in-
human study of vistusertib has been conducted in subjects with 
advanced solid tumors (NCT01026402; Basu et al 2016) and 
several Phase 1 and 2 studies are currently being conducted. 
Pharmacodynamic analyses of the subject samples from the first-
in-human study showed inhibition of phosphorylation of S6 and 
protein kinase B (AKT) providing evidence for mTORC1 and 
mTORC2 inhibition, respectively.  Preliminary findings from an 
ongoing Phase 2 study (
) evaluating vistusertib 
monotherapy in DLBCL appear to show acceptable tolerability and 
activity in DLBCL.   
The mechanism of action of vistusertib suggests the potential to 
combine it with a number of anticancer treatments, including BTK 
inhibitors.  The multiplicity of mechanisms involved in transducing 
signals from the BCR and the existence of multiple negative 
feedback loops support the hypothesis that inhibiting BTK signaling 
together with inhibition of mTORC1/2 may deliver clinical benefit.  
In support of this theory, preclinical studies using a DLBCL cell line 
have shown greater efficacy when combining vistusertib with either 
ibrutinib or acalabrutinib compared with each agent administered 
alone. 
This proof-of-concept study will assess the clinical potential of a 
dual BTK and mTORC1/2 inhibition approach by evaluating the 
safety, pharmacokinetics (PK), pharmacodynamics (PD) and 
efficacy of acalabrutinib and vistusertib in relapsed/refractory 
subsets of B-cell malignancies.  
Study Design: 
This study is a multicenter, open-label, randomized (Part 1 only) 
parallel group study to be conducted at approximately 15 to 20 
sites.  The study was originally designed to be divided into 2 parts. 
The Phase 1 portion of the study (Part 1) evaluated the safety, PK, 
and PD of combining acalabrutinib 100 mg twice a day (bid) and 
vistusertib (various doses and schedules).  Part 1 was to be used 
to select the vistusertib dose and schedule for Phase 2.  The 
Phase 2 portion of the study (Part 2) was to allow for expansion 
groups in select B-cell histologies to further evaluate safety, 
CCI
CCI


 
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efficacy, and PKPD of the combination treatment; however, the 
sponsor has decided to close the study prior to initiating Part 2. 
Part 1 
Part 1 of the study will include adult subjects with any of the 
following relapsed/refractory disease types: 
• 
De novo DLBCL 
• 
Transformed DLBCL 
• 
Richter syndrome (RS) 
Subjects will take acalabrutinib twice per day at approximately 
12-hour intervals.  A treatment cycle is defined as 28 days.  The 
acalabrutinib dose will be 100 mg bid.  Acalabrutinib is 
administered on every day of the 28-day cycle.  Section 3.2 of the 
protocol provides the rationale for the study design and the 
rationale for the vistusertib dose and schedules evaluated in this 
protocol.  The study schema is presented in Figure 2. 
Although acalabrutinib monotherapy has not demonstrated dose-
limiting toxicities (DLTs) to date, the safety of the combination of 
acalabrutinib and vistusertib in this patient population needs to be 
assessed.  Therefore, a safety analysis (see Section 3.14) will 
occur when 6 subjects have been enrolled in each schedule (see 
below).  Eligible subjects will be randomized (1:1) to Schedule 1 or 
Schedule 2, Level -1 for both, using an Interactive Voice/Web 
Response System (IXRS). 
The following doses/schedules for vistusertib will be evaluated in 
combination with acalabrutinib 100 mg bid in Part 1: 
 
Level -1 
(Starting 
Dose) 
Target Level 
Level +1 
Continuous 
dosing 
schedule 
(Schedule 1) 
35 mg bid 
(daily) 
n=6 
50 mg bid 
(daily) 
n=6 
75 mg bid 
(daily) 
n=6 
Intermittent 
dosing 
schedule 
(Schedule 2) 
100 mg bid 
(2 days on/5 
days off) 
n=6 
125 mg bid 
(2 days on/5 
days off) 
n=6 
150 mg bid 
(2 days on/5 
days off) 
n=6 
Abbreviations: bid = twice per day 
Standard DLT criteria (defined below) will be used to assess safety 
of the combination during the first cycle of treatment.  Each 
schedule is independently assessed.  Escalation to the next level 
cannot occur until the DLT review as occurred.  If ≤1 DLTs occur 
during cycle 1 in the 6 subjects enrolled in a given schedule, then 
the dose of vistusertib will be escalated as outlined above and 


 
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6 new subjects will be enrolled and assessed for DLT.  Detailed 
information on DLT review and toxicity monitoring is provided in 
Section 3.7 and Section 3.14 of the protocol. 
The safety and PKPD results of subjects treated in Part 1 were to 
be used to select the vistusertib dose/schedule for Part 2.   
Any DLTs attributed to the combination after cycle 1 were also to 
be taken into consideration when determining the vistusertib dose 
and schedule for Part 2.   
Amendment 2 of this protocol added a higher dose level of 
vistusertib (Level +1) to Part 1 of the protocol.  However, as 
mentioned previously, the sponsor stopped the study after 
evaluating the efficacy, safety, PD, and PK data from the subjects 
treated with the lower dose levels of vistusertib. 
Part 2 
Part 2 was designed to consist of expansion groups of 15 or 20 
subjects per histology (N≤35 total for Part 2) provided the safety 
results from Part 1 of the study indicated that further evaluation of 
the combination was warranted.  As mentioned above, the study 
was closed before initiating Part 2. 
Subjects showing clinical benefit (ie, no disease progression) and 
who are tolerating study treatment may remain on study for up to a 
total of 12 cycles of treatment.  Subjects who have received 12 
cycles of treatment (ie, been on study for approximately 
12 months) and are deriving clinical benefit from acalabrutinib 
monotherapy or the combination of acalabrutinib and vistusertib 
may remain on study treatment beyond the first 12 months until 
disease progression occurs or be eligible to enroll in either a 
rollover study of acalabrutinib monotherapy or a rollover study of 
the combination of acalabrutinib and vistusertib, respectively. 
The schedule of assessments for combination treatment is 
provided in Appendix 1 and for acalabrutinib monotherapy is 
provided in Appendix 2. 
Definition of 
Dose-limiting 
Toxicity: 
Throughout the study, severity of adverse events (AEs) will be 
graded using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE). 
For Part 1, a DLT will be defined as the occurrence of any of the 
following AEs (Note that all AEs of the specified grades should be 
recorded as DLTs with the exception of those that are clearly, and 
incontrovertibly, due to extraneous causes such as disease 
progression): 
1. Any Grade ≥3 nonhematologic toxicity except Grade 3 nausea, 
vomiting, or diarrhea that respond to supportive therapy (eg, 
improvement by 1 or more severity grade within 48 hours).    
2. Any of the following hematologic toxicities: 


 
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a. Grade 4 neutrophil count decrease lasting >7 days, 
despite growth factor support 
b. Grade 4 platelet count decrease or Grade 3 platelet 
count decrease with bleeding  
c. Grade t3 febrile neutropenia 
d. Grade 4 anemia, unexplained by underlying disease  
3. Clinical tumor lysis syndrome (TLS) (defined in Table 3) that 
occurs despite protocol-recommended management will be 
considered a DLT. 
4. Laboratory TLS (defined in Table 4) will be considered a DLT if 
the metabolic abnormalities do not resolve within 72 hours 
despite protocol-required management. 
5. Dosing delay due to drug-related toxicity for >28 consecutive 
days 
A DLT excludes: 
1. Alopecia of any grade 
2. Isolated laboratory changes of any grade without clinical 
sequelae or clinical significance 
Study Objectives: 
Primary Objectives: 
Part 1 Objective: 
To determine a dose and schedule for vistusertib in combination 
with acalabrutinib 100 mg bid for evaluation in Part 2 
Part 2 Objective: 
To evaluate the safety of acalabrutinib and vistusertib when 
coadministered 
Secondary Objectives: 
x 
To evaluate the PK of acalabrutinib and vistusertib when 
coadministered 
x 
To evaluate the clinical activity of acalabrutinib and 
vistusertib, when coadministered, as measured by ORR, 
including CR rate, DOR, durable response rate (DRR), 
progression-free survival (PFS) and overall survival (OS) 
Exploratory Objectives: 
x 
 
 
 
 
 
 
CCI


 
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Safety Parameters: 
Type, frequency, severity, and relationship to study drug of any 
treatment-emergent adverse events (TEAEs) or abnormalities of 
laboratory tests, serious adverse events (SAEs), DLTs or AEs 
leading to discontinuation of study drug(s). 
Pharmacokinetic 
Parameters: 
The plasma PK of acalabrutinib and vistusertib will be 
characterized using noncompartmental analysis. The following PK 
parameters will be calculated, whenever possible, from plasma 
concentrations of analytes (Note: These will not be collected or 
assessed for subjects whose study participation extends past the 
first 12 cycles.): 
x 
AUC0-last:  Area under the plasma concentration-time curve 
calculated using linear trapezoidal summation from 
time 0 to time last, where “last” is the time of the last 
measurable concentration 
x 
AUC0-inf:  Area under the plasma concentration-time curve 
from 0 to infinity, calculated using the formula: 
AUC0-inf = AUC0-last + Clast / ȜzZKHUHȜz is the apparent 
terminal elimination rate constant 
x 
Cmax:  Maximum observed plasma concentration 
x 
Tmax:  Time of the maximum plasma concentration 
(obtained without interpolation) 
x 
t½:  Terminal elimination half-life (whenever possible) 
x 
Ȝz:  Terminal elimination rate constant (whenever possible) 
x 
CL/F:  Oral clearance 
CCI


 
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• 
Vz/F:  Oral volume of distribution 
Pharmacodynamic 
Parameters: 
The occupancy of BTK by acalabrutinib will be measured in 
peripheral blood mononuclear cells (PBMCs) with the aid of an 
acalabrutinib analogue probe.  The effect of acalabrutinib and 
vistusertib on biologic markers of B-cell function will also be 
evaluated in PBMCs and/or tumor tissue.  Cell populations will be 
monitored for effect of treatment, which may include, but are not 
limited to, leukocyte or lymphocyte subsets (eg, T, B and natural 
killer [NK] cells) and their activation states.  Additional PD markers 
include, but are not limited to, pS6, pBTK, pAKT, p4EBP1 and 
pPLCγ2. 
Efficacy Parameters: 
• 
ORR (CR + PR) 
• 
DRR 
• 
CR rate 
• 
DOR 
• 
PFS 
• 
OS 
Analysis of efficacy parameters is provided in Section 5.5.4.  The 
efficacy evaluations will not be assessed for subjects whose study 
participation extends past the first 12 cycles. 
Sample Size: 
A maximum of 3 dose levels were to have been explored in each 
of the two schedules (continuous/intermittent vistusertib dosing). 
The maximum number of subjects in Part 1 was therefore 36.  The 
sponsor stopped the study in Part 1 after treating 25 subjects with 
the first 2 dose levels of vistusertib. 
Inclusion Criteria: 
1. Diagnosis of relapsed/refractory DLBCL as documented by 
medical records and with histology based on criteria 
established by WHO: 
a. If a subject has de novo DLBCL, the diagnosis is 
confirmed by biopsy and is immunohistologically 
characterized as de novo non-GCB DLBCL or de novo 
GCB DLBCL.  Note that primary mediastinal B-cell 
lymphoma (PMBCL) is excluded from this protocol.  
Tumor tissue must also be available for sending to 
the sponsor for central cell of origin testing. 
b. If the subjects has RS, the diagnosis is confirmed by 
biopsy and is immunohistologically characterized as 
transformation to DLBCL.  Tumor tissue must also be 
available for sending to the sponsor for central 
pathology testing.  This histology applies to Part 1 
only. 
c. If the subjects has transformed DLBCL, the diagnosis is 
confirmed by biopsy and is immunohistologically 


 
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characterized as transformation to DLBCL from indolent 
lymphoma (eg, follicular lymphoma).  Tumor tissue 
must also be available for sending to the sponsor 
for central pathology testing.  This histology 
applies to Part 1 only. 
2. Men and women ≥18 years of age. 
3. Prior treatment for lymphoid malignancy: 
a. If the subject has DLBCL, there is no curative option 
with conventional therapy and the prior treatment 
included ≥1 prior combination chemoimmunotherapy 
regimen (eg, anthracycline-based therapy with 
rituximab, such as rituximab + cyclophosphamide, 
doxorubicin, vincristine, and prednisone [R-CHOP]).  
Also subjects should have relapsed after autologous 
stem cell transplant [ASCT] or should be noncandidates 
for ASCT. 
b. If the subject has RS, the subject must have had 
≥1 prior treatment with a combination 
chemoimmunotherapy regimen. 
4. Presence of radiographically measurable lymphadenopathy or 
extranodal lymphoid malignancy (defined as the presence of a 
≥1.5 cm lesion, as measured in the longest dimension by 
computed tomography [CT] scan for all histologies).   
5. Documented active disease that is relapsed or refractory 
defined as: 
a. Relapse:  disease progression after completion of the 
treatment regimen preceding entry into the study. 
b. Refractory:  progressive disease or stable disease as 
best response at any point during chemotherapy 
(>4 cycles of first-line or 2 cycles of later-line therapy) 
or relapsed at ≤12 months from autologous stem cell 
transplantation (Crump et al 2017). 
6. Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤2. 
7. Adequate hematologic function, independent of transfusion and 
growth factor support for ≥14 days before screening, defined 
as: 
a. Absolute neutrophil count (ANC) >1000 cells/mm3 
(1.0 x 109/L) 
b. Platelet count >75,000 cells/mm3 (75 x 109/L) or 
>50,000 cells/mm3 with bone marrow involvement 
c. Hemoglobin >8.0 g/dL 
8. Adequate hepatic and renal function at screening defined as: 
a. Serum aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤2.5 x upper limit of normal 
(ULN) if no demonstrable liver involvement or ≤3 x ULN 
in the presence of liver metastases 


 
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b. Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to 
Gilbert's syndrome or of non-hepatic origin) 
c. Serum creatinine ≤1.5 times ULN and creatinine 
clearance >30 mL/min (measured or calculated by 
Cockcroft and Gault equation [(140-Age) • Mass 
(kg)/(72 • creatinine mg/dL) • multiply by 0.85 if female]) 
9. Prothrombin time/international normalized ratio (PT/INR) 
<1.5 x ULN and activated partial thromboplastin time (aPTT) 
<1.5 x ULN. 
10. Serum potassium within normal range. 
11. Women should be using adequate contraceptive measures, 
should not be breast feeding and must have a negative 
pregnancy test before start of dosing if of child-bearing 
potential or must have evidence of nonchildbearing potential by 
fulfilling one of the following criteria at screening: 
a. Postmenopausal women, defined as either women 
aged >50 years and amenorrheic for ≥12 months 
following cessation of all exogenous hormonal 
treatments, or, women under 50 years old who have 
been amenorrheic for ≥12 months following the 
cessation of exogenous hormonal treatments, and have 
serum follicle-stimulating hormone (FSH) and luteinizing 
hormone (LH) levels in the postmenopausal range for 
the institution. 
b. Documentation of irreversible surgical sterilization by 
hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy but not tubal ligation. 
c. Medically confirmed, irreversible premature ovarian 
failure. 
Women who are sexually active and of childbearing potential 
must be willing to use 2 forms of contraception (see 
Section 3.11.7) from the time of screening to 90 days after 
discontinuing study drug(s). 
12. Men who are sexually active must use barrier contraception (ie, 
condoms) in addition to the highly effective contraception and 
refrain from sperm donation during the study and until 2 days 
after the subject’s last dose of acalabrutinib or 16 weeks after 
the subject’s last dose of vistusertib, whichever is longer.  If not 
done previously, storage of sperm before receiving vistusertib 
will be advised to male subjects with a desire to have children. 
13. Willing and able to participate in all required evaluations and 
procedures in this study protocol including swallowing 
capsules/tablets without difficulty. 
14. Willing to follow sunlight protection measures while taking 
vistusertib (eg, using sunscreen and avoiding excessive sun 
exposure) and for 90 days after the last dose of vistusertib. 
15. Ability to understand the purpose and risks of the study and 
provide signed and dated informed consent and authorization 


 
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to use protected health information (in accordance with 
national and local patient privacy regulations). 
 
Host genetics research study (optional): 
For inclusion in the optional genetic component of the study, 
subjects must fulfil the following additional criteria: 
16. Provision of signed, written, and dated informed consent for 
genetic research.  If a subject declines to participate in the 
genetic component of the study, there will be no penalty or loss 
of benefit to the subject.  The subject will not be excluded from 
other aspects of the study described in this protocol, so long as 
they consented to the main study. 
17. Whole blood transfusion given within 120 days of genetic 
sample collection should be leukocyte depleted. 
 
Tumor biopsy study (optional): 
For inclusion in the optional tumor biopsy component of the study, 
subjects must fulfil the following additional criteria: 
18. Provision of signed, written, and dated informed consent for 
fresh lymph node tumor biopsies (at baseline, on study and at 
progression).  If a subject declines to participate in the tumor 
biopsy component of the study, there will be no penalty or loss 
of benefit to the subject.  The subject will not be excluded from 
other aspects of the study described in this protocol, so long as 
they consented to the main study. 
19. Presence of superficial lymphadenopathy for the lymph node 
biopsy. 
Exclusion Criteria: 
All Parts: 
1. History of prior malignancy except for the following: 
a. Malignancy treated with curative intent and with no 
evidence of active disease present for more than 
2 years before screening and felt to be at low risk 
for recurrence by treating physician.   
b. Adequately treated lentigo maligna melanoma 
without current evidence of disease or adequately 
controlled nonmelanomatous skin cancer. 
c. Adequately treated carcinoma in situ without current 
evidence of disease.    
2. As judged by the Investigator, any evidence of severe or 
uncontrolled systemic disease (eg, severe hepatic impairment, 
interstitial lung disease [bilateral, diffuse, parenchymal lung 
disease]), or current unstable or uncompensated respiratory or 
cardiac conditions, or uncontrolled hypertension, history of, or 
active, bleeding diatheses (eg, hemophilia or von Willebrand 
disease) or uncontrolled active systemic fungal, bacterial, viral, 
or other infection (defined as exhibiting ongoing 
signs/symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other 


 
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treatment), or intravenous anti-infective treatment within 
2 weeks before first dose of study drug. 
3. Diagnosis of PMBCL. 
4. Known history of infection with human immunodeficiency virus 
(HIV). 
5. Serologic status reflecting active hepatitis B or C infection.   
a. Subjects who are hepatitis B core antibody positive 
(anti-HBc) and who are surface antigen negative will 
need to have a negative polymerase chain reaction 
(PCR) result before enrollment.  Those who are 
hepatitis B surface antigen positive or hepatitis B 
PCR positive will be excluded. 
b. Subjects who are hepatitis C antibody positive will 
need to have a negative PCR result before 
enrollment.  Those who are hepatitis C PCR 
positive will be excluded. 
6. Active cytomegalovirus (CMV) infection (positive CMV 
immunoglobulin M [IgM] and/or positive PCR result) 
7. Undergone any of the following procedures or experienced any 
of the following conditions currently or in the preceding 
6 months: 
a. coronary artery bypass graft 
b. angioplasty 
c. vascular stent 
d. myocardial infarction 
e. angina pectoris 
f. congestive heart failure (New York Heart 
Association [NYHA] Grade ≥2) 
g. ventricular arrhythmias requiring continuous therapy 
h. supraventricular arrhythmias, including atrial 
fibrillation, which are uncontrolled 
i. 
hemorrhagic or thrombotic stroke, including 
transient ischemic attacks or any other central 
nervous system bleeding. 
8. Current refractory nausea and vomiting, malabsorption 
syndrome, disease significantly affecting gastrointestinal (GI) 
function, resection of the stomach, extensive small bowel 
resection that is likely to affect absorption, symptomatic 
inflammatory bowel disease, partial or complete bowel 
obstruction, or gastric restrictions and bariatric surgery, such 
as gastric bypass. 
9. History of central nervous system (CNS) lymphoma, 
leptomeningeal disease or spinal cord compression. 
10. History of severe allergic or anaphylactic reactions to kinase 
inhibitors or history of hypersensitivity to active or inactive 
excipients of vistusertib or acalabrutinib or drugs with a similar 
chemical structure or class to vistusertib or acalabrutinib. 


 
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11. Presence of a GI ulcer diagnosed by endoscopy within 
3 months before screening. 
12. Uncontrolled Type 1 or Type 2 diabetes mellitus (eg, 
hemoglobin A1c ≥7%). 
13. Any clinically significant pre-existing severe renal disease (eg, 
glomerulonephritis, nephritic syndrome, Fanconi Syndrome or 
renal tubular acidosis) or high risk of developing severe renal 
impairment. 
14. Major surgical procedure within 28 days before first dose of 
study drug.  Note:  If a subject had major surgery, they must 
have recovered adequately from any toxicity and/or 
complications from the intervention before the first dose of 
study drug. 
15. Unresolved toxicities from prior anticancer therapy, defined as 
having not resolved to CTCAE [Version 5.0] Grade 0 or 1, or to 
the levels dictated in the inclusion/exclusion criteria, with the 
exception of alopecia. 
16. Any hematopoietic growth factors (eg, filgrastim [granulocyte 
colony-stimulating factor; G-CSF], sargramostin [granulocyte-
macrophage colony-stimulating factor; GM-CSF]) within 7 days 
of the first dose of study drug or pegylated G-CSF 
(pegfilgrastim) or darbepoetin within 14 days of the first dose of 
study drug. 
17. Vaccinated with live, attenuated vaccines within 4 weeks of first 
dose of study drug. 
18. Abnormal echocardiogram (ECHO) or multi-gated acquisition 
scan (MUGA) at baseline (left ventricular ejection fraction 
[LVEF] <40% and shortening fraction <15%).  Appropriate 
correction to be used, if a MUGA is performed. 
19. Mean resting corrected QT interval (QTc) calculated using 
Fridericia's formula (QTcF) >450 msec obtained from 
3 electrocardiograms (ECGs); family or personal history of long 
or short QT syndrome; Brugada syndrome or known history of 
QTc prolongation or torsade de pointes within 12 months of the 
subject entering the study. 
20. Factors that increase the risk of QTc prolongation or risk of 
arrhythmic events such as heart failure, or family history of 
sudden unexplained death under 40 years of age.  
Concomitant medications known to prolong QTc should be 
used with caution and cannot be used during the first 28 days 
on study. 
21. Any therapeutic antibody within 4 weeks of first dose of study 
drugs. 
22. Prior use of standard antilymphoma therapy or radiation 
therapy within 14 days of receiving the first dose of study drug 
(not including palliative radiotherapy).  Subjects must have 
recovered from acute toxicity due to prior treatment.  Note:  
Subjects previously treated with BTK, mTOR or 
phosphoinositide 3 kinase (PI3K) inhibitors are not excluded 


 
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from this protocol; however, the 14-day washout and recovery 
from acute toxicity from these agents still applies. 
23. Ongoing immunosuppressive therapy, including systemic (eg, 
intravenous or oral) corticosteroids for treatment of lymphoid 
cancer or other conditions. Note:  Subjects may use topical or 
inhaled corticosteroids or low-dose steroids (≤10 mg of 
prednisone or equivalent per day) as therapy for comorbid 
conditions. During study participation, subjects may also 
receive systemic corticosteroids as needed for treatment-
emergent comorbid conditions. 
24. Exposure to strong or moderate inhibitors or inducers of 
cytochrome P450 (CYP) 3A4/5, permeability glycoprotein (P-
gp), or breast cancer resistance protein (BCRP), if taken within 
the stated washout periods before the first dose of study drug 
(see Appendix 4). 
25. Exposure to specific substrates of the drug transporters 
OATP1B1, OATP1B3, MATE1 and MATE2K within the 
appropriate washout period for each drug (a minimum of 5 x 
reported elimination half-life) before the first dose of study drug 
(see Appendix 4). 
26. Requires or receiving therapeutic anticoagulants, with the 
exception of short-acting heparins, within 7 days of first dose of 
study drug. 
27. Requires treatment with proton-pump inhibitors (eg, 
omeprazole, esomeprazole, lansoprazole, dexlansoprazole, 
rabeprazole, or pantoprazole).  Subjects receiving proton-pump 
inhibitors who switch to H2-receptor antagonists or antacids 
are eligible for enrollment to this study. 
28. Recent history (past 12 months) of drug abuse or alcohol 
abuse, as judged by the investigator. 
29. Concurrent participation in another therapeutic clinical trial. 
Dosage Form and 
Strength: 
Acalabrutinib drug product is provided as hard gelatin capsules for 
oral administration.  The capsules contain 100 mg of acalabrutinib. 
Vistusertib drug product is provided as round or oval, film-coated 
tablets for oral administration.  Tablets contain either 25, 35 or 
50 mg of vistusertib. 
Dose Regimen/Route 
of Administration: 
Acalabrutinib and vistusertib are orally administered products.  
Both drugs will be administered concomitantly.  On dosing days, 
each drug is administered bid and should be administered 
approximately 12 hours apart. 
The regimens evaluated in this protocol are specified in the study 
design section. 
Concomitant 
Medications: 
Subjects should avoid the use of calcium carbonate containing 
drugs or supplements for a period of ≥2 hours before and ≥2 hours 
after taking acalabrutinib.  Use of omeprazole, esomeprazole, 
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acalabrutinib is not recommended due to a potential decrease in 
study drug exposure. Although the effect of H2-receptor 
antagonists (such as famotidine or ranitidine) on acalabrutinib 
absorption has not been evaluated, if treatment with an H2-
receptor antagonist is required, the H2-receptor antagonist should 
be taken approximately 2 hours after an acalabrutinib dose.  
Use of concomitant medications which are moderate or strong 
inhibitors or inducers of CYP3A4/5, P-gp and BCRP, or specific 
substrates of the drug transporters OATP1B1, OATP1B3, MATE1 
and MATE2K should be avoided when possible.  Detailed 
information on short-term concomitant administration of these 
drugs is provided in the protocol.  
Details on permitted and required concomitant medications are 
provided in the protocol. 
Statistics: 
Descriptive statistics (including means, standard deviations, and 
medians for continuous variables and proportions and confidence 
intervals [CIs] for discrete variables) will be used to summarize 
data as appropriate.  Response rate will be investigator assessed 
using standard response criteria (Cheson et al 2014; see 
Appendix 9).  Kaplan-Meier (KM) methods will be used to estimate 
DOR, PFS, and OS and corresponding quartiles (including the 
median). 
The primary objective of this study is evaluating the safety of 
acalabrutinib 100 mg bid with vistusertib (either continuous dosing 
or intermittent dosing).  The objective of Part 1 is to select a 
vistusertib dose and regimen for the Phase 2 portion of the study 
(Part 2).  
In Part 1 (DLT assessment), 12 to 36 subjects will be enrolled to 
evaluate different dose levels and schedules of vistusertib. 
In Part 2 (expansion groups), enrollment of approximately 15 or 
20 subjects per histology (approximately N=35 total) was to offer 
the opportunity to evaluate further the safety and PKPD of the 
chosen dose/schedule for vistusertib from Part 1.  However, the 
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1.0 
BACKGROUND INFORMATION 
Note the information provided in this section of the protocol represents the most up to 
date information available when the protocol was being drafted.  For the most up to date 
information, particularly with regard to clinical safety information, please refer to the most 
recent version of the Acalabrutinib Investigator Brochure or the Vistusertib Investigator 
Brochure.  
1.1 
ACALABRUTINIB (ACP-196) 
Acalabrutinib is (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)-imidazo[1,5-α]pyrazin-1-
yl)-N-(pyridin-2-yl)-benzamide.  Acalabrutinib is a selective, irreversible small molecule 
BTK inhibitor.  Acalabrutinib is also known as ACP-196. 
The first BTK inhibitor developed for clinical use, ibrutinib (IMBRUVICA®), has been 
approved in the United States and Europe for the treatment of CLL/SLL, MCL and WM.  
Ibrutinib also has recently been approved in the United States for MZL.  While potent in 
inhibiting BTK, ibrutinib has also shown in vitro activity against other kinases with a 
cysteine (Cys) in the same relative position as Cys481 of BTK, to which the drug 
covalently binds (Honigberg et al 2010).  These off-target activities may contribute to the 
toxicity profile observed for ibrutinib (Warnings and Precautions, ibrutinib prescribing 
information) and could lead to discontinuation of ibrutinib.  In addition, ibrutinib is 
primarily metabolized by CYP3A.  Thus, ibrutinib dosing must be halted or reduced when 
coadministered with drugs that are strong or moderate inhibitors of CYP3A (ibrutinib 
prescribing information).  Recent data suggest ibrutinib treatment breaks (eg, treatment 
breaks >14 days including discontinuation) negatively impact overall survival in patients 
with CLL (UK CLL Forum 2016).  Therefore, development of alternative BTK inhibitors is 
needed for the treatment of B-cell malignancies. 
Acerta Pharma is developing acalabrutinib for the treatment of patients with cancer.  
Acalabrutinib is orally administered in humans and is suitable for formulating in capsules.  
For clinical testing, acalabrutinib has been manufactured and formulated according to 
current Good Manufacturing Practices (cGMP). 
Acalabrutinib (CALQUENCE®) has been approved in the United States and other 
markets for the treatment of adult patients with MCL who have received at least 1 prior 
therapy (CALQUENCE package insert).   


 
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1.1.1 
Safety Pharmacology and Toxicology 
In vitro and in vivo safety pharmacology and toxicology studies with acalabrutinib have 
demonstrated a favorable nonclinical safety profile; for detailed information, refer to the 
Acalabrutinib Investigator Brochure.   
1.1.2 
Drug-drug Interaction Potential 
For detailed information on drug-drug interaction potential for acalabrutinib, refer to the 
Acalabrutinib Investigator Brochure.  Please refer to Section 3.11.5 of this protocol for 
guidance on drugs that may cause drug-drug interactions. 
1.1.3 
Clinical Experience  
As of 03 September 2017, acalabrutinib has been administered to over 2000 participants 
in clinical studies, including subjects with hematologic malignancies, solid tumors, or 
rheumatoid arthritis, and participants who are healthy volunteers or with mild to 
moderate hepatic impairment.  No SAEs have been reported in the hepatic impairment 
study or in the healthy volunteer studies.  No DLTs have been identified in any studies 
for acalabrutinib monotherapy or in combination with other agents.  Identified risks for 
acalabrutinib include bleeding events (eg, epistaxis, bruising, and hematoma), 
headaches, gastrointestinal events (eg, diarrhea and nausea/vomiting), and rash; all 
mostly low grade and nonserious.  For detailed information on the clinical experience for 
acalabrutinib, please refer to the Acalabrutinib Investigator Brochure.   
Preliminary efficacy data are summarized below from ACE-CL-001 (
), an 
ongoing nonrandomized, sequential group, dose-escalation Phase 1/2 study in subjects 
with relapsed/refractory or previously untreated CLL, RS or prolymphocytic leukemia. 
As of 01 October 2015, 60 subjects with relapsed CLL have been evaluated for tumor 
response based on modified International Working Group response criteria (Hallek et al 
2008) as recently updated (Cheson et al 2012) to include PR with treatment-induced 
lymphocytosis.  With a median follow up of 14.3 months, an ORR of 95% has been 
observed (Byrd et al 2016).  Few subjects have had disease progression. 
As of 28 February 2017, 124 subjects with relapse/refractory MCL treated with 
acalabrutinib 100 mg twice per day (bid) have been evaluated for tumor response using 
the Lugano Classification (Cheson et al 2014).  At a median follow-up of 15.2 months, 
100 (81%) subjects achieved an overall response and 49 (40%) subjects achieved a 
complete response (Wang et al 2017). The Kaplan-Meier estimated medians for duration 
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of response, progression-free survival, and overall survival were not reached; the 
12-month rates were 72% (95% CI 62–80), 67% (58–75), and 87% (79–92%), 
respectively (Wang et al 2017). 
1.2 
VISTUSERTIB (AZD2014) 
Vistusertib, also known as AZD2014, is an inhibitor of mTOR kinase, which plays a 
critical role in regulating cellular energy sensing, growth and metabolism.  Deregulation 
of mTOR signaling is observed in many tumors types (Chiarini et al 2015; Xu et al 2014), 
and mutations or loss of function of upstream regulators have been reported in most 
types of human tumors (Thorpe et al 2015; Martini et al 2014).  The PI3K/AKT/mTOR 
cellular signaling pathway is summarized in Figure 1. 
The mTOR kinase forms 2 distinct multiprotein complexes called mTORC1 and 
mTORC2.  The mTORC1 complex plays a key role in coupling nutrient sensing with the 
regulation of protein translation and cellular metabolism processes.  It directly 
phosphorylates proteins such as p70S6K (S6K) (Magnuson et al 2012) and 4E-BP1 
(Hsieh et al 2010), which are involved in controlling cellular growth and proliferation, as 
well as sterol regulatory element-binding protein (SREBP) (Bakan & Laplante 2012), a 
key modulator of metabolism and lipid synthesis.  The mTORC1 complex also 
phosphorylates a number of substrates that modulate autophagy and lysosome 
biogenesis (Betz & Hall 2013).  The mTORC2 complex has been reported to play a role 
in the cellular response to extracellular growth factors through largely unknown 
mechanisms.  Its activation requires association with ribosomes and results in the 
phosphorylation of downstream targets such as the AGC family of protein kinases, which 
includes AKT, serine/threonine-protein kinase (SGK), and protein kinase C (PKC) (Su & 
Jacinto 2011). 
Rapamycin and its analogues (rapalogues) are potent inhibitors of mTORC1 and have 
been shown to be clinically effective in certain cancer types such as endometrial cancer, 
MCL, DLBCL, FL, renal cell carcinoma, and breast cancer (Faivre et al 2006; Witzig et al 
2005; Witzig et al 2011, Baselga et al 2012).  However, resistance to rapamycin and its 
analogues has been shown to limit their response rates in clinical studies. 
Vistusertib is a selective inhibitor of mTOR kinases and, unlike rapalogues, inhibits 
signaling of mTORC1 and mTORC2 complexes (Guichard et al 2015).  Vistusertib is 
therefore molecularly differentiated from rapamycin and its analogues (eg, everolimus 
and temsirolimus), which are solely mTORC1 inhibitors.  In addition to its dual inhibition 


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of mTORC1 and mTORC2, vistusertib achieves a more profound inhibition of mTORC1 
and shows a broader range of growth inhibitory activity in vitro across tumors types 
compared with rapalogues.   
While early clinical data using allosteric mTORC1 inhibitors have suggested some 
activity in a number of hematologic diseases, these agents have shown limited efficacy 
as monotherapies.  However, the multiplicity of mechanisms involved in transducing 
signals from the BCR and the existence of multiple negative feedback loops, suggests 
that inhibition of BTK in combination with inhibition of mTOR may deliver clinical benefit 
in BCR driven cancers (Lee et al 2016). 
AstraZeneca is developing vistusertib for the treatment of patients with cancer.  
Vistusertib is orally administered in humans and is suitable for formulating in tablets.  For 
clinical testing, vistusertib has been manufactured and formulated according to current 
cGMP. 
Vistusertib is an investigational product and has not been approved for marketing in any 
country.  Further details are provided in the Vistusertib Investigator Brochure. 
Figure 1.  PI3K/AKT/mTOR pathway 
 


 
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Simplified scheme of the mTOR signaling network.  Signals from diverse extra- and intracellular 
cues (such as growth factors, stress, energy, and nutrients) are sensed and integrated by the 
output of the two functionally distinct complexes — mammalian target of rapamycin complex 1 
(mTORC1) and mTORC2 — to deliver a coordinated cellular response.  Abbreviations:  AKT, 
protein kinase B ;4EBP1, eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1; 
AMPK, AMP-activated protein kinase; BAD Bcl-2-associated death promoter; FOXO Forkhead 
box protein O1; GSK3, Glycogen synthase kinase 3; PDK1, phosphoinositide-dependent protein 
kinase 1; PHLPP, PH domain and leucine rich repeat protein phosphatases; PI3K, 
phosphoinositide 3 kinase; PIP, phosphatidylinositol phosphate; PRAS40, proline-rich AKT 
substrate of 40 kDa; PTEN, phosphatase and tensin homologue; Rheb, Ras homolog enriched in 
brain; S6K, S6 kinase; TSC, tuberous sclerosis protein. 
 
1.2.1 
Safety Pharmacology and Toxicology 
In vitro and in vivo safety pharmacology and toxicology studies with vistusertib have 
demonstrated that vistusertib has an acceptable safety profile for administration to 
patients with cancer; for detailed information, refer to the Vistusertib Investigator 
Brochure.   
1.2.2 
Drug-drug Interaction Potential 
For detailed information on drug-drug interaction potential for vistusertib, refer to the 
Vistusertib Investigator Brochure. 
Please refer to Section 3.11.5 for guidance on drugs that may cause drug-drug 
interactions. 
1.2.3 
Clinical Experience 
As of cut-off date of 05 October 2015, 547 subjects have been enrolled in studies with 
vistusertib; 252 in AstraZeneca-sponsored studies, and 295 in externally sponsored 
collaborative research (ESCR) studies.  A total of 465 subjects have received vistusertib: 
252 in AstraZeneca -sponsored studies and approximately 213 in ESCR studies.   
Two AstraZeneca-sponsored Phase 1 studies were designed to assess the safety, 
tolerability, PK and preliminary efficacy of vistusertib: D2270C00001 (monotherapy in 
subjects with advanced cancer; the first-in-human study), and D2270C00005 (in 
combination with fulvestrant in subjects with metastatic breast cancer).  
Pharmacodynamic analyses of the subject samples from the first-in-human study 
(D2270C00001) showed inhibition of phosphorylation of S6 and protein kinase B (AKT) 
providing evidence for mTORC1 and mTORC2 inhibition, respectively (NCT01026402; 
Basu et al 2016).  Study D2270C00001 is now complete and Clinical Study Report 
(CSR) is available, while study D2270C00005 is ongoing. 


 
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In addition, vistusertib has been administered as monotherapy to Japanese subjects with 
advanced solid malignancies in Study D2270C00005 (Japan PK) and to subjects with 
relapsed or refractory squamous non-small cell lung cancer after at least one line of 
therapy in combination with paclitaxel in Study D2274C00001 (STORK). 
Several doses and dosing schedules of vistusertib have been explored in the 
monotherapy (D2270C00001) and combination (D2270C00005) studies:   
Table 1.  Vistusertib monotherapy (D2270C00001) 
Dosing schedule 
Doses explored 
Defined MTD 
Intermittent weekly bid 
dosing (2 consecutive 
days, 2 days on, 5 days 
off) 
100 mg, 125 mg 170 mg, 225 
mg  
125 mg (2 consecutive 
days, 2 days on, 
5 days off) 
Continuous bid dosing 
25 mg, 50 mg, 75 mg, 100 mg  
50 mg  
Continuous qd dosing 
75 mg, 100 mg, 125 mg, 175 
mg  
100 mg  
Abbreviations:  bid = twice daily dosing; qd = once daily dosing; MTD = maximum 
tolerated dose. 
 
Table 2.  Vistusertib in combination with fulvestrant (D2270C00005) 
Dosing schedule 
Doses explored 
Recommended dose/ 
defined MTD 
Intermittent bid dosing (2 
consecutive days, 2 days 
on 5 days off) 
125 mg, 170 mg 
125 mg (2 consecutive 
days, 2 days on 5 days 
off), under fasting and 
fed conditions 
Continuous bid dosing 
35 mg, 50 mg 
50 mg 
Continuous qd dosing 
75 mg, 100 mg 
75 mg 
Abbreviations:  bid = twice daily dosing; qd = once daily dosing; MTD = maximum 
tolerated dose. 
 
Details of all vistusertib studies, including 10 ESCRs, are summarized in the Vistusertib 
Investigator Brochure.   
Key Efficacy Findings for Vistusertib   
Monotherapy 
In the monotherapy study (D2270C00001) at the 50-mg bid dose in a total of 
40 subjects, 2 subjects had an objective response; 1 subject with pancreatic acinar cell 


 
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type cancer and 1 subject with estrogen receptor positive breast cancer had confirmed 
PR according to Response Evaluation Criteria In Solid Tumors (RECIST) and received 
vistusertib treatment for 175 and 206 days, respectively.  In addition, 12 subjects in the 
50-mg bid group, and 4 subjects each in the 100-mg qd and 125-mg intermittent cohort 
achieved stable disease.  
Combination with fulvestrant (Faslodex®) 
For the combination study with fulvestrant (D2270C00005) information is included the 
Vistusertib Investigator Brochure on the best objective responses in all subjects and in 
subjects with measurable disease at baseline.   
Based on data from 05 October 2015, vistusertib in combination with fulvestrant has 
demonstrated encouraging response rate data in this Phase 1 setting at maximum 
tolerated doses (MTDs) for the continuous and intermittent dosing schedules.  There 
were PRs (confirmed and unconfirmed) at every MTD dose group: 3/11 (27%) with a 
confirmed response rate of 2/11 (18%) in the 50-mg bid continuous dosing group, 
3/13 (23%) with a confirmed response rate of 2/13 (15%) in the 75-mg qd continuous 
dosing group, and 3/20 (15%) with a confirmed response rate of 1/20 (5%) in the 125-mg 
bid intermittent dosing group. 
Key Safety Findings for Vistusertib 
The overall safety findings at vistusertib MTDs in Phase 1 trials in monotherapy and in 
combination with fulvestrant were very similar and the main AEs observed are consistent 
with AEs already reported for other mTOR inhibitors: rash, pruritus, mucositis, fatigue, 
nausea, vomiting, diarrhea, constipation and decreased appetite.   
Monotherapy 
In Study D2270C00001, 87% of subjects experienced ≥1 AE considered related to 
vistusertib by the reporting investigator.  The most common AEs related to study 
treatment (occurring in ≥15% subjects overall across all cohorts) were fatigue (59%), 
nausea (48%), mucositis (30%), diarrhea (28%), rash (27%), decreased appetite (22%), 
vomiting (22%) and hyperglycemia (16%).  Dose-limiting toxicities (DLTs) reported at 
nontolerated doses were fatigue, diarrhea, mucositis, nausea, vomiting and rash.  During 
the study, 55/135 (41%) subjects had an SAE, and 24/135 (18%) had a treatment-
related SAE.  One subject died due to an AE of pulmonary embolism during the study; 
this was deemed unrelated to treatment by the investigator.  Twenty-six subjects (19%) 


 
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reported at least 1 AE leading to discontinuation.  The most common AEs leading to 
discontinuation of vistusertib (reported in ≥4 subjects overall) were fatigue (7%), nausea 
(4%), decreased appetite (3%), diarrhea (3%), mucositis (3%), rash (3%), and vomiting 
(3%). 
Although most subjects experienced an AE, the drug was considered to be well tolerated 
with easily manageable side effects by the investigators.  A total of 68 subjects (50%) 
experienced an AE Grade 3, 1 subject (1%) had a Grade 4 AE, and 1 subject (1%) had a 
Grade 5 AE (incidence rates include DLTs at non-tolerated doses).  Fifteen (12%) 
subjects on doses below the MTD experienced AEs that led to the discontinuation of 
vistusertib, and no subjects on a dose below the MTD for the qd continuous and 
intermittent (2 consecutive days, 2 days on, 5 days off) dosing schedules reported any 
AEs which led to discontinuation.  AEs that defined the drug’s nontolerability were 
generally reversible within a week of stopping treatment with vistusertib.  One hundred 
and five subjects (78%) had a duration of treatment (including periods of dose 
interruption) of >3 months.  One subject had duration of treatment of 18 months. 
Combination with fulvestrant (Faslodex®) 
At the Study D2270C00005 (Study 5, combination with fulvestrant) MTD doses 
(continuous and intermittent dosing), the most frequently reported AEs related to 
vistusertib (reported in ≥15% subjects overall) were fatigue, nausea, rash, diarrhea, 
decreased appetite, vomiting, hyperglycemia, mucositis, pruritus, headache, anemia, 
asthenia, dry skin, constipation, dizziness and skin hyperpigmentation.  The most 
frequently reported AEs of Grade ≥3 (reported in >1 subject at an MTD, irrespective of 
causality) were rash, fatigue, nausea, infections, mucositis, vomiting, anemia, diarrhea, 
hyperglycemia, and hypophosphatemia. 
At the Study D2270C00005 (Study 5, combination with fulvestrant) MTD doses, no SAE 
Medical Dictionary for Regulatory Activities (MedDRA) term was reported in >1 subject. 
The SAEs in the continuous dosing groups of 50 mg bid plus fulvestrant and 75 mg qd 
plus fulvestrant were pulmonary embolism, infections, neutropenia, renal impairment, 
and spinal compression fracture. The SAEs in the intermittent dosing group of 125 mg 
bid plus fulvestrant were vomiting, nausea, hypercalcemia, diarrhea, infections, colitis, 
enteritis and subdural hematoma. Two subjects had related SAEs: 1 subject (75 mg qd) 
had Grade 4 febrile neutropenia; and 1 subject (125 mg bid) had Grade 3 nausea, Grade 


 
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3 vomiting, and Grade 3 diarrhea. All these SAEs were considered by the investigator to 
be related to vistusertib, but not fulvestrant. 
There was one death due to an AE in the Study D2270C00005 (Study 5, combination 
with fulvestrant) MTD of 75 mg qd + fulvestrant (continuous dosing). This was an AE of 
sepsis of unknown etiology, which was deemed unrelated to treatment by the 
investigator.   
Although there has been no formal comparison of the safety of vistusertib administered 
alone or in combination with fulvestrant, the safety profiles appear similar. 
Additional clinical safety information for vistusertib in combination with paclitaxel can be 
found in the Vistusertib Investigator Brochure. 
1.3 
BENEFIT/RISK 
Aberrant activation of mTOR can occur via variety of mechanisms in BCR-driven 
malignancies, including activation/mutation of PI3K, activation of spleen tyrosine kinase 
(SYK), PKC or BTK.  The evidence that mTOR functions at the convergence of many of 
the above signaling pathways, provides a solid rationale for the use of mTOR in 
combination with BTK inhibitors in hematologic diseases. 
Agents that target components of the PI3K-AKT-mTOR pathway are under investigation 
for the treatment of DLBCL (Blum 2015).  Given the highly heterogeneous nature of 
DLBCL, it is not clear whether all subtypes of DLBCL will be susceptible to PI3K 
inhibitors, or whether inhibition of TORC1 alone will deliver efficacy in this disease.  The 
mTOR inhibitor, everolimus, has shown clinical activity in MCL, DLBCL and high-grade 
FL (Witzig et al 2005; Witzig et al 2011).  Preliminary findings from an ongoing Phase 2 
study (
) evaluating vistusertib monotherapy in DLBCL appear to show 
acceptable tolerability and activity in GCB and non-GCB subtypes of DLBCL.  Ibrutinib 
monotherapy has shown clinical activity in patients with de novo DLBCL, including 
patients with GCB subtype of DLBCL showing that the BTK pathway can be active even 
in patients with GCB subtype (Wilson 2015).  Ibrutinib monotherapy has also shown 
clinical activity in RS, as has acalabrutinib (Ayers & Mato 2016, Hillmen et al 2016).   
In nonclinical models of DLBCL, the combination of the BTK inhibitor, ibrutinib, with 
vistusertib delivered regressions and strong apoptosis induction. In these models, 
synergistic inhibition of BCR signaling was observed, particularly inhibition of cap-
dependent translation and NF-ț%VLJQDOLQJEzell et al 2014).  Similar results have been 
CCI


 
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obtained with acalabrutinib in combination with vistusertib (see Section 3.2.1).  In 
summary, there is compelling nonclinical and clinical rationale for exploring the 
combination of mTOR and BTK inhibition for the treatment of patients with B-cell 
malignancies. 
As of 03 September 2017, acalabrutinib has been administered to over 2000 participants 
in clinical studies, including subjects with hematologic malignancies, solid tumor, or 
rheumatoid arthritis, and participants who are healthy volunteers or with mild to 
moderate hepatic impairment.  No SAEs have been reported in the hepatic impairment 
trial or in the healthy volunteer trials.  Acalabrutinib has been administered alone and in 
combination with other kinase inhibitors, anti-CD20 antibodies, chemoimmunotherapy 
(eg, bendamustine/rituximab), and an anti-programmed cell death 1 (PD-1) receptor 
antibody.  No DLTs have been identified for acalabrutinib monotherapy or when 
administered in combination with the aforementioned agents.  Current clinical safety 
data supports combining acalabrutinib with other agents. 
As of 05 October 2015, 547 subjects have been enrolled in studies with vistusertib.  A 
total of 465 subjects have received vistusertib alone or in combination with other agents.  
DLTs reported at nontolerated doses for vistusertib were fatigue, diarrhea, mucositis, 
nausea, vomiting and rash.  Of these AEs, gastrointestinal effects (eg, diarrhea, nausea 
and vomiting, and rash) are overlapping with observed AEs for acalabrutinib.  Therefore, 
the primary objective of this protocol is to determine the safety of this combination in 
subjects with relapsed/refractory disease and few therapeutic options.  As such, this 
study includes a formal DLT assessment of subjects dosed with the combination (see 
Section 3.0).  In addition, toxicity management guidelines are provided in this protocol 
for potential overlapping toxicities and other AEs (see Section 3.9).  Lastly, this protocol 
includes study-stopping guidelines as outline in Section 3.13. 
2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE: 
Part 1 Primary Objective: 
To determine a dose and schedule for vistusertib in combination with acalabrutinib 
100 mg bid for evaluation in Part 2 
Part 2 Primary Objectives: 
To evaluate the safety of acalabrutinib and vistusertib when coadministered 


 
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2.2 
SECONDARY OBJECTIVES: 
x 
To evaluate the PK of acalabrutinib and vistusertib when coadministered 
x 
To evaluate the clinical activity of acalabrutinib and vistusertib, when 
coadministered, as measured by ORR, including CR rate, DOR, DRR, PFS and 
OS 
2.3 
EXPLORATORY OBJECTIVES: 
x 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
3.0 
STUDY DESIGN 
This study is a multicenter, open-label, randomized (Part 1 only) parallel group study to 
be conducted at approximately 15 to 20 sites.  The study was originally designed to be 
divided into 2 parts. The Phase 1 portion of the study (Part 1) evaluated the safety, PK, 
and PD of combining acalabrutinib 100 mg bid and vistusertib (various doses and 
schedules).  Part 1 was to be used to select the vistusertib dose and schedule for Phase 
2.  The Phase 2 portion of the study (Part 2) was to allow for expansion groups in select 
B-cell histologies to further evaluate safety, efficacy, and PKPD of the combination 
treatment; however, the Sponsor has decided to close the study prior to initiating Part 2. 
Part 1 
Part 1 of the study will include adult subjects with any of the following relapsed/refractory 
disease types: 
x 
De novo DLBCL 
x 
Transformed DLBCL 
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• 
RS 
Subjects will take acalabrutinib bid at approximately 12-hour intervals.  A treatment cycle 
is defined as 28 days.  The acalabrutinib dose will be 100 mg bid.  Acalabrutinib is 
administered on every day of the 28-day cycle.  Eligible subjects will be randomized 1:1 
to receive one of the following starting regimens of vistusertib using an IXRS: 
Schedule 1 (continuous dosing):  Vistusertib 35 mg bid continuous dosing (1 cycle = 
28 days), n=6 
--Or-- 
Schedule 2 (intermittent dosing):  Vistusertib 100 mg bid intermittent dosing (2 days 
on/ 5 days off over the 28 day cycle), n=6 
The rationale for study design and dose selection is provided in Section 3.2 of this 
protocol.  The study schema is presented in Figure 2. 
Although acalabrutinib monotherapy has not demonstrated DLTs to date, the safety of 
the combination of acalabrutinib and vistusertib in this patient population needs to be 
assessed.  Therefore, a safety analysis (see Section 3.14) will occur when 6 subjects 
have been enrolled in each schedule.  Standard DLT criteria (defined below) will be used 
to assess safety during the first cycle of treatment of the combination treatment.  (To be 
evaluable for DLT, subjects who have not experienced DLT must have received at least 
75% of schedule doses.  Subjects who have experienced DLT do not have a minimum 
dosing requirement.)  Each schedule is independently assessed.  Escalation to the next 
dose level of vistusertib cannot occur until the DLT review period has been completed.   
If ≤1 DLTs occur during cycle 1 in the 6 subjects enrolled in a given schedule, then the 
dose of vistusertib will be escalated as outlined below and 6 new subjects will be 
enrolled and assessed for DLT.   
 
Level -1 
(Starting Dose) 
Target Level 
Level +1 
Continuous dosing 
schedule (Schedule 1) 
35 mg bid 
(daily) 
n=6 
50 mg bid 
(daily) 
n=6 
75 mg bid 
(daily) 
n=6 
Intermittent dosing 
schedule (Schedule 2) 
100 mg bid  
(2 days on/ 5 days 
off) 
n=6 
125 mg bid  
(2 days on/ 5 days 
off) 
n=6 
150 mg bid 
(2 days on/ 
5 days off) 
n=6 
Abbreviations:  bid = twice per day 
1 cycle = 28 days for vistusertib dosing 
 


 
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If ≥2 DLTs occur during cycle 1 in the 6 subjects enrolled in the continuous dosing 
schedule at the starting dose, then Schedule 1 will be considered not tolerated and no 
further enrollment will occur.  
If ≥2 DLTs occur during cycle 1 in the 6 subjects enrolled in the intermittent dosing 
schedule at the starting dose, then 6 additional subjects will be enrolled at 75 mg bid 
2 days on / 5 days off (ie, Level -2) and assessed for DLTs.  If ≥2 DLTs occur at Level -2 
for the intermittent dosing schedule, then Schedule 2 will be considered not tolerated 
and no further enrollment will occur. 
Part 1 will enroll approximately 12 to 36 subjects depending on safety.  The safety 
results (eg, DLTs, discontinuation due to adverse events and tolerability) of Part 1 were 
to be used to select the vistusertib dose/schedule for Part 2.  Any DLTs attributed to the 
combination after cycle 1 were also to be taken into consideration when determining the 
vistusertib dose and schedule for Part 2.   
Enrollment into Dose Level 1 and beyond (Part 2) was discontinued by the sponsor.  The 
primary reason for discontinuation of Part 2 was that inhibition of the Torc-2 protein, 
which is a target of vistusertib, was not adequate as determined by PD studies.  In 
addition, PK data from subjects at vistusertib Dose Level 0 suggested that increasing the 
dose to Level 1 would only increase exposure by approximately 20%, which is not 
expected to provide sufficient Torc-2 coverage to differentiate from approved Torc-1 
inhibitors and could increase risk for toxicity. 
Part 2 
Part 2 was designed to consist of expansion groups of 15 or 20 subjects per histology 
(N≤35 total for Part 2) provided the safety results from Part 1 of the study indicated that 
further evaluation of the combination was warranted.  As mentioned above, the study 
was closed before initiating Part 2. 
Subjects showing clinical benefit (ie, no disease progression) and who are tolerating 
study treatment may remain on study for up to a total of 12 cycles of treatment.  Subjects 
who have received 12 cycles of treatment (ie, been on study for approximately 
12 months) and are deriving clinical benefit from acalabrutinib monotherapy or the 
combination of acalabrutinib and vistusertib may remain on study treatment beyond the 
first 12 months until disease progression occurs or becomes eligible to enroll in either a 
rollover study of acalabrutinib monotherapy or a rollover study of the combination of 
acalabrutinib and vistusertib, respectively.  


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Refer to Appendix 1 and Appendix 2 for a comprehensive list of study assessments and 
their timing.  The study schema is provided below (Figure 2). 
Figure 2.  Study Schema 
 
Abbreviations:  bid = twice daily; cont. = continuous dosing: DLBCL = diffuse large B-cell lymphoma; GCB = 
germinal center B-cell; interm. = intermittent dosing; non-GCB = non-germinal center B-cell; R/R = 
relapsed/refractory; RS = Richter syndrome 
Note:  On 21 May 2018, a decision was made by the sponsor to stop enrollment and close the study before 
initiating Dose Level 1 and Part 2. 
 
3.1 
STUDY PARAMETERS 
3.1.1 
Safety Parameters 
Type, frequency, severity, and relationship to study drug of any TEAEs or abnormalities 
of laboratory tests, SAEs, DLTs, or AEs leading to discontinuation of study drug(s). 
For consistency of interpretation, AEs and laboratory results will be coded using 
MedDRA, and the severity of AEs will be graded using the CTCAE, Version 5.0 or 
higher.  Standard definitions for seriousness will be applied (see Section 6.1.2). 


 
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3.1.2 
Pharmacodynamic, Pharmacokinetic and Biomarker 
Parameters 
The occupancy of BTK by acalabrutinib will be measured in PBMCs with the aid of an 
acalabrutinib analogue probe.  The effect of acalabrutinib and vistusertib on biologic 
markers of B-cell function will also be evaluated.  Cell populations will be monitored for 
effect of treatment, which may include, but are not limited to, leukocyte or lymphocyte 
subsets (eg, T, B and NK cells) and their activation states.  
 
 
 
  
 
 
   
The following PK parameters will be calculated, whenever possible, from plasma 
concentrations of acalabrutinib and vistusertib (Note: These will not be collected or 
assessed for subjects whose study participation extends past the first 12 cycles.): 
x 
AUC0-last: Area under the plasma concentration-time curve calculated using linear 
trapezoidal summation from time 0 to time last, where “last” is the time of the last 
measurable concentration 
x 
AUC0-inf: Area under the plasma concentration-time curve from 0 to infinity, 
calculated using the formula: AUC0-inf=AUC0-last + Clast ȜzZKHUHȜz is the 
apparent terminal elimination rate constant (whenever possible) 
x 
Cmax: Maximum observed plasma concentration 
x 
Tmax: Time of the maximum plasma concentration (obtained without interpolation) 
x 
t½: Terminal elimination half-life  
x 
Ȝz: Terminal elimination rate constant 
x 
CL/F: Oral clearance 
x 
Vz/F: Oral volume of distribution 
3.1.3 
Efficacy Parameters 
x 
ORR (CR + PR) 
x 
DRR 
x 
CR rate 
x 
DOR 
x 
PFS 
CCI


 
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• 
OS 
Analysis of efficacy parameters is provided in Section 5.5.4.  The efficacy evaluations 
will not be assessed for subjects whose study participation extends past the first 
12 cycles.   
3.2 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
3.2.1 
Rationale for Combining mTOR and BTK Inhibition 
Decades of research across various oncologic diseases support the fact that multidrug 
regimens (eg, polychemotherapy or chemoimmunotherapy) produce higher and more 
durable CR rates than single-agent chemotherapy.  However, these benefits are often 
outweighed with the increased toxicity associated with multidrug regimens.  The high 
risk:benefit ratio of multidrug regimens means these regimens are less likely to be used 
in elderly patients or patients with comorbid conditions.  The advent of highly selective, 
targeted agents to treat B-cell malignancies, such as BCR signaling antagonists, has 
changed the risk:benefit paradigm traditionally associated with chemotherapy agents.  
When administered as single agents, they have produced high ORR in some patients 
with B-cell malignancies.  For example, ibrutinib, a small molecule inhibitor of BTK, has 
been approved for the treatment for CLL/SLL, MCL, MZL and WM.  In addition, ibrutinib 
has shown clinical efficacy in other B-cell malignancies including FL (Advani et al 2012), 
as well as in de novo (Wilson et al 2015) and transformed DLBCL (specifically RS; Ayers 
& Mato 2016).  Acalabrutinib has also shown clinical activity in CLL and RS (Byrd et al 
2016, Hillmen et al 2016) and MCL (Wang et al 2017). 
However, the proportion of patients with CRs when treated with BCR signaling 
antagonists, as monotherapy, is low compared with traditional polychemotherapy or 
chemoimmunotherapy (Advani et al 2012, Blum 2015).  Also, in more aggressive 
histologies the median DOR can be low (<12 months) (Blum 2015).  The question 
remains whether “targeted combination” therapy can produce more durable responses 
and potentially more CRs, including MRD negativity, than single agents without an 
undue associated increase in toxicity.   
The mechanism of action of vistusertib (Section 1.2) suggests the potential to combine it 
with a number of anticancer treatments, including BTK inhibitors.  The multiplicity of 
mechanisms involved in transducing signals from the BCR and the existence of multiple 
negative feedback loops support the hypothesis that inhibiting BTK signaling together 
with inhibition of mTORC1/2 may deliver clinical benefit.  This theory has been evaluated 


 
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preclinically in a non-GLP xenograft model.  Briefly, mice (n=10/group) were implanted 
with OCI-Ly-10 (a DLBCL cell line) and 14 days after tumor implantation were orally 
gavaged with test articles for 28 days. 
Figure 3 shows greater efficacy when combining vistusertib with either ibrutinib or 
acalabrutinib compared with each agent administered alone. 
Figure 3.  Tumor Volume Over Time 
 
Abbreviations:  ACP-196 = acalabrutinib; AZD2014 = vistusertib; BID = twice per day; d = days; 
QD = once per day 
 
As is typical of dose-finding studies, Part 1 of this study includes “all comer” patients with 
relapsed/refractory DLBCL (ie, either de novo or transformed DLBCL, including RS).  
The expansion portion of the study will enroll only de novo DLBCL and will focus on 
evaluating the efficacy of combination therapy in GCB (n=15) vs non-GCB (n=20) 
subtypes.  Preliminary findings from an ongoing Phase 2 study (
) 
evaluating vistusertib monotherapy in de novo DLBCL appear to show acceptable 
tolerability and activity in GCB and non-GCB subtypes.  In addition, though ibrutinib 
monotherapy has shown preferential activity in the activated B cell-like (ABC) subtype of 
DLBCL, a partial response was observed in a patient with GCB subtype and tumor 
regressions were also seen in 4 additional patients with GCB subtype (Wilson et al 
2015)—providing clinical evidence that the BTK pathway is activated in some patients 
with GCB subtype.  Therefore, the purpose of Part 2 was to evaluate the combination 
therapy in both subtypes to determine whether the combination therapy is active across 
subtypes or shows preferential activity for a particular subtype.  On 21 May 2018, a 
decision was made by the sponsor to stop enrollment and close this study after 
25
30
35
40
45
50
55
60
0
250
500
750
1000
1250
1500
vehicle
AZD2014 20 mg/kg BID, 2d on/5d off
AZD2014 15 mg/kg QD
Ibrutinib 12 mg/kg QD
ACP-196 12.5 mg/kg  BID
AZD2014 (20mg/kg) + Ibrutinib
AZD2014 (15mg/kg) + Ibrutinib
AZD2014 (20mg/kg) + ACP-196
AZD2014 (15mg/kg) + ACP-196
Treatment
Days Post Implant
Tumor Volume (mm3)
GeoMean r SE
CCI


 
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evaluating the safety, efficacy, PK, and PD of acalabrutinib in combination with 
vistusertib at Dose Level -1 and Dose Level 0.  In general, the acalabrutinib and 
vistusertib (an mTOR1 and mTOR2 dual inhibitor) combination was well tolerated in 
subjects with relapsed/refractory DLBCL enrolled in Dose Level -1 and Dose Level 0.  
However, modest clinical efficacy was observed at both dose levels.  Clinical PD 
biomarker data demonstrated expected acalabrutinib PD but variable vistusertib PD on 
TORC1 and TORC2 biomarkers as measured in surrogate tissue (ie, lymphocytes).  
More specifically, the TORC2 biomarker was minimally modulated.  PK modeling 
indicated that increasing dose levels and/or changing dosing schedules would not 
improve target engagement.   
3.2.2 
Dose Selection Rationale 
As described in Section 1.1.3, acalabrutinib is currently being evaluated in a Phase 1/2 
study in subjects with CLL, RS, or prolymphocytic leukemia (
; Byrd et al 
2016).  In this study, subjects have received oral dosages of 100 to 400 mg qd and 
100 to 200 mg bid of acalabrutinib.  All tested dose levels have been well tolerated.  No 
DLT has occurred at any dose level and the MTD was not reached.  PD results from this 
study also show 100 and 200 mg bid have the highest BTK occupancy at 24 hours of all 
the regimens evaluated.  Robust clinical responses have been observed.  Acalabrutinib 
is also being evaluated in Phase 3 studies in subjects with CLL or MCL.  The dosage 
selected for these studies is 100 mg bid based on PD results of the dose escalation 
study and is, likewise, the dosage selected for this protocol.   
Acalabrutinib 100 mg bid has also been evaluated in various indications (ie, B-cell 
malignancies and solid tumors) alone and in combination with anti-CD20 antibodies, 
chemotherapy, a PI3K inhibitor, and an anti-PD-1 antibody.  No DLTs have been 
identified for acalabrutinib alone or when given in combination with the aforementioned 
agents.  Therefore, the proposed dosage for this protocol for acalabrutinib is 100 mg bid.   
Vistusertib has been evaluated at several doses and schedules.  Monotherapy 
vistusertib 50 mg bid continuous and 125 mg bid 2 days on and 5 days off has been well 
tolerated.  However, to reduce the potential for overlapping toxicities, the vistusertib 
dosages being evaluated have been reduced to 35 mg bid continuous (Level -1 for 
continuous dosing schedule) and 100 mg bid 2 days on and 5 days off (Level -1 for 
intermittent dosing schedule).  Amendment 2 of this protocol added a higher dose level 
of vistusertib (Level +1) to Part 1 of the protocol.  However, as mentioned previously, the 
CCI


 
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sponsor stopped the study after evaluating the efficacy, safety, PD, and PK data from 
the subjects treated with the lower dose levels of vistusertib.   
This proof-of-concept study will assess the clinical potential of a dual BTK and 
mTORC1/2 inhibition approach by evaluating the safety, PK, PD and efficacy of 
acalabrutinib and vistusertib in relapsed/refractory subsets of B-cell malignancies. 
3.3 
SELECTION OF STUDY POPULATION 
3.3.1 
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the 
following criteria:  
1. Diagnosis of relapsed/refractory DLBCL as documented by medical records and with 
histology based on criteria established by WHO: 
a. If a subject has de novo DLBCL, the diagnosis is confirmed by biopsy and 
is immunohistologically characterized as de novo non-GCB DLBCL or de 
novo GCB DLBCL.  Note that PMBCL is excluded from this protocol.  
Tumor tissue must also be available for sending to the sponsor for 
central cell of origin testing. 
b. If the subjects has RS, the diagnosis is confirmed by biopsy and is 
immunohistologically characterized as transformation to DLBCL.  Tumor 
tissue must also be available for sending to the sponsor for central 
pathology testing.  This histology applies to Part 1 only. 
c. If the subjects has transformed DLBCL, the diagnosis is confirmed by 
biopsy and is immunohistologically characterized as transformation to 
DLBCL from indolent lymphoma (eg, follicular lymphoma).  Tumor tissue 
must also be available for sending to the sponsor for central 
pathology testing.  This histology applies to Part 1 only. 
2. Men and women ≥18 years of age. 
3. Prior treatment for lymphoid malignancy: 
a. If the subject has DLBCL, there is no curative option with conventional 
therapy and the prior treatment included ≥ 1 prior combination 
chemoimmunotherapy regimen (eg, anthracycline based therapy with 
rituximab such R-CHOP).  Also subjects should have relapsed after 
ASCT or should be noncandidates for ASCT. 
b. If the subject has RS, the subject must have had ≥1 prior treatment with a 
combination chemoimmunotherapy regimen. 
4. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid 
malignancy (defined as the presence of a ≥1.5 cm lesion, as measured in the longest 
dimension by CT scan for all histologies).   
5. Documented active disease that is relapsed or refractory defined as: 
a. Relapse:  disease progression after completion of the treatment regimen 
preceding entry into the study. 
b. Refractory:  progressive disease or stable disease as best response at 
any point during chemotherapy (>4 cycles of first-line or 2 cycles of later-


 
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line therapy) or relapsed at ≤12 months from autologous stem cell 
transplantation (Crump et al 2017). 
6. ECOG performance status of ≤2. 
7. Adequate hematologic function, independent of transfusion and growth factor 
support for ≥14 days before screening, defined as: 
a. ANC >1000 cells/mm3 (1.0 x 109/L) 
b. Platelet count >75,000 cells/mm3 (75 x 109/L) or >50,000 cells/mm3 with 
bone marrow involvement 
c. Hemoglobin >8.0 g/dL 
8. Adequate hepatic and renal function at screening defined as: 
a. Serum AST and ALT ≤2.5 x ULN if no demonstrable liver involvement or 
≤3 x ULN in the presence of liver metastases 
b. Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or 
of non-hepatic origin) 
c. Serum creatinine ≤1.5 times ULN and creatinine clearance >30 mL/min 
(measured or calculated by Cockcroft and Gault equation [(140-Age) • 
Mass (kg)/(72 • creatinine mg/dL) • multiply by 0.85 if female]) 
9. PT/INR <1.5 x ULN and aPTT <1.5 x ULN. 
10. Serum potassium within normal range.  
11. Women should be using adequate contraceptive measures, should not be breast 
feeding and must have a negative pregnancy test before start of dosing if of child-
bearing potential or must have evidence of nonchildbearing potential by fulfilling one 
of the following criteria at screening: 
a. Postmenopausal women, defined as either women aged >50 years and 
amenorrheic for ≥12 months following cessation of all exogenous 
hormonal treatments, or, women under 50 years old who have been 
amenorrheic for ≥12 months following the cessation of exogenous 
hormonal treatments, and have serum FSH and LH levels in the 
postmenopausal range for the institution. 
b. Documentation of irreversible surgical sterilization by hysterectomy, 
bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. 
c. Medically confirmed, irreversible premature ovarian failure. 
Women who are sexually active and of childbearing potential must be willing to use 
2 forms of contraception (see Section 3.11.7) from the time of screening to 90 days 
after discontinuing study drug(s). 
12. Men who are sexually active must use barrier contraception (ie, condoms) in addition 
to the highly effective contraception and refrain from sperm donation during the study 
and until 2 days after the subject’s last dose of acalabrutinib or 16 weeks after the 
subject’s last dose of vistusertib, whichever is longer.  If not done previously, storage 
of sperm before receiving vistusertib will be advised to male subjects with a desire to 
have children. 
13. Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules/tablets without difficulty. 
14. Willing to follow sunlight protection measures while taking vistusertib (eg, using 
sunscreen and avoiding excessive sun exposure) and for 90 days after the last dose 
of vistusertib. 


 
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15. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information (in 
accordance with national and local patient privacy regulations). 
 
Host genetics research study (optional): 
For inclusion in the optional genetic component of the study, subjects must fulfil the 
following additional criteria: 
16. Provision of signed, written, and dated informed consent for genetic research.  If a 
subject declines to participate in the genetic component of the study, there will be no 
penalty or loss of benefit to the subject.  The subject will not be excluded from other 
aspects of the study described in this protocol, so long as they consented to the main 
study. 
17. Whole blood transfusion given within 120 days of genetic sample collection should 
be leukocyte depleted. 
 
Tumor biopsy study (optional): 
For inclusion in the optional tumor biopsy component of the study, subjects must fulfil the 
following additional criteria: 
18. Provision of signed, written, and dated informed consent for fresh lymph node tumor 
biopsies (at baseline, on study and at progression).  If a subject declines to 
participate in the tumor biopsy component of the study, there will be no penalty or 
loss of benefit to the subject.  The subject will not be excluded from other aspects of 
the study described in this protocol, so long as they consented to the main study. 
19. Presence of superficial lymphadenopathy for the lymph node biopsy. 
 
3.3.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. History of prior malignancy except for the following: 
a) Malignancy treated with curative intent and with no evidence of active disease 
present for more than 2 years before screening and felt to be at low risk for 
recurrence by treating physician.   
b) Adequately treated lentigo maligna melanoma without current evidence of 
disease or adequately controlled nonmelanomatous skin cancer. 
c) Adequately treated carcinoma in situ without current evidence of disease.   
2. As judged by the Investigator, any evidence of severe or uncontrolled systemic 
disease (eg, severe hepatic impairment, interstitial lung disease [bilateral, diffuse, 
parenchymal lung disease]), or current unstable or uncompensated respiratory or 
cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding 
diatheses (eg, hemophilia or von Willebrand disease) or uncontrolled active systemic 
fungal, bacterial, viral, or other infection (defined as exhibiting ongoing 
signs/symptoms related to the infection and without improvement, despite 
appropriate antibiotics or other treatment), or intravenous anti-infective treatment 
within 2 weeks before first dose of study drug. 
3. Diagnosis of PMBCL. 
4. Known history of infection with HIV. 
5. Serologic status reflecting active hepatitis B or C infection.   


 
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a) Subjects who are anti-HBc positive and who are surface antigen negative will 
need to have a negative PCR result before enrollment.  Those who are hepatitis 
B surface antigen positive or hepatitis B PCR positive will be excluded. 
b) Subjects who are hepatitis C antibody positive will need to have a negative PCR 
result before enrollment.  Those who are hepatitis C PCR positive will be 
excluded. 
6. Active CMV infection (positive CMV IgM and/or positive PCR result) 
7. Undergone any of the following procedures or experienced any of the following 
conditions currently or in the preceding 6 months: 
a) coronary artery bypass graft 
b) angioplasty 
c) vascular stent 
d) myocardial infarction 
e) angina pectoris 
f) congestive heart failure (NYHA Grade ≥2) 
g) ventricular arrhythmias requiring continuous therapy 
h) supraventricular arrhythmias, including atrial fibrillation, which are uncontrolled 
i) hemorrhagic or thrombotic stroke, including transient ischemic attacks or any 
other central nervous system bleeding. 
8. Current refractory nausea and vomiting, malabsorption syndrome, disease 
significantly affecting GI function, resection of the stomach, extensive small bowel 
resection that is likely to affect absorption, symptomatic inflammatory bowel disease, 
partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, 
such as gastric bypass. 
9. History of CNS lymphoma, leptomeningeal disease or spinal cord compression. 
10. History of severe allergic or anaphylactic reactions to kinase inhibitors or history of 
hypersensitivity to active or inactive excipients of vistusertib or acalabrutinib or drugs 
with a similar chemical structure or class to vistusertib or acalabrutinib. 
11. Presence of a GI ulcer diagnosed by endoscopy within 3 months before screening. 
12. Uncontrolled Type 1 or Type 2 diabetes mellitus (eg, hemoglobin A1c ≥7%). 
13. Any clinically significant pre-existing severe renal disease (eg, glomerulonephritis, 
nephritic syndrome, Fanconi Syndrome or renal tubular acidosis) or high risk of 
developing severe renal impairment. 
14. Major surgical procedure within 28 days before first dose of study drug.  Note:  If a 
subject had major surgery, they must have recovered adequately from any toxicity 
and/or complications from the intervention before the first dose of study drug. 
15. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
CTCAE, Version 5.0 Grade 0 or 1, or to the levels dictated in the inclusion/exclusion 
criteria, with the exception of alopecia. 
16. Any hematopoietic growth factors (eg, filgrastim [G-CSF], sargramostin [GM-CSF]) 
within 7 days of the first dose of study drug or pegylated G-CSF (pegfilgrastim) or 
darbepoetin within 14 days of the first dose of study drug. 
17. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 
18. Abnormal ECHO or MUGA at baseline (LVEF <40% and shortening fraction SF 
<15%).  Appropriate correction to be used, if a MUGA is performed. 


 
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19. Mean resting QTc calculated using Fridericia's formula (QTcF) >450 msec obtained 
from 3 ECGs; family or personal history of long or short QT syndrome; Brugada 
syndrome or known history of QTc prolongation or torsade de pointes within 
12 months of the subject entering the study. 
20. Factors that increase the risk of QTc prolongation or risk of arrhythmic events such 
as heart failure, or family history of sudden unexplained death under 40 years of age.  
Concomitant medications known to prolong QTc should be used with caution and 
cannot be used during the first 28 days on study. 
21. Any therapeutic antibody within 4 weeks of first dose of study drugs. 
22. Prior use of standard antilymphoma therapy or radiation therapy within 14 days of 
receiving the first dose of study drug (not including palliative radiotherapy).  Subjects 
must have recovered from acute toxicity due to prior treatment.  Note:  Subjects 
previously treated with BTK, mTOR or PI3K inhibitors are not excluded from this 
protocol; however, the 14-day washout and recovery from acute toxicity from these 
agents still applies. 
23. Ongoing immunosuppressive therapy, including systemic (eg, intravenous or oral) 
corticosteroids for treatment of lymphoid cancer or other conditions. Note:  Subjects 
may use topical or inhaled corticosteroids or low-dose steroids (≤ 10 mg of 
prednisone or equivalent per day) as therapy for comorbid conditions. During study 
participation, subjects may also receive systemic corticosteroids as needed for 
treatment-emergent comorbid conditions. 
24. Exposure to strong or moderate inhibitors or inducers of CYP3A4/5, P-gp, or BCRP, 
if taken within the stated washout periods before the first dose of study drug (see 
Appendix 4). 
25. Exposure to specific substrates of the drug transporters OATP1B1, OATP1B3, 
MATE1 and MATE2K within the appropriate washout period for each drug (a 
minimum of 5 x reported elimination half-life) before the first dose of study drug (see 
Appendix 4). 
26. Requires or receiving therapeutic anticoagulants, with the exception of short-acting 
heparins, within 7 days of first dose of study drug. 
27. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).  Subjects receiving 
proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible 
for enrollment to this study. 
28. Recent history (past 12 months) of drug abuse or alcohol abuse, as judged by the 
investigator. 
29. Concurrent participation in another therapeutic clinical trial. 
3.3.3 
Replacement of Subjects 
Subjects will not be replaced in this study unless needed to meet the requirement of 6 
subjects for DLT review as described in Section 3.0.   
3.3.4 
Enrollment and Randomization Procedures 
Enrollment of a subject into the study will be performed according to the following 
procedure:  


 
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• 
The study center will notify the sponsor when a clinically eligible subject is 
identified and is ready to screen, to ensure enrollment availability on the study. 
• 
After the subject has signed and dated the Informed Consent Form (ICF), all 
screening procedures have been completed, and eligibility has been confirmed, 
the subject can be officially enrolled into the study.  
• 
To confirm eligibility, the study center will fax/email a completed Enrollment 
Confirmation Form to the sponsor.  The enrollment date will be the date that the 
sponsor confirms enrollment. 
• 
The sponsor will aim to fax/email a completed Enrollment Confirmation Form to 
the study center within 48 to 72 hours of receipt.   
• 
Treatment assignment for Part 1 only will occur through the use of an IXRS.  As 
subjects qualify for enrollment, designated study center personnel will contact the 
IXRS, which will assign a treatment arm to each eligible subject. 
Treatment must begin within the screening window (see Appendix 1) and, for Part 1 
only, after the site has received the treatment allocation per IXRS.   
3.4 
STUDY DRUG 
3.4.1 
Premedications 
No specific premedications or supporting medications are required in conjunction with 
acalabrutinib or vistusertib administration.  
3.4.2 
Formulation, Packaging, and Storage 
Acalabrutinib and vistusertib are manufactured according to cGMP regulations and will 
be provided to the investigational site by Acerta Pharma or designee.  Study drug should 
be stored according to the instructions on the label affixed to the package of the drug 
product. 
If a drug shipment arrives damaged, or if there are any other drug complaints, a Product 
Complaint Form should be completed and emailed or faxed to the sponsor or the 
sponsor’s representative.  Refer to the Acalabrutinib Investigator Brochure and 
Vistusertib Investigator Brochure for additional information regarding the drug products 
to be used in this trial. 
3.4.3 
Administration of Study Drug  
Investigators are prohibited from supplying study drug to any subjects not properly 
enrolled in this study.  The investigator must ensure that subjects receive study drug 
only from personnel who fully understand the procedures for administering the drug. 


 
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Acalabrutinib and vistusertib are intended to be administered orally twice daily with 
8 ounces (approximately 240 mL) of water (avoid grapefruit juice or Seville orange juice 
due to potential inhibition of CYP3A).  Study drugs can be administered without regard to 
food.  Doses should be administered 12 hours apart (a window of ±1 hour is allowed) at 
approximately the same times each day.  If subjects are enrolled in Level -1 (intermittent 
dosing for vistusertib), then vistusertib will be taken bid for 2 days followed by 5 days of 
drug holiday (no vistusertib dosing) before starting again with 2 days of dosing. 
The acalabrutinib capsules and vistusertib tablets should be taken concomitantly and 
should be swallowed intact.  Subjects should not attempt to open capsules/break or 
crush tablets or dissolve in water.  If vomiting occurs after taking study drug(s), the 
subject should not retake study drug(s) until the next scheduled dose. 
For either drug, if a dose is not taken within the allowed window, it can be taken up to 
2 hours after the scheduled time with a return to the normal schedule the same or 
following day.  If it has been >2 hours, the dose should not be taken and the subject 
should take the next dose at the next scheduled time.  The missed dose will not be 
made up and must be returned to the site at the next scheduled visit.  If a subject needs 
to take a dose earlier than scheduled, the subject can take the dose up to 2 hours earlier 
than the scheduled time.  Subjects should make every reasonable effort to take the 
study drug(s) on time. 
Guidance on co-administration of acalabrutinib with agents that affect gastric pH is 
provided in Section 3.11.5. 
3.4.4 
Assuring Subject Compliance 
For treatments that are taken in the clinic, subjects should take the dose from the drug 
dispensed for them for that particular time period.  All other study drug treatments will be 
taken at home.  Subjects will receive a drug diary to record the specific time each dose 
was taken and to record reasons for any missed doses.   
Subject compliance with acalabrutinib/vistusertib dosing will be assessed at every visit 
and recorded in the electronic data capture (EDC) system.  The subject will be instructed 
to bring the diary and any remaining capsules/tablets to the clinic at their next visit.  The 
study staff will review the diary and ask the subject if all of the capsules/tablets were 
administered.  Any remaining or returned capsules/tablets will be counted and recorded 
as described in Section 7.6.  Returned capsules/tablets must not be redispensed to 
another subject.  


 
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3.5 
STUDY TREATMENT SCHEDULE 
Acalabrutinib 100 mg will be administered twice daily every day of the 28-day cycle.  The 
following doses and schedules of vistusertib are being evaluated in this protocol: 
Vistusertib Dose Levels and Schedules 
 
Dose Level 
Schedule Type 
Dose Schedule 
Weekly Dose 
SCHEDULE 1 
Starting dose 
(Level -1) 
Continuous  
35 mg twice 
daily continuous 
490 mg 
Target dose 
(Level 0) 
Continuous  
50 mg twice 
daily continuous 
700 mg 
 
 
 
 
 
SCHEDULE 2 
Level -2 dose 
Intermittent 
75 mg twice 
daily 2 days 
on/5 days off 
300 mg 
Starting dose 
(Level -1) 
Intermittent 
100 mg twice 
daily 2 days 
on/5 days off 
400 mg 
Target dose 
(Level 0) 
Intermittent 
125 mg twice 
daily 2 days 
on/5 days off 
500 mg 
Note: 1 cycle is 28 days. 
 
To initiate a new cycle of therapy with vistusertib, the subject must have an 
ANC ≥1,000/µL and a platelet count ≥50,000/µL and no drug-related nonhematologic 
Grade ≥3 toxicity on day 1 of each cycle.  If these criteria are not met, vistusertib may be 
held for a maximum of 28 days to allow for retreatment.  Treatment may only be 
restarted once the results of repeat assessments indicate that these criteria have been 
met. 
Refer to Section 3.8 for information on dose delays and modifications. 
3.6 
DURATION OF THERAPY 
Treatment with acalabrutinib and vistusertib, in Part 1, may be continued until disease 
progression or an unacceptable drug-related toxicity occurs as defined in the protocol.  


 
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Subjects who do not tolerate vistusertib may continue to receive acalabrutinib 
monotherapy provided they are deriving clinical benefit. 
Subjects showing clinical benefit and who are tolerating study treatment may remain on 
study for up to 12 cycles of treatment.  Subjects who have received 12 cycles of 
treatment (ie, been on study for approximately 12 months) and are deriving clinical 
benefit from acalabrutinib monotherapy or the combination of acalabrutinib and 
vistusertib may remain on study treatment beyond the first 12 months until disease 
progression occurs or becomes eligible to enroll in either a rollover study of acalabrutinib 
monotherapy or a rollover study of the combination of acalabrutinib and vistusertib, 
respectively. 
The end of study for this protocol is when the last subject on the study has either 
discontinued the study or been transitioned to a rollover protocol. 
3.7 
ASSESSMENT OF DOSE-LIMITING TOXICITY (DLT) 
For Part 1, a DLT will be defined as the occurrence of any of the following AEs (Note 
that all AEs of the specified grades should be recorded as DLTs with the exception of 
those that are clearly, and incontrovertibly, due to extraneous causes such as disease 
progression): 
1. Any Grade ≥3 nonhematologic toxicity except Grade 3 nausea, vomiting, or diarrhea 
that respond to supportive therapy (eg, improvement by 1 or more severity grade 
within 48 hours).   
2. Any of the following hematologic toxicities: 
a. Grade 4 neutrophil count decrease lasting >7 days, despite growth factor 
support.  
b. Grade 4 platelet count decrease or Grade 3 platelet count decrease with 
bleeding.  
c. Grade ≥3 febrile neutropenia.  
d. Grade 4 anemia, unexplained by underlying disease.  
3. Clinical TLS (defined in Table 3) that occurs despite protocol-recommended 
management will be considered a DLT. 
4. Laboratory TLS (defined in Table 4) will be considered a DLT if the metabolic 
abnormalities do not resolve within 72 hours despite protocol-required management. 
5. Dosing delay due to toxicity for >28 consecutive days. 
A DLT excludes: 


 
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1. Alopecia of any grade 
2. Isolated laboratory changes of any grade without clinical sequelae or clinical 
significance 
Table 3.  Howard definition of clinical tumor lysis syndrome 
The presence of laboratory TLS and one or more of the following criteria: 
1. Acute kidney injurya defined as creatinine increase in serum creatinine level of 
0.3 mg/dL (26.5 μmol/L) or the presence of oliguria, defined as average urine 
output of <0.5 mL/kg/hr for 6 hours (or a single value >1.5 times the upper limit 
of the age-appropriate normal range if no baseline creatinine measurement is 
available) 
2. Cardiac dysrhythmia or sudden death probably or definitely caused by 
hyperkalaemia  
3. Cardiac dysrhythmia, sudden death, seizure, neuromuscular irritability (tetany, 
paresthesias, muscle twitching, carpopedal spasm, Trousseau’s sign, 
Chvostek’s sign, laryngospasm or bronchospasm), hypotension, or heart 
failure probably or definitely caused by hypocalcaemiab 
Abbreviations:  hr = hour; TLS = tumor lysis syndrome; ULN = upper limit of normal 
a. 
By definition, if acute kidney injury is present, the patient has clinical TLS. 
b. 
Not directly attributable to a therapeutic agent. 
Modified from Howard et al 2011 
 
Table 4.  Howard definition of laboratory tumor lysis syndrome 
Uric acid 
>476 μmol/L (>8.0 mg/dL) 
Potassium  
>6.0 mmol/L (>6.0 mEq/L) 
Phosphorous 
>1.5 mmol/L (>4.5 mg/dL) 
Corrected calcium  
<1.75 mmol/L (<7.0 mg/dL) or ionized calcium <1.12 
(0.3 mmol/L)a 
Laboratory tumor lysis syndrome is the presence of 2 or more electrolyte changes above or below the 
thresholds described above occurring during the same 24-hour period within 3 days before the start of 
therapy or 7 days afterward.  This assessment assumes that a subject has or will receive adequate 
hydration (±alkalinisation) and a hypouricemic agent(s). 
a. 
The corrected calcium level in milligrams per decilitre is the measured calcium in milligrams per decilitre 
+(0.8 x [4-albumin in grams per decilitre]) 
Modified from Howard et al 2011 
3.8 
DOSING DELAYS AND MODIFICATIONS 
Substantial acute toxicities should be managed as medically indicated and with 
temporary suspension of study drug(s), as appropriate.  Dose reductions or holds and 
initiation of supportive care are allowed as clinically indicated by the treating physician.  
In general, for each subject, a maximum of 2 dose reductions will be allowed; however, 
exceptions from this rule may be discussed with the medical monitor on a case-by-case 
basis.    
Possible dose reduction options for vistusertib are presented in Table 5.  If a subject’s 
vistusertib dose is reduced, then dose re-escalation of vistusertib is not permitted.  


 
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However, for subjects receiving lower doses of vistusertib at study entry, they may be 
escalated to higher doses when the higher dose levels clear DLT review.  These 
intrapatient escalations from the dose at study entry will occur on a case-by-case basis 
with input from the Medical Monitor.  Any changes to the dosing regimen must be 
recorded on the appropriate electronic case report form (eCRF). 
Table 5.  Vistusertib dose reduction options 
Starting dose 
1st dose 
reduction 
2nd dose 
reduction 
3rd dose 
reductiona 
35 mg 
25 mg 
discontinue 
not applicable 
50 mg 
35 mg  
25 mg 
discontinue 
75 mg 
50 mg 
25 mg 
discontinue 
100 mg 
75 mg 
50 mg 
25 mg 
125 mg 
100 mg 
75 mg 
50 mg 
a. If allowed after consultation with medical monitor  
 
To initiate a new cycle of therapy with vistusertib, the subject must have an ANC 
≥1,000/µL and a platelet count ≥50,000/µL and no drug-related nonhematologic 
Grade ≥3 toxicity on day 1 of each cycle.  If these criteria are not met, vistusertib may be 
held for a maximum of 28 days to allow for retreatment.  Treatment may only be 
restarted once the results of repeat assessments indicate that these criteria have been 
met. 
Table 6 provides dose reduction options for acalabrutinib.   
Table 6.  Acalabrutinib dose reduction options 
Starting dose 
1st dose reduction 
2nd dose reduction 
100 mg bid 
100 mg qd 
Discontinue 
 
Note: Temporary withholding of acalabrutinib for as little as 7 days can cause a 
transient worsening of disease and/or of constitutional symptoms.  Transient 
worsening of disease during temporary interruption of study therapy (eg, for drug-related 
toxicity, surgery, or intercurrent illness) may not indicate disease progression.  In such 
circumstances, and if medically appropriate, following discussion with the medical 
monitor, subjects may resume therapy and relevant clinical, laboratory, and/or radiologic 
assessments should be done to document whether tumor control can be maintained or 
whether actual disease progression has occurred. 


 
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If acalabrutinib is reduced for apparent treatment-related toxicity, the dose need not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.  However, if 
the subject tolerates a reduced dose of acalabrutinib for ≥4 weeks then the dose may be 
increased to the next higher dose level, at the discretion of the investigator.  Such 
re-escalation may be particularly warranted if further evaluation reveals that the AE that 
led to the dose reduction was not treatment related.  Any changes to the dosing regimen 
must be recorded on the appropriate eCRF. 
Dose reduction and discontinuation guidelines for hematologic and nonhematologic 
toxicities are shown below in Table 7 and Table 8, respectively. 
In general, if a subject experiences a Grade 1 or Grade 2 hematologic or 
nonhematologic toxicity, no dose modification is required.  
If a subject experiences a Grade 3 or Grade 4 toxicity, not attributable to the disease or 
disease-related processes under investigation, dosing will be interrupted and/or the dose 
reduced (see Table 7 and Table 8) and supportive therapy administered as required. 
If the toxicity resolves or reverts to CTCAE Grade ≤2 within 28 days and the subject was 
showing clinical benefit, treatment with study drug(s) may be restarted. 
If the toxicity does not resolve to CTCAE Grade ≤2 within 28 days, then the subject 
should be withdrawn from the study and observed until resolution of the toxicity.  
Maximal drug holiday allowed is 28 consecutive days. 
3.8.1 
Dose modifications for hematologic toxicities 
Please refer to Table 7 for dose modifications due to hematologic toxicities. The number 
of dose reduction levels available for vistusertib and acalabrutinib will vary depending on 
the starting dose as described above.  
If the table indicates that the vistusertib dose should be reduced and the subject is 
already on the lowest dose available for vistusertib as per Table 5, vistusertib should be 
discontinued. If the table indicates that the acalabrutinib dose should be reduced and the 
subject is already on 100 mg/day (see Table 6), acalabrutinib should be discontinued.  If 
vistusertib is discontinued, acalabrutinib monotherapy can continue on this protocol 
(Appendix 2). However, vistusertib monotherapy cannot continue if acalabrutinib is 
discontinued.   


 
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Table 7.  Dose modifications for hematologic toxicities 
NCI CTCAE Grade 
Acalabrutinib Action 
Vistusertib Action 
Febrile neutropenia 
Grade 3 or 4 
Withhold acalabrutinib and vistusertib until infection is 
resolved, antibiotics no longer required and ANC Grade ≤2 or 
baseline 
acalabrutinib restart with 
1 level dose reduction or 
discontinue (see Table 6) 
vistusertib restart with 
1 level dose reduction or 
discontinue (see Table 5) 
2nd episode of febrile 
neutropenia Grade 3 or 4 
Withhold acalabrutinib and vistusertib until infection is 
resolved, antibiotics no longer required and ANC Grade ≤2 or 
baseline 
acalabrutinib restart with 
1 level dose reduction or 
discontinue (see Table 6) 
vistusertib restart with 
1 level dose reduction or 
discontinue (see Table 5) 
3rd episode of febrile 
neutropenia Grade 3 or 4 
Discontinue acalabrutinib and vistusertib 
 
Neutrophil count decrease 
Grade 4 lasting >7 days 
despite growth factor support 
Withhold acalabrutinib and vistusertib until Grade ≤2 or 
baseline 
acalabrutinib restart at the 
same dose level 
vistusertib restart with 
1 level dose reduction or 
discontinue (see Table 5) 
2nd episode of neutrophil 
count decrease Grade 4 
lasting >7 days despite 
growth factor support 
Withhold acalabrutinib and vistusertib until Grade ≤2 or 
baseline 
acalabrutinib restart with 1 
level dose reduction or 
discontinue (see Table 6) 
vistusertib restart with 
1 level dose reduction or 
discontinue (see Table 5) 
3rd episode of neutrophil 
count decrease Grade 4 
lasting >7 days despite 
growth factor support 
Discontinue acalabrutinib and vistusertib 
 
 
Platelet count decrease, 
Grade 4 without bleeding 
requiring blood or platelet 
transfusion 
Withhold acalabrutinib and vistusertib until Grade ≤2 or 
baseline 
acalabrutinib restart at the 
same dose level 
vistusertib restart with 
1 level dose reduction or 
discontinue (see Table 5) 
2nd episode of platelet count 
decrease, Grade 4 without 
bleeding requiring blood or 
platelet transfusion 
Withhold acalabrutinib and vistusertib until Grade ≤2 or 
baseline 
acalabrutinib restart with 1 
level dose reduction or 
discontinue (see Table 6) 
vistusertib restart with 
1 level dose reduction or 
discontinue (see Table 5) 


 
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NCI CTCAE Grade 
Acalabrutinib Action 
Vistusertib Action 
3rd episode of platelet count 
decrease, Grade 4 without 
bleeding requiring blood or 
platelet transfusion 
Discontinue acalabrutinib and vistusertib 
 
 
Platelet count decrease, 
Grade 3 or 4 with bleeding 
requiring blood or platelet 
transfusion 
Withhold acalabrutinib and vistusertib until Grade ≤2 or 
baseline 
acalabrutinib restart with 
1 level dose reduction or 
discontinue (see Table 6) 
vistusertib restart with 
1 level dose reduction or 
discontinue (see Table 5) 
2nd episode of platelet count 
decrease, Grade 3 or 4 with 
bleeding requiring blood or 
platelet transfusion  
Discontinue acalabrutinib and vistusertib 
Abbreviations: ANC = absolute neutrophil count; CTCAE = Common Terminology 
Criteria for Adverse Events; NCI = National Cancer Institute 
 
3.8.2 
Dose modifications for nonhematologic toxicities 
In case of Grade 4 treatment-related nonhematologic toxicity, discontinue acalabrutinib 
and vistusertib. 
Grade 3 toxicities require dose modifications, temporary treatment interruptions or 
discontinuation of vistusertib and acalabrutinib. 
Please refer to Table 8 for dose modifications due to Grade 3 nonhematologic toxicities. 
The number of dose reduction levels available for vistusertib and acalabrutinib will vary 
depending on the starting dose.  


 
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Table 8.  Dose modification guidance in the event of Grade 3 nonhematologic 
toxicities except liver dysfunction* 
Occurrence 
Acalabrutinib Action 
Vistusertib Action 
First 
Withhold acalabrutinib and vistusertib until recovery to Grade ≤2 or 
baseline 
acalabrutinib restart at the same 
dose 
vistusertib restart with 1 level 
dose reduction or discontinue (see 
Table 5) 
Second 
Withhold acalabrutinib and vistusertib until recovery to Grade ≤2 or 
baseline 
acalabrutinib restart with 1 level 
dose reduction or discontinue (see 
Table 6) 
vistusertib restart with 1 level 
dose reduction or discontinue (see 
Table 5) 
Third 
Withhold acalabrutinib and vistusertib until recovery to Grade ≤2 or 
baseline  
acalabrutinib restart with 1 level 
dose reduction or discontinue (see 
Table 6) 
vistusertib restart with 1 level 
dose reduction or discontinue (see 
Table 5) 
*For guidance on liver toxicity refer to Section 3.9.12 and Appendix 5. 
 
3.9 
MANAGEMENT OF TOXICITES 
This section provides recommendations for treatment of potential toxicities associated 
with vistusertib, acalabrutinib or the combination of vistusertib and acalabrutinib and 
guidance about modifying the doses of acalabrutinib and vistusertib due to those 
toxicities. 
Generally, Grade 1 or 2 nonhematologic and/or hematologic toxicities do not require 
vistusertib or acalabrutinib dose reductions and should be managed as medically 
indicated (with or without short dose interruptions) by the treating physician.  
Grade 3 and 4 toxicities require dose modifications, temporary treatment interruptions or 
discontinuation of vistusertib and acalabrutinib.  These are described in Section 3.8.1 for 
hematologic and Section 3.8.2 for nonhematologic toxicities. 
3.9.1 
Recommendations for Evaluation and Treatment of Severe 
Fatigue 
Severe fatigue is an identified risk for vistusertib.  Subjects should be advised of the 
potential for severe fatigue associated with vistusertib use.  If Grade ≥3 fatigue occurs, 


 
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the dosing should be held for ≤14 days before being restarted at a lower dose 
(Section 3.8.2). 
Routine clinical work-up to exclude reasons other than the underlying disease and/or 
vistusertib treatment may be performed, including laboratory analyses to rule out 
anemia, metabolic (acidosis, hyperglycemia) or hormonal (adrenal or thyroid) problems, 
infections, or cardiac problems.   
3.9.2 
Recommendations for Treatment of Diarrhea 
Diarrhea is an overlapping risk for vistusertib and acalabrutinib.  Subjects should be 
made aware of the risk of diarrhea while receiving treatment with vistusertib and 
acalabrutinib.  Subjects should be advised to drink sufficient fluids and have a supply of 
loperamide available throughout treatment. However, loperamide should not be 
administered prophylactically. 
As soon as the first liquid stool occurs, subjects should start treatment with loperamide 
immediately and take electrolyte-containing fluids.  Subjects should inform their study 
doctor. 
The recommended antidiarrheal treatment is loperamide, to be administered as per 
package information and usual clinical practice.  Loperamide should not be administered 
for more than 48 consecutive hours. 
Hospitalization is recommended for management of diarrhea under the following 
circumstances: 
• 
Diarrhea associated with fever 
• 
Diarrhea requiring intravenous hydration 
• 
Diarrhea persisting beyond 48 hours after the initiation of high-dose loperamide 
therapy. 
Please refer to Section 3.8.2 for dose modifications required for Grade ≥3 diarrhea. 
3.9.3 
Recommendations for the Treatment of Nausea and Vomiting 
Nausea and vomiting are overlapping risks for acalabrutinib and vistusertib.  Subjects 
should be made aware of the risk of nausea/vomiting while receiving treatment with 
vistusertib and acalabrutinib.  Not all subjects require antiemetics, and therefore they 
should not receive antiemetics prophylactically.  However, once a subject has 
experienced nausea and vomiting, serotonin (5-HT3) antagonists should be 
administered on subsequent dosing days, eg, dolasetron 100 mg by mouth daily, 
granisetron 2 mg by mouth daily or 1 mg by mouth bid. 


 
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Please see National Comprehensive Cancer Network (NCCN) Clinical Practice 
Guidelines in Oncology: Antiemesis 2016 (NCCN 2016) for further information. 
Aprepitant should not be used as it is a moderate CYP3A4/5 inhibitor (Appendix 4). 
Please refer to Section 3.8.2 for dose modifications required for Grade ≥3 nausea and/or 
vomiting. 
If nausea and vomiting are not being managed with the regimen above, start a 
breakthrough treatment with the addition of 1 agent of a different drug class, for 
example: 
• 
dexamethasone 8 mg PO at day 1 of the vistusertib dosing period or  
• 
metoclopramide 10 to 40 mg PO or 
• 
olanzapine 5 to 10 mg PO  or  
• 
promethazine (Phenergan)12.5 to 25 mg every 6 hours 
on the vistusertib dosing days before the vistusertib dose.    
If this is still not managing the nausea and vomiting sufficiently, add lorazepam 0.5 to 
2 mg by mouth or sublingually every 4 to 6 hours as needed, but only on the vistusertib 
dosing days. 
Should upper abdominal pain develop, an H2 blocker can be added.  See Section 3.11.5 
regarding guidance on concomitant administration of acalabrutinib and H2 blockers. 
3.9.4 
Recommendations for Treatment of Decreased Appetite 
Decreased appetite should be treated according to local clinical practice.  Dietary review 
is recommended. 
3.9.5 
Recommendations for Treatment of Rash/Skin Toxicity 
Rash/skin toxicity is an overlapping risk for vistusertib and acalabrutinib.  Subjects 
should be made aware of the risk of rash/skin toxicity while receiving treatment with 
vistusertib and acalabrutinib.  Early identification and intervention is critical for the 
optimal management of rash.  Preliminary clinical evidence suggests that 
antihistaminergic drugs may ameliorate occurrence/severity of rash.  Therefore, subjects 
who develop Grade 1 or 2 changes in their skin condition should be treated with the 
investigator’s choice of antihistaminergic drugs, over the counter moisturizing cream or 


 
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ointment, local antihistamines and/or topical or systemic steroids. If bacterial infection is 
suspected, local and/or systemic antibiotics may be added. 
For Grade 3 rash, topical and/or systemic steroids with or without topical and/or systemic 
antibiotics (to be considered if bacterial infection is suspected) are indicated, together 
with dose modifications as described in Section 3.8.2; short courses (≤14 days) of 
corticosteroid treatment at doses that do not exceed 100 mg per day of prednisone or 
equivalent may be given. 
Some example treatments are listed below: 
• 
topical steroids: triamcinolone acetonide 0.025%; desonide 0.05%; fluticasone 
propionate 0.05%, aclometasone 0.05% 
• 
topical antipruritics: pramoxine 1%; doxepin 5% cream 
• 
oral antihistamines: loratidine, cetirizine, fexofenadine; diphenhydramine 25 to 
50 mg every 8 hours; hydroxyzine 25 mg every 8 hours 
• 
topical antibiotics: clindamycin 1-2%; erythromycin 1-2%; metronidazole 1%; 
silver sulphadiazine1% 
• 
oral antibiotics: doxycycline 100 mg bid; minocycline 100 mg bid; oxytetracycline 
500 mg 
 
3.9.6 
Recommendations for treatment of Stomatitis/Oral 
Mucositis/Mouth Ulcers  
Stomatitis/oral mucositis/mouth ulcers are identified risks for vistusertib.  Subjects should 
be advised of the potential for stomatitis/oral mucositis/mouth ulcers associated with 
vistusertib use.  For mild toxicity (Grade 1), use conservative measures such as 
nonalcoholic mouth wash or salt water (0.9%) mouth wash several times immediately 
after drug administration (1 to 3 hours) and during the day as required until resolution. 
For more severe toxicity (Grade 2 or 3), the suggested treatments are topical analgesic 
mouth treatments (ie, local anesthetics such as benzocaine, butyl aminobenzoate, 
tetracaine hydrochloride, menthol, or phenolic compounds), with or without topical 
corticosteroids, such as triamcinolone oral paste 0.1% (eg, Kenalog in Orabase®) or 
alcohol-free 0.5 to 2 mg/5 mL dexamethasone oral solution (ie, for example Dexsol® or 
PMS dexamethasone 0.5 mg/5 mL elixir).  The mouth rinse will be self-administered at a 
daily dose of 10 mL three times per day.  Most importantly, subjects must be instructed 
to swish and expectorate the mouth rinse to avoid systemic exposure to 
dexamethasone.   
For further information, please refer to published guidelines (Seiler et al 2014). 


 
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For Grade 3 stomatitis/oral mucositis/mouth ulcers, systemic painkillers are indicated 
(eg, oral or subcutaneous morphine) and dose modification as described in 
Section 3.8.2. 
Vistusertib should be stopped until stomatitis improves to Grade ≤1, and then resumed 
without a dose reduction.  If Grade 2 to 3 stomatitis recurs, dose reduce vistusertib. 
Agents containing hydrogen peroxide, iodine, and thyme derivatives may worsen mouth 
ulcers.  It is preferable to avoid these agents. 
3.9.7 
Recommendations for Treatment of Hyperglycemia 
Hyperglycemia may occur with vistusertib use.  Subjects should be made aware of this 
potential risk.  Management of hyperglycemia should be performed according to local 
standards at the discretion of the Investigator.  Due to the predicted short half-life of 
vistusertib, only a short period of hyperglycemia with insulin resistance might be 
expected.  Therefore, early treatment with insulin and/or oral anti-diabetes medication 
should be carefully evaluated and blood sugars and hypokalemia monitored as per 
standard clinical practice.  If blood glucose levels are <250 mg/dL (Grade 2), generally 
no medical treatment is required. Dietary modification may be initiated. 
For Grade ≥3 hyperglycemia, dose modifications are required (see Section 3.8.2). 
3.9.8 
Recommendations for Evaluation and Treatment of Electrolyte 
Changes Including Hypokalemia and Hypophosphatemia 
Vistusertib, like other mTOR inhibitors, inhibits pump mechanisms in renal tubules, 
leading to hypokalemia and hypophosphatemia in a small proportion of subjects.  The 
presence of biochemical abnormalities should be monitored as per the protocol and 
electrolyte abnormalities should be corrected using oral supplements.  The investigator 
should also consider whether other medication the subject may be receiving, such as 
diuretics, might have contributed to these abnormalities. 
3.9.9 
Recommendations for Evaluation and Treatment of Interstitial 
Lung Disease 
A baseline thorax CT scan must be available for all subjects treated with vistusertib, for 
retrospective analysis and comparison with a high resolution CT scan, should it be 
required, if symptoms occur during study conduct.  Should a subject experience any new 
respiratory symptoms including cough, dyspnea, lower respiratory tract infections not 
clearly explained by other factors such as disease progression or anemia, a high 


 
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resolution CT scan and pulmonary function tests should be performed, including 3 forced 
expiratory volumes, forced vital capacity, and carbon monoxide diffusing capacity 
(DLCO% & DLCO).  A recent hemoglobin measurement should also be available at the 
time of the DLCO evaluation.  If these investigations are suggestive of pneumonitis or 
interstitial lung disease and causality with the study drug cannot be excluded, treatment 
should be interrupted.  In more severe cases treatment with corticosteroids should be 
considered as per reference Willemsen et al 2016.  
3.9.10 
Recommendations for Evaluation and Management of 
Electrocardiogram (ECG) Changes 
Subjects who develop persistent, confirmed T-wave repolarization abnormalities 
(inversion or flattening) on regularly scheduled ECGs should be referred for a cardiology 
opinion and undergo a follow-up LVEF measurement using the same technology to that 
used at baseline.  As a summary, the following should be evaluated from baseline 
throughout the study; ECGs should be reported with immediate reference to all previous 
ECGs to allow trends to be identified without delay. 
• 
ECG and troponin monitoring: 
o screening 
o Cycle 1 Day 1, 15, 22 
o Cycle 2 to 6 Day 1 
o 30-day SFU visit 
• 
Left ventricular (LV) function assessment:  
o screening 
o approximately 2 weeks after a new T-wave inversion or flattening is first 
recorded (and as clinically indicated) 
o 30-day follow-up visit  
3.9.11 
Recommendations for Evaluation and Treatment of Renal 
Effects 
Renal effects have been classified as a potential risk for vistusertib and, in animal 
studies, administration of acalabrutinib at high doses was associated with reversible 
findings in the kidney (details provided in respective Investigator Brochure).  However, 
no clinically significant renal findings were reported at any dose of vistusertib or 
acalabrutinib so far. 
This study protocol excludes subjects with any clinically significant pre-existing severe 
renal disease (eg, glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal 
tubular acidosis) or high risk of developing severe renal impairment (Section 3.3.2, 


 
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Exclusion Criteria #13).  Adequate renal function for inclusion at screening is defined in 
Section 3.3.1 Inclusion Criteria #8. 
If Grade ≥3 renal dysfunction develops while the subject is on study, follow dose 
modification advice shown in Section 3.8.2.   
3.9.12 
Recommendations for Evaluation and Treatment of Liver 
Function Test Abnormalities (Risk for Vistusertib and/or 
Acalabrutinib) 
Acalabrutinib and vistusertib are metabolized in the liver, and transaminase elevations 
are a potential risk for both study drugs. Subjects should be made aware of the risk of 
possible overlapping toxicities of transaminase elevations while receiving both drugs.  
Evidence of abnormal liver function should be monitored as per the protocol guidelines.  
Increased levels of AST, ALT, or serum bilirubin should trigger an investigation of the 
cause, which may include viral infection or disease progression with liver infiltration. The 
Investigator should consider whether the abnormal liver function meets the criteria for 
expedited reporting (see Appendix 5: Actions required in case of increases in liver 
biochemistry and evaluation of Hy’s law). 
Vistusertib is metabolized in the liver. For subjects who develop mild liver impairment 
while on study (Child-Pugh Class A), the recommended dose for vistusertib is 2 dose 
levels lower than the starting dose, see Table 5. If a dose 2 levels lower than the starting 
dose is not available, vistusertib should be discontinued.  Subjects who develop 
moderate or severe hepatic impairment (Child-Pugh Class B or C) must hold study drug 
until resolved to mild impairment (Child-Pugh Class A) or better and will be re-treated at 
2 dose levels lower than the starting dose for vistusertib (or discontinue if applicable), 
see Table 5.  Refer the current Acalabrutinib Investigator Brochure for information on 
administering acalabrutinib to subjects with mild or moderate hepatic impairment. 
For guidance on treating liver toxicity, please refer to Table 9 of this protocol. 


 
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Table 9.  Recommendations for acalabrutinib and vistusertib dose modifications 
for abnormal liver function results 
 
Recommendation 
NCI CTCAE Grade 
Acalabrutinib 
Vistusertib 
 
Elevations in ALT, AST, or bilirubin 
Grade 1 
(ALT/AST ≤3 x ULN) 
(Bilirubin ≤1.5 x ULN) 
Maintain current dose level 
and schedule.  Monitor ALT, 
AST, ALP, and bilirubin at 
least 1x per week. 
 
Maintain current dose level and 
schedule.  Monitor ALT, AST, 
ALP, and bilirubin at least 1x 
per week. 
 
Grade 2 
(ALT/AST >3-5 x ULN) 
(Bilirubin >1.5- ≤3 x ULN) 
Withhold or continue 
acalabrutinib (at investigator 
discretion, after discussion 
with the medical monitor).  
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week.  
After 7 days if hepatic 
enzymes appear to be 
improving and acalabrutinib 
was withheld, restart 
acalabrutinib at current dose 
level (to prevent disease 
progression, monitor disease 
parameters closely). 
 
Also, see Appendix 5 for 
further guidance and actions if 
the subject meets Potential 
Hy’s law criteria. 
Withhold vistusertib. 
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week 
until all abnormalities have 
returned to Grade ≤ 1. 
Administer corticosteroids 
(initial dose of 0.5 to 
1 mg/kg/day prednisone 
[≥40 mg] or equivalent followed 
by taper); when all 
abnormalities have returned to 
Grade ≤ 1, recommend tapering 
steroids over no less than 
4 weeks.  Once abnormalities 
have returned to Grade ≤ 1, 
vistusertib may resume at a 
lower dose level (if applicable, 
see Table 5).  
 
Also, see Appendix 5 for further 
guidance and actions if the 
subject meets Potential Hy’s 
law criteria. 
Grade 3 
(ALT/AST >5-20 x ULN) 
(Bilirubin >3-10 x ULN) 
See recommendations for 
Grades 2 
 
Also, see Appendix 5 for 
further guidance and actions if 
the subject meets Potential 
Hy’s law criteria. 
Discontinue vistusertib 
permanently. 
 
Also, see Appendix 5 for further 
guidance and actions if the 
subject meets Potential Hy’s 
law criteria. 
Grade 4 
(ALT/AST >20 x ULN) 
(Bilirubin >10 x ULN) 
Discontinue acalabrutinib 
permanently. 
 
Also, see Appendix 5 for 
further guidance and actions if 
the subject meets Potential 
Hy’s law criteria. 
Discontinue vistusertib 
permanently.  
 
Also, see Appendix 5 for further 
guidance and actions if the 
subject meets Potential Hy’s 
law criteria. 
 


 
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3.9.13 
Recommendations for Evaluation and Treatment of Infections 
Subjects receiving treatment with vistusertib or acalabrutinib may be at an increased risk 
of infection.  Subjects should be made aware of the risk of possible overlapping risk of 
infections elevations while receiving both drugs.  This should be managed as per clinical 
practice. In case of Grade 3 infections, the guidelines provided in Section 3.8.2 should 
be followed. 
3.9.14 
Recommendations for Other Nonhematologic Toxicities 
Other toxicities should be managed as per clinical practice. In case of Grade 3 toxicity, 
the guidelines provided in Section 3.8.2 should be followed. 
Acalabrutinib and vistusertib must be discontinued in case of Grade 4 treatment-related 
nonhematologic toxicity. 
3.9.15 
Recommendations for Treatment of Hematologic Findings and 
Associated Dose Modifications 
Cytopenia could be an overlapping toxicity for acalabrutinib and vistusertib.  In the 
presence of CTCAE Grade 3/4 neutropenia/leucopenia/thrombocytopenia/anemia, 
subject’s blood counts should be monitored, using local laboratories, at least twice 
weekly until recovery.   
Please refer to Table 7 for dose modifications due to hematologic toxicities. The number 
of dose reduction levels available for vistusertib and acalabrutinib will vary depending on 
the starting dose (Section 3.8).  
If the table indicates that the vistusertib dose should be reduced and the subject is 
already on the lowest dose available for vistusertib as per Table 5, vistusertib should be 
discontinued. If the table indicates that the acalabrutinib dose should be reduced and the 
subject is already on 100 mg/day (see Table 6), acalabrutinib should be discontinued.  
3.9.16 
Recommendations for Tumor Lysis Syndrome (TLS) 
TLS is a potential risk for the combination of vistusertib and acalabrutinib.  TLS 
prophylaxis will be at investigator discretion following institutional guidelines.  Table 10 
provides recommended TLS prophylaxis, which should be followed in addition to 
institutional guidelines.  
Clinical or laboratory TLS (defined in Table 3 and Table 4) may trigger dose modification 
in accordance with guidelines provided in Section 3.8.2. 


 
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Table 10.  Recommended TLS prophylaxis based on risk 
 
Risk 
Type of Cancer 
High 
Intermediate 
Low 
NHL 
Burkitt lymphoblastic, B-ALL 
OR 
Any LN ≥10 cm 
DLBCL/Richter syndrome OR 
Any LN 5 cm to <10 cm 
 
Indolent NHL 
AML/MDS 
WBC ≥50,000, monoblastic 
WBC 10,000-50,000 
WBC ≤10,000 
CLL/ALL 
Any LN ≥10 cm OR 
ALC ≥25 x109/L 
AND 
any LN ≥5 cm 
Any LN 5 cm to <10 cm 
OR 
ALC ≥25 x109/L 
All LN <5 cm AND 
ALC <25 x109/L 
Multiple myeloma 
 
Rapid proliferation with 
expected rapid response to 
therapy 
Remainder of patients 
 
Recommended Prophylaxis 
Hydrationa 
Oral (1.5-2L) 
and intravenous 
(150-200 mL/hr 
as tolerated) 
Oral 
(1.5-2 L) 
and consider 
additional 
intravenous 
Oral 
(1.5-2 L) 
Antihyperuricemics 
Allopurinolb; 
consider rasburicase 
if baseline uric acid 
is elevated 
Allopurinolb 
Allopurinolb 
Abbreviations: ALC = absolute lymphocyte count; ALL = acute lymphocytic leukemia; AML = acute myeloid 
leukemia, B-ALL = Burkitt acute lymphoblastic leukemia; CLL = chronic lymphocytic leukemia; DLBCL = 
diffuse large B-cell lymphoma; hr = hour; LN = lymph node; MDS = myelodysplastic syndrome; NHL = 
nonHodgkin lymphoma; WBC = white blood cell count 
a. 
Administer intravenous hydration for any patient who cannot tolerate oral hydration. 
b. 
Start allopurinol or xanthine oxidase inhibitor 2 to 3 days before initiation of both study drugs. 
Modified from Coiffier et al 2008.  
 
TLS Monitoring 
Monitoring for TLS includes checking blood urea nitrogen (BUN), creatinine, 
phosphate/phosphorus, uric acid, calcium, potassium and lactate dehydrogenase (LDH) 
levels at least every 6 hours (or more frequently as clinically indicated) in patients at high 
risk for TLS and as required per institutional standards.  Fluid balance must be 
monitored per institutional standards.   
3.10 
CONCOMITANT THERAPY 
3.10.1 
Permitted Concomitant Therapy 
Supportive medications in accordance with standard practice (such as for emesis, 
diarrhea, and nausea; see also Section 3.9.2 and Section 3.9.3) are permitted.  Use of 
granulocyte growth factors (filgrastim and pegfilgrastim) or red blood cell growth factors 
(erythropoietin) is permitted per institutional policy and in accordance with the American 
Society of Clinical Oncology guidelines (Smith et al 2015).  Please note that treatment 
with concomitant/prophylactic hematopoietic growth factors should only be considered 


 
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during vistusertib drug interruptions, but may be given concomitantly with acalabrutinib.  
Blood and platelet transfusions may be given in accordance with institutional policy. 
For subjects considered at risk for tumor lysis syndrome (see also Section 3.9.16):  
Administer appropriate hydration and allopurinol or rasburicase per institutional 
standards before initiating treatment. 
For subjects at risk for pneumonitis based on prior history or comorbid conditions:  In 
selected subjects (eg, those with a history of recurrent pneumonias), anti-infectious 
prevention should be considered. Initiation of antibiotic prophylaxis against 
pneumocystis infection (eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized 
pentamidine, or atovaquone) beginning before study drug administration may be 
warranted.  Such support may also offer the benefit of reducing the risk for other 
bacterial infections (Stern et al 2014).  Prophylaxis with intravenous immunoglobulins 
(Ig) may be appropriate in subjects with low Ig levels (Raanani et al 2009).  Local 
practices or guidelines regarding infection prophylaxis may be followed.   
For infections (see also Section 3.9.13):  Bacterial/viral/fungal prophylaxis is allowed per 
institutional standards.  Per the protocol, blood counts are monitored at least every 
2 weeks for the first 6 cycles of treatment.  However, in subjects with 
ANC <1000 cells/mm3, blood counts should be monitored weekly or more frequently as 
clinically indicated.  Subjects with active CMV infection are excluded from the trial.  
However, should a subject acquire CMV infection during treatment, then the subject 
should be discontinued from treatment and treated for CMV appropriately. 
3.10.2 
Prohibited or Restricted Concomitant Therapy 
Any chemotherapy, anticancer immunotherapy, corticosteroids (at dosages equivalent to 
prednisone >20 mg/day), therapeutic anticoagulants (with the exception of short-acting 
heparins), experimental therapy, and radiotherapy are prohibited.   
At study entry, subjects may be using topical or inhaled corticosteroids or low-dose 
steroids (≤10 mg of prednisone or equivalent per day) as therapy for comorbid 
conditions, but use of corticosteroids as therapy of the lymphoid cancer is not permitted.  
During study participation, subjects may also receive corticosteroids at any required 
dosage as needed for treatment-emergent adverse events (for example see 
Section 3.9).  


 
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Live vaccines within 30 days before the first dose of trial treatment and while 
participating in the trial are prohibited.  Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, 
BCG, and typhoid (oral) vaccine.  Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed.  However, intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines and are not allowed. 
Concomitant medications known to prolong QT should be used with caution and cannot 
be used during the first 28 days on study.  The following website (or a similar site) 
should be consulted to search for drugs with QT prolongation potential:   
https://crediblemeds.org 
Refer to Section 3.11.5 for guidance/restrictions on drugs that may cause drug-drug 
interactions. 
3.11 
PRECAUTIONS 
3.11.1 
Hepatitis B Reactivation 
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated 
with a BTK inhibitor (De Jésus Ngoma et al 2015).  Therefore, subjects who are anti-HBc 
positive, or have a known history of HBV infection, should be monitored monthly with a 
quantitative PCR test for HBV DNA.  Monthly monitoring should continue until 12 months 
after last dose of acalabrutinib.  Any subject with a rising viral load (above lower limit of 
detection) should discontinue acalabrutinib and have antiviral therapy instituted and a 
consultation with a physician with expertise in managing hepatitis B.  Insufficient data 
exist regarding the safety of resuming acalabrutinib in subjects who develop HBV 
reactivation. 
3.11.2 
Progressive multifocal leukoencephalopathy (PML) 
Cases of PML have been reported in subjects treated with acalabrutinib.   
Signs and symptoms of PML may cognitive and behavioral changes, language 
disturbances, visual disturbances, sensory deficits, weakness, and coordination and gait 
difficulties 
If PML is suspected, hold further treatment with acalabrutinib treatment until PML is 
excluded. A diagnostic evaluation may include (but is not limited to): 
• 
Neurologic consultation 


 
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• 
Brain magnetic resonance imaging (MRI) 
• 
PCR analysis for John Cunningham (JC) virus DNA in cerebrospinal fluid 
If PML is confirmed, permanently discontinue acalabrutinib. 
3.11.3 
Phototoxicity 
Phototoxicity has been classified as a potential risk for vistusertib; however, there have 
been no relevant clinical findings so far.  Subjects should be advised of the need for 
sunlight protection measures such as use of sunscreen and wearing of sunglasses 
during administration of vistusertib. Use of sun beds and tanning booths should be 
avoided.  These measures should be adopted for a period of 3 months after receiving 
their final dose of vistusertib. 
3.11.4 
Dietary Restrictions 
Acalabrutinib and vistusertib can be taken with or without food.  Because acalabrutinib 
and vistusertib are metabolized by CYP3A, subjects should be strongly cautioned 
against consumption of grapefruit, grapefruit juice, or Seville orange juice (which contain 
potent CYP3A inhibitors) or using herbal remedies or dietary supplements (in particular, 
St John’s wort, which is a potent CYP3A inducer). 
Otherwise, subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting. 
3.11.5 
Drug-drug Interactions 
Acalabrutinib 
The effect of agents that reduce gastric acidity (antacids or proton pump inhibitors) on 
acalabrutinib absorption was evaluated in a healthy volunteer study (ACE HV 004). 
Results from this study indicate that subjects should avoid the use of calcium carbonate 
containing drugs or supplements for a period of at least 2 hours before and at least 
2 hours after taking acalabrutinib.  Use of omeprazole, esomeprazole, lansoprazole or 
any other proton pump inhibitors while taking ACP-196 is not recommended due to a 
potential decrease in study drug exposure.  However, the decision to treat with proton-
pump inhibitors during the study is at the investigator’s discretion, with an understanding 
of the potential benefit to the subject’s gastrointestinal condition and a potential risk of 
decreased exposure to acalabrutinib.  Although the effect of H2-receptor antagonists 
(such as famotidine or ranitidine) on acalabrutinib absorption has not been evaluated, if 


 
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treatment with an H2-receptor antagonist is required, the H2-receptor antagonist should 
be taken approximately 2 hours after an acalabrutinib dose. 
Acalabrutinib is not a strong direct inhibitor or inducer or CYP isoforms; thus, 
acalabrutinib, at the currently used clinical doses, is unlikely to be a perpetrator of a 
drug-drug interaction at the level of inhibition or induction of CYP isoforms.  Acalabrutinib 
is partially metabolized by CYP3A; its exposure is affected when coadministered with 
strong CYP3A inducers or inhibitors.  Consequently, the concomitant use of strong 
inhibitors/inducers of CYP3A (see Appendix 4) should be avoided when possible.  If co-
administration of moderate or strong CYP3A inhibitors is required when a subject is 
receiving acalabrutinib, monitor for potential toxicity. 
Vistusertib 
Drug interactions have been classified as an important potential risk for vistusertib.   
While subjects may not enter the study if they have taken (within the appropriate 
washout period for each drug before the first dose of study treatment) any of the 
CYP3A4/5, P-gp, or BCRP inhibitors or inducers detailed in Appendix 4, it could be 
possible to allow their short-term administration during the study under the following 
circumstances: 
• 
If a subject requires short-term administration of a restricted CYP3A4/5, P-gp, or 
BCRP inhibitor, vistusertib treatment must be withheld 3 days before the first 
dose and not restarted until at least the concomitant therapy has been 
discontinued for the appropriate washout period described in Appendix 4. 
• 
If a subject requires short-term administration of a restricted CYP3A4/5, P-gp, or 
BCRP inducer, this should be clearly documented in the eCRF and may then be 
permitted, but this could lead to lower levels of vistusertib and a potential 
reduction in clinical efficacy. 
• 
If a subject requires short-term administration of restricted substrates of 
OATP1B1, OATP1B3, MATE1 or MATE2K transporters, vistusertib treatment 
must be withheld for 3 days before the first dose and not restarted until the 
concomitant therapy has been discontinued for the appropriate washout period 
described in Appendix 4 and until at least after the end of Cycle 1. 
The lists of CYP and transporter inhibitors/inducers and transporter substrates are not 
exhaustive and the absence of a drug from these lists does not imply that its 


 
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combination with vistusertib is safe.  Investigators should discuss with the Medical 
Monitor before initiating treatment with concomitant medications that might pose drug 
interactions with vistusertib. 
Information on any treatment in the 4 weeks before starting study drug(s) and all 
concomitant treatments given during the study with reasons for the treatments should be 
recorded.  If medically feasible, subjects taking regular medication, with the exception of 
those excluded from this study (ie, substrates of OATP1B1, OATP1B3, MATE1 and 
MATE2K drug transporters), should be maintained on it throughout the study period. 
3.11.6 
Surgery 
Susceptibility to bleeding has been observed with ibrutinib (IMBRUVICA® prescribing 
information).  As a precaution, it is suggested that acalabrutinib be withheld for 3 days 
before and 3 days after any major surgical procedure. 
3.11.7 
Reproductive Toxicity 
Reproductive toxicity has been classified as an important potential risk for vistusertib.  It 
is not currently known whether vistusertib affects fertility in humans.  If not done 
previously, storage of sperm/eggs before receiving vistusertib will be advised to 
male/female subjects with a desire to have children.  Results from studies of 
acalabrutinib on fertility and embryofetal development are provided in the Acalabrutinib 
Investigator Brochure. 
Definition of contraception: 
Highly effective methods of contraception (to be used during heterosexual activity) are 
defined as methods that can achieve a failure rate of <1% per year when used 
consistently and correctly.  Such methods include the following: 
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation, which may be oral, intravaginal, or 
transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation, 
which may be oral, injectable, or implantable 
• 
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 


 
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• 
Vasectomy of a female subject’s male partner (with medical assessment and 
confirmation of vasectomy surgical success) 
• 
Sexual abstinence (only if refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments) 
Hormonal contraception may be susceptible to interaction with study or other drugs, 
which may reduce the efficacy of the contraception method. 
Abstinence (relative to heterosexual activity) can only be used as the sole method of 
contraception if it is consistently employed during the entire period of risk associated 
with the study treatments as the subject’s preferred and usual lifestyle.  Periodic 
abstinence (eg, calendar, ovulation, sympto-thermal, and post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
If a contraceptive method is restricted by local regulations/guidelines, then it does not 
qualify as an acceptable highly effective method of contraception for subjects 
participating at sites in the relevant country/region. 
Women who are sexually active and of childbearing potential must use the contraceptive 
methods described above from the time of screening to 90 days after discontinuing study 
drug(s). 
Men who have a partner who is a woman of childbearing potential must use highly 
effective contraception with the additional use of a condom during the study and for 
16 weeks after the subject’s last dose of vistusertib.  Male subjects should refrain from 
donating sperm from the start of dosing until 16 weeks after the subject’s last dose of 
vistusertib.  If male subjects wish to father children, they should be advised to arrange 
for freezing of sperm samples before receiving the first dose of vistusertib. 
Subjects should promptly notify the investigator if they or their partners become pregnant 
during this study or within 2 days after their last dose of acalabrutinib or 16 weeks after 
the subject’s last dose of vistusertib, whichever is longer.  If a woman becomes pregnant 
during the treatment period, she must discontinue acalabrutinib and vistusertib.  
Pregnancy must be reported as outlined in Section 6.2.3.   
3.11.8 
Overdose Instructions 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the highest dose being studied.  An overdose or incorrect administration of study 
drug is not an AE unless it results in untoward medical effects. 


 
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Any study drug overdose or incorrect administration of study drug should be noted on 
the appropriate eCRF. 
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the eCRF.  If the associated AE fulfills serious criteria, the event should be 
reported to the sponsor immediately (ie, no more than 24 hours after learning of the 
event). 
For any subject experiencing an acalabrutinib overdose, observation for any 
symptomatic side effects should be instituted, and vital signs, biochemical and 
hematologic parameters should be followed closely (consistent with the protocol or more 
frequently, as needed).  Appropriate supportive management to mitigate adverse effects 
should be initiated.  If the overdose ingestion of acalabrutinib is recent and substantial, 
and if there are no medical contraindications, use of gastric lavage or induction of 
emesis may be considered. 
A dose of vistusertib in excess of the highest dose specified according to the protocol 
will constitute an overdose.  There is currently no known antidote to vistusertib, and the 
treatment of overdose should be supportive for the underlying symptoms.  To date, no 
subject has experienced an overdose with vistusertib that was associated with AEs.   
3.12 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
The investigator, in consultation with the medical monitor, may withdraw any subject 
from study treatment, if, in the investigator’s opinion, it is not in the subject’s best interest 
to continue.  
Any subject has the right to withdraw from the study at any time.  In addition, subjects 
may be withdrawn from study treatment for the following reasons: 
• 
Progressive disease 
• 
Completed treatment 
• 
Start of alternative anticancer therapy 
• 
Adverse event 
• 
Pregnancy 
• 
Investigator decision 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study 
• 
Subject lost to follow-up 


 
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• 
Death 
• 
Other 
3.13 
REASONS FOR STUDY EXIT/TERMINATION 
Reasons for study exit include: 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study 
• 
Subject lost to follow-up 
• 
Death 
In case a subject is lost to follow-up, every possible effort must be made by the study 
site personnel to contact the subject and determine the reason for discontinuation.  The 
measures taken to follow up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal must 
be documented in the eCRF and in the source documents.  Subjects who withdraw 
consent should still be encouraged to complete the SFU assessments before 
withdrawing consent, but these assessments cannot be mandated once consent is 
withdrawn.  Subjects who are withdrawn or removed from study treatment will not be 
replaced. 
The sponsor may decide to prematurely terminate the study at any time.  Potential 
reasons for terminating the study include: 
• 
Inadequate enrollment 
• 
Undue safety risk (eg, drug-related deaths or toxicities leading to study drug 
discontinuation) 
• 
Lack of efficacy (eg, low response rate or low durability of response) 
3.14 
DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the sponsor’s pharmacovigilance 
procedures.  AEs and SAEs will be reviewed internally as part of ongoing safety 
surveillance.  Quarterly conference calls with the investigators and applicable site staff 
will be conducted to discuss study progress, obtain investigator feedback and exchange, 
and discuss "significant safety events" (ie, DLTs, AEs leading to dose reductions or 
discontinuation, related SAEs, and deaths).  In addition, for the DLT review, mandatory 
safety teleconferences will occur before any vistusertib dose escalation can occur and 


 
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before the expansion phase of the protocol can open.  The DLT review meeting(s) will 
require the attendance of the investigators (or delegated subinvestigators) and the 
sponsor medical monitor and biostatistician.  The expansion phase of the protocol will 
not open unless a tolerated dose and schedule for vistusertib has been identified in 
Part 1. 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 1 for combination treatment and in 
Appendix 2 for acalabrutinib monotherapy.  Descriptions of the scheduled evaluations 
are outlined below and complete information on study drug and dosing is provided in 
Section 3.4. 
Before study entry, throughout the study, and at the follow-up evaluation, various clinical 
and diagnostic laboratory evaluations are outlined.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  
Clinical evaluations and laboratory studies may be repeated more frequently if clinically 
indicated.  This study will primarily use central laboratory testing for safety laboratory 
evaluations.   
4.1 
DESCRIPTION OF PROCEDURES 
4.1.1 
Informed Consent 
The subject must read, understand and sign the ICF approved by the IRB/IEC, 
confirming his or her willingness to participate in this study before initiating any 
screening activity that is not considered standard of care by institutional standards.  
Subjects must also grant permission to use protected health information, if required by 
local regulations.  This protocol also has optional DNA and tumor tissue sampling 
procedures that subjects may elect to participate in through the consent process. 
4.1.2 
Confirmation of Eligibility 
Subject eligibility for enrollment will be assessed per Section 3.3.  All screening 
procedures, unless otherwise indicated, should be completed within 30 days of the first 
dose of study drug(s). 
4.1.3 
Medical History 
Collect and record the subject’s complete history through review of medical records and 
by interview.  Concurrent medical signs and symptoms must be documented to establish 


 
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baseline severities.  A disease history, including the date of initial diagnosis and list of all 
prior anticancer treatments, and responses and duration of response to these 
treatments, also will be recorded. 
4.1.4 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1.  The AE 
reporting period is described in Section 6.2.1.  Important additional requirements for 
reporting SAEs are explained in Section 6.2. 
4.1.5 
Concomitant Medications and Therapy 
Document all concomitant medications and procedures from the start of screening 
procedures through the survival follow-up period. 
4.1.6 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 3. 
4.1.7 
Cumulative Illness Rating Scale-Geriatric (CIRS-G) 
CIRS-G (Appendix 7) is an indicator of illness severity and comorbidity in older subjects 
(Extermann et al 1998).  CIRS-G scoring is to be performed by a licensed provider (eg, 
physician, physician assistant, or nurse) for all subjects. 
Rating Strategy 
Please see specific scoring guidelines below for each organ system. 
0: No Problem. 
1: Current mild problem or past significant problem. 
2: Moderate disability or morbidity/requires “first line” therapy. 
3: Severe/constant significant disability/”uncontrollable” chronic problems. 
4: Extremely severe/immediate treatment required/end organ failure/severe 
impairment of function. 
4.1.8 
Physical Examination, Vital Signs, Height & Weight 
The screening physical examination will include, at a minimum, the general appearance 
of the subject, height (screening only) and weight, and examination of the skin, eyes, 
ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous 
system, and lymphatic system. 


 
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Symptom-directed physical exams will be done during the treatment period and at the 
SFU visits. 
Vital signs (blood pressure, pulse, oxygen saturation and body temperature) will be 
assessed after the subject has rested in the sitting position for at least 5 minutes.   
4.1.9 
Electrocardiogram  
Subjects should be in supine position and resting for at least 10 minutes before any 
study-related ECGs.   
Triplicate ECGs are required at screening and Cycle 6 only, or if clinically indicated, at all 
other visits, single ECGs are required.  If an unscheduled ECG is done at any time, then 
an electrolyte panel (ie, calcium, magnesium, and potassium) must be done to coincide 
with the ECG testing. 
4.1.10 
ECHO/MUGA 
In addition to screening, an ECHO should be done 14 days after an abnormal ECG 
finding (T wave inversion/flattening), or when clinically indicated.  If an ECHO cannot be 
taken, a MUGA scan to assess LVEF will be done.  In case of any T wave abnormality, 
the ECHO (or MUGA) should be repeated at the SFU visit to address the question of 
recovery, during the off-treatment period.  Note:  An ECHO is preferred over MUGA to 
avoid unnecessary radiation exposure to subjects. 
4.1.11 
CT Scan of Thorax 
A baseline thorax CT scan must be available for all subjects treated with vistusertib, for 
retrospective analysis and comparison with a high-resolution CT scan, should it be 
required, should symptoms of interstitial lung disease occur during study conduct.  Note:  
A separate scan of only the thorax is not required for subjects who have baseline CT 
scans for tumor assessments per Section 4.3. 
4.1.12 
Hematology 
Hematology studies must include complete blood count (CBC) with differential including, 
but not limited to white blood cell count, hemoglobin, hematocrit, platelet count, ANC, 
and absolute lymphocyte count (ALC).   
4.1.13 
Serum Chemistry 
Chemistry will include albumin, alkaline phosphatase, ALT, AST, bicarbonate, BUN, 
calcium, chloride, cholesterol, C-peptide, creatinine, glucose, LDH, magnesium, 


 
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phosphate/phosphorus, potassium, sodium, triglycerides, total bilirubin, total protein, and 
uric acid for subjects on combination treatment.  Cholesterol, C-peptide and triglyceride 
testing not required for subjects who have discontinued vistusertib and are only receiving 
acalabrutinib.   
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, 
magnesium, and potassium) must be done to coincide with the ECG testing.   
4.1.14 
Pregnancy Testing 
Pregnancy testing is required in women of childbearing potential. 
4.1.15 
Cardiac Troponin 
Cardiac troponin testing will be done per the schedule in Appendix 1. 
4.1.16 
Coagulation 
Coagulation studies must include PT, INR and aPTT.   
4.1.17 
Hepatitis B and C Testing 
Hepatitis serology testing must include hepatitis B surface antigen (HBsAg), hepatitis B 
surface antibody (anti-HBs), anti-HBc, and HCV antibody.  In addition, any subjects 
testing positive for any hepatitis serology must have PCR testing during screening and 
on study (see Appendix 1 and exclusion criterion #5).     
Subjects who are anti-HBc positive should have quantitative PCR testing for HBV DNA 
performed during screening and monthly thereafter.  Monthly monitoring should continue 
until 12 months after last dose of study drug(s).  Any subject with a rising viral load 
(above lower limit of detection) should discontinue study drug and have antiviral therapy 
instituted and a consultation with a physician with expertise in managing hepatitis B.  As 
IVIG may cause false positive hepatitis serology, monthly PCR testing is not required in 
subjects who are currently receiving or received prophylactic IVIG within 3 months 
before study enrollment and have a documented negative anti-HBc test before the 
initiation of IVIG therapy.  PCR testing should be performed when clinically indicated (eg, 
in the setting of rising transaminase levels).  
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive 
should be tested for HCV RNA performed during screening and at Cycle 6.  No further 
testing beyond Cycle 6 is necessary if PCR results are negative. 


 
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Refer to Section 3.11.1, Appendix 1, and Appendix 2 regarding monitoring of subjects 
who are anti-HBc positive or hepatitis C antibody positive or who have a known history 
of HBV or HCV. 
4.1.18 
CMV Testing 
CMV testing at screening must include serology testing for CMV IgG, CMV IgM, and 
CMV PCR testing. 
4.1.19 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.   
4.1.20 
T/B/NK Cell Count 
Flow cytometry testing of peripheral blood will include CD3+, CD4+, CD8+, CD19+ and 
CD16/56+ cells.   
4.1.21 
Serum Immunoglobulin  
Serum immunoglobulin testing will include IgG, IgM, and IgA. 
4.1.22 
Pharmacokinetics 
Vistusertib PK blood sampling (2 mL per sample) will be collected at predose and at 
approximately 1, 2, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 22 for all 
subjects in Part 1. 
Acalabrutinib PK blood sampling (2 mL per sample) will be collected.  For Part 1, 
samples will be collected from all subjects on Cycle 1 Day 1 and Cycle 1 Day 22 
predose and at approximately 1, 2, 4 and 6 hours postdose. 
The predose sample can be taken up to 30 minutes before dosing.  The window for 
other timepoints is ± 5 minutes.  Leftover plasma from PK analysis may be repurposed 
for exploratory acalabrutinib and/or vistusertib plasma metabolite analysis.  Testing will 
be done by a central lab.  Refer to the laboratory manual for instructions on collection 
and shipment of PK samples. 
4.1.23 
Archival Tumor Sample (Required for Study Entry) 
Formalin-fixed tumor tissue embedded in paraffin blocks are to be retrieved for all 
subjects.  If baseline biopsy samples can also be collected, retrieval of the archival 
diagnostic tumor material is still highly encouraged, to provide data on how the tumor 
has evolved since diagnosis.  The archival samples are preferably from excisional 


 
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biopsies from the primary tumor and/or metastatic site.  Freshly prepared unstained 
slides (minimum of 20 is preferred) 4 to 5 micron sections from the archival tumor block 
are acceptable, if tumor blocks cannot be submitted.  Because uncontrolled oxidation 
processes affect tumor sections, tumor tissue blocks are preferred.  From submitted 
archival tumor blocks, 2 cores may be removed to construct tissue microarrays for later 
biomarker analysis.  The remaining part of the tumor block will be returned to the 
institution. 
Details of sample collection, processing, shipping, and storage will be described in the 
laboratory manual. 
4.1.24 
Optional Fresh Tumor Biopsy Sample 
 
 
 
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4.1.25 
Pharmacodynamic Samples 
4.1.26 
ctDNA Samples 
4.1.27 
Exploratory Blood Biomarker Samples 
CCI
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4.1.28 
Optional Pharmacogenetics Sample 
4.1.29 
Bone Marrow Biopsy/Aspirate 
Bone marrow biopsy and aspirate with flow cytometry analysis at baseline will be 
performed locally to show any bone marrow involvement for all subjects. 
A further bone marrow biopsy and aspirate is required to confirm a CR, if the baseline 
sample is positive.   
4.1.30 
Tumor Assessments 
For all histologies: 
Baseline tumor assessments will be performed using radiologic imaging by CT with 
contrast and PET-CT covering neck, chest, abdomen, and pelvis within 30 days before 
the first dose of study drug.  Radiologic scans (ie, contrast CT) will be repeated every 
3 cycles (ie, approximately every 12 weeks ± 7 days).  PET-CT also will be repeated on 
the same schedule, when required, per Section 4.3 of the protocol.  For subjects with 
baseline hepatosplenomegaly, the cranial-caudal measurement of the spleen and 
longest diameter of the liver will be assessed at screening and subsequent response 
evaluations.   
MRI may be used for imaging assessments if a contrast CT scan is contraindicated or 
unobtainable.  In cases where MRI is desirable, the MRI must be obtained at baseline 
and at all subsequent response evaluations. 
4.1.31 
Study Drug Accountability 
See Section 7.6. 
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4.2 
BIOLOGIC SAMPLING PROCEDURES 
4.2.1 
Handling, Storage, and Destruction of Biologic Samples 
Refer to the laboratory manual for specific guidelines and instructions. 
The samples will be used up, or disposed of, after analyses or retained for further use as 
described here. 
Biologic samples for future research will be retained at the Research & Development 
site, on behalf of AstraZeneca for a maximum of 15 years after the last subject’s last visit 
in the study.  The results from future analysis will not be reported in the CSR, but 
separately in a Scientific Report. 
4.2.2 
Pharmacokinetic Samples 
PK samples will be disposed of after the Bioanalytical Report finalization or 6 months 
after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested 
for future analyses, such as metabolite testing. 
PK samples may be disposed of, or destroyed, and anonymized by pooling.  Additional 
analyses may be conducted on the anonymized, pooled PK samples to further evaluate 
and validate the analytical method.  Any results from such analyses may be reported 
separately from the CSR.  Anonymized samples will be retained for 5 years after the 
CSR is finalized. 
Incurred sample reproducibility analysis, if any, will be performed alongside the 
bioanalysis of the test samples.  The results from the evaluation will not be reported in 
the CSR but separately in a Bioanalytical Report. 
4.2.3 
Samples for Exploratory Research 
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4.2.4 
Chain of Custody of Biologic Samples 
4.2.5 
Withdrawal of Informed Consent for Donated Biological 
Samples 
Subjects may withdraw from any aspects of the voluntary exploratory research at any 
time, without prejudice to further treatment and independent of any decision concerning 
participation in other aspects of the main study. 
CCI
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If a subject withdraws consent for use of donated biologic samples, then the samples will 
be disposed of/destroyed, and the action documented.  If samples are already analyzed, 
the sponsor is not obliged to destroy the results of this research.  
If consent to use of biologic samples is withdrawn, the subject may continue in the study. 
The investigator: 
• 
Ensures the sponsor is notified immediately of the subject’s withdrawal of 
informed consent to the use of donated biologic samples 
• 
Ensures that biologic samples from that subject, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented 
• 
Ensures the local laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site 
• 
Ensures that the subject and the sponsor are informed about the sample 
disposal. 
The sponsor and AstraZeneca ensure the central laboratory(ies) holding the samples 
is/are informed about the withdrawn consent immediately and that samples are disposed 
of/destroyed, the action documented and the document returned to the study site. 
4.3 
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO 
TREATMENT 
Tumor assessments will be made for measurable disease, non-measurable disease, and 
new lesions on CT and combined with visual assessment of PET-CT for response 
assessment according to the revised response criteria for malignant lymphoma (Cheson 
et al 2014 in Appendix 9). 
CT scans 
Bidimensional measurements will be recorded for lymph nodes ≥1.5 cm in longest 
diameter in the eCRF.   
Up to a maximum of 6 dominant, measurable lymph nodal lesions should be assessed 
as target lesions. These nodes or masses should be selected according to all of the 
following:  
• 
They should be clearly measurable in at least 2 perpendicular dimensions 


 
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• 
If possible they should be from disparate regions of the body 
• 
They should include mediastinal and retroperitoneal areas of disease whenever 
these sites are involved. 
The perpendicular long and short axis diameters will be measured and recorded in the 
transverse plain at baseline and follow-up.  When appropriate, measurable extranodal 
disease (eg, hepatic nodules) may be included in the 6 representative, measured 
lesions. 
For the selected target lymph nodal lesions, the sum of the product of the perpendicular 
diameters will be calculated with the percentage change from baseline for assessment of 
response and nadir for assessment of progression.  
All other lesions (including nodal, extranodal, and assessable disease) should be 
followed as nonmeasured disease (eg, cutaneous, GI, bone, spleen, liver, kidneys, 
pleural or pericardial effusions, ascites) and should be factored into overall response 
assessment. 
Table 11.  Revised criteria for response assessment for non-Hodgkin lymphoma 
(NHL) 
Response and Site 
PET-CT Based response 
CT-Based Response 
Complete:  
 
Lymph nodes and 
extralymphatic sites 
Complete metabolic response:  
Score 1, 2, or 3* with or without a 
residual mass on 5PS† 
It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with 
activation within spleen or 
marrow (eg, with chemotherapy 
or myeloid colony-stimulating 
factors), uptake may be greater 
than normal mediastinum and/or 
liver. In this circumstance, 
complete metabolic response 
may be inferred if uptake at sites 
of initial involvement is no 
greater than surrounding normal 
tissue even if the tissue has high 
physiologic uptake 
Complete radiologic response (all 
of the following):  
Target nodes/nodal masses must 
regress to ≤1.5 cm in LDi  
No extralymphatic sites of disease 
 
 
Nonmeasured 
lesion 
Not applicable  
Absent 
 
Organ enlargement 
Not applicable 
Regress to normal 
 
New lesions 
None 
None 
 
Bone marrow  
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if 
indeterminate, IHC negative 


 
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Table 11.  Revised criteria for response assessment for non-Hodgkin lymphoma 
(NHL) 
Response and Site 
PET-CT Based response 
CT-Based Response 
Partial: 
 
Lymph nodes and 
extralymphatic sites 
 
Partial metabolic response:  
Score 4 or 5† with reduced uptake 
compared with baseline and 
residual mass(es) of any size 
Partial remission (all of the 
following):  
≥50% decrease in SPD of up to 
6 target measureable nodes 
and extranodal sites 
 
At interim, these findings suggest 
responding disease  
When a lesion is too small to 
measure on CT, assign 5 mm x 5 
mm as the default valve 
 
At end of treatment, these findings 
indicate residual disease 
When no longer visible 0 x 0 mm 
For a node >5 mm x 5 mm, but 
smaller than normal, use 
actual measurement for 
calculation  
 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no 
increase  
 
Organ enlargement  
Not applicable 
Spleen must have regressed by 
>50% in length beyond normal  
 
 
New lesions  
None 
None 
 
Bone marrow 
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent 
focal changes in the marrow in 
the context of a nodal response, 
consideration should be given to 
further evaluation with MRI or 
biopsy or an interval scan 
Not applicable 
 
No response or stable 
disease: 
No metabolic response: 
Stable disease: 
 
Target nodes/nodal 
masses, extranodal 
lesions 
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment 
<50% decrease from baseline in 
SPD of up to 6 dominant, 
measureable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with 
progression 
 
Organ enlargement 
Not applicable  
No increase consistent with 
progression 
 
New lesions 
None 
None 
 
Bone marrow 
No change form baseline 
Not applicable 
Progressive disease: 
Progressive metabolic disease: 
Progressive disease requires at 
least 1 of the following PPD 
progression: 
 
Individual target 
nodes/nodal masses 
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
An individual node/lesion must be 
abnormal with:  
LDi >1.5 cm and  
Increase by ≥ 50% from PPD nadir 
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Table 11.  Revised criteria for response assessment for non-Hodgkin lymphoma 
(NHL) 
Response and Site 
PET-CT Based response 
CT-Based Response 
An increase in LDi or SDi from 
nadir  
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions >2 cm 
 
 
Extranodal lesions 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-
treatment assessment 
 
In the setting of splenomegaly, the 
splenic length must increase by 
>50% of the extent of its prior 
increase beyond baseline (eg, 
a 15-cm spleen must increase 
to >16 cm). If no prior 
splenomegaly, must increase 
by at least 2 cm from baseline 
New or recurrent splenomegaly 
 
Nonmeasured 
lesions 
None 
New or clear progression of pre-
existing nonmeasured lesions 
 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (eg, infection, 
inflammation). If uncertain 
regarding etiology of new 
lesions, biopsy or interval scan 
may be considered 
 
Regrowth of previously resolved 
lesions 
A new node >1.5 cm in any axis 
A new extranodal site >1.0 cm in 
any axis; if <1.0 cm in any axis, 
its presence must be 
unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
 
Abbreviations: 5PS, 5-point scale; CT computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; 
PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, 
shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple 
lesions.  
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of 
an interim scan. However, in trails involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid under treatment). Measured dominant lesions: Up to 
6 of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in 
2 diameters. Nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver 
spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured 
lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be 
considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected 
as dominant or measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult 
to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal 
disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In 
Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in 
the mediastinum with complete metabolic response, but should be no higher than surrounding normal 
physiologic uptake (eg, with marrow activation as a result of chemotherapy of myeloid growth factors).  
†PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 
4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of 
uptake unlikely to be related to lymphoma. 
 
 


 
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Visual interpretation of PET-CT scans 
The International Working Group criteria for reviewing PET scans were based on visual 
interpretation, using mediastinal blood pool as the comparator. The current 
recommendation is to use the 5-point scale (Cheson et al 2014). 
Assessment of non-measurable lesions 
An overall assessment will be made for all other non-target lesions of present, absent or 
present with progression will be recorded and factored into response assessment. 
Assessment of new lesions 
Appearance of any new lesions more than 1.5 cm in any axis during or at the end of 
therapy, even if all other lesions are decreasing should be considered progression. 
Increased FDG uptake in a previously unaffected site should only be considered 
progression after confirmation with other modalities (eg, CT, MRI or x-ray). 
In subjects with no history of pulmonary lymphoma, new nodules identified by CT are 
benign and should be considered negative for lymphoma.  These lesions typically 
represent infectious or inflammatory lesions and therefore if FDG positive should not be 
considered positive for lymphoma in the absence of confirmatory tests, eg, histology. 
The presence or absence of new lesions will be recorded on the eCRF. 
4.4 
SAFETY FOLLOW-UP (SFU) VISITS 
Each subject should be followed until the SFU visit at 30 (+7) days after his or her last 
dose of study drug to monitor for resolution or progression of AEs and to document the 
occurrence of any new events, regardless of whether the subject receives a new 
anticancer therapy or demonstrates disease progression within this timeframe.  Subjects 
who withdraw consent for study treatment should still be encouraged to complete the 
SFU assessments before withdrawing consent, but these assessments cannot be 
mandated if subject consent for further study participation is withdrawn.  The Schedule 
of Assessments (Appendix 1and Appendix 2) describes the procedures required for the 
SFU visit.  
4.5 
FOLLOW-UP FOR PROGRESSION AND SURVIVAL 
Subjects who discontinue both study drugs before documented disease progression will 
be followed according to standard of care until documented disease progression is 
captured in the EDC system.  During this period, information will also be collected in the 


 
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EDC system on any new anticancer agents and on any SAEs considered related to 
study drug(s) or study procedures.  The long-term follow up will not apply to subjects 
who withdraw consent or are lost to follow-up. 
All subjects will be followed for survival until death, loss to follow up, sponsor decision to 
stop trial, or withdrawal of consent, whichever occurs first.  Subjects will be followed for 
survival by telephone calls or clinic visits approximately every 3 months.  During this 
period, information will also be collected on any SAEs considered related to study 
drug(s) or study procedures. 
4.6 
MISSED EVALUATIONS 
Missed evaluations should be rescheduled and performed as close to the original 
scheduled date as possible.  An exception is made when rescheduling becomes, in the 
investigator’s opinion, medically unnecessary or unsafe because it is too close in time to 
the next scheduled evaluation.  In that case, the missed evaluation should be 
abandoned. 
5.0 
STATISTICAL METHODS OF ANALYSIS  
5.1 
GENERAL CONSIDERATIONS 
Descriptive statistics (including means, standard deviations, and medians for continuous 
variables and proportions and confidence intervals [CIs] for discrete variables) will be 
used to summarize data as appropriate.  Response rate will be investigator assessed 
using standard response criteria (Cheson et al 2014).  KM methods will be used to 
estimate DOR, PFS, OS and corresponding quartiles (including the median). 
5.2 
RATIONALE FOR SAMPLE SIZE 
In Part 1 (dose selection), enrollment of 6 subjects per dose level limits the number of 
subjects exposed consistent with the expected safety profiles of the study drugs, but 
includes sufficient subjects to explore effects on PD biomarkers of BTK and mTOR 
inhibition.  The trial employed the standard NCI definition of MTD (dose associated with 
DLT in <33.3% of subjects assessed during cycle 1).  
A maximum of 3 dose levels were to have been explored in each of the two schedules 
(continuous/intermittent vistusertib dosing). The maximum number of subjects in Part 1 
was therefore 36.  The sponsor stopped the study in Part 1 after treating 25 subjects 
with the first 2 dose levels of vistusertib. 


 
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5.3 
DEFINITION OF ANALYSIS SETS 
The analysis of data will be based on different subsets according to the purpose of the 
analysis. 
Analysis sets are presented in Table 12. 
Table 12.  Analysis sets 
Analysis set 
Definition 
Safety 
All subjects who took ≥1 dose of either study drug. 
Data will be presented by initial dose received. 
Pharmacokinetics 
All subjects in the safety analysis set with evaluable PK parameters. 
Efficacy 
All subjects in the safety analysis set with a baseline tumor 
assessment. 
Data will be presented by planned dose. 
 
5.4 
MISSING DATA HANDLING 
No imputation of values for missing data will be performed except that missing or partial 
start and end dates for AEs and concomitant medication will be imputed according to 
prespecified, conservative imputation rules.  Subjects lost to follow-up (or drop out) will 
be included in statistical analyses to the point of their last evaluation.   
5.5 
OUTCOME DATA ANALYSIS 
5.5.1 
Safety 
Verbatim descriptions of AEs will be mapped according to the MedDRA thesaurus terms 
and graded according to NCI CTCAE, v5.0 or higher.  Extent of exposure to study 
drug(s), all AEs, SAEs, any adverse events leading to study drug(s) discontinuation, and 
study drug(s) related-adverse events will be summarized.  The frequency of AEs will be 
summarized by system organ class and preferred terms according to MedDRA, as well 
as per severity per NCI CTCAE grade.  Treatment-emergent AEs will be summarized, 
unless otherwise specified.  For events with varying severity, the worst reported grade 
will be used.  
Laboratory abnormalities will be defined based on laboratory normal ranges (universal 
normal ranges, if central lab).  Selected laboratory parameters may be analyzed with 
shift tables and summaries of changes from baseline to worst post-treatment value.   
Vital sign assessments will be tabulated and summarized. 


 
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5.5.2 
Demographics and Baseline Characteristics 
Analyses will include summaries of subject demographics, baseline characteristics, and 
concurrent treatments.  Concomitant medications will be coded and tabulated according 
to the World Health Organization Drug Dictionary (WHODRUG). 
5.5.3 
Exposure to Study Drug(s) 
Descriptive statistics (n, mean, standard deviation, median, and range) will be used to 
summarize the following:    
• 
duration of exposure (the interval between first dose date and last dose date) 
• 
average daily dose (the ratio of total dose administered and treatment duration) 
• 
relative dose intensities (the ratio of total actual dose and total planned dose) 
5.5.4 
Analysis of Efficacy Parameters 
5.5.4.1 
Overall Response Rate (ORR) and Complete Response (CR) 
Rate 
The ORR is defined as the rate of subjects who achieve either a PR or CR, according to 
the revised response criteria for malignant lymphoma (Cheson et al 2014), as assessed 
by investigators before receiving any other anticancer therapy.  ORR and CR will be 
presented by histology.  The corresponding 95% two-sided CI will be derived for ORR 
and CR rate.   
5.5.4.2 
Progression-Free Survival (PFS) 
Disease progression will be determined by the investigators according to the revised 
response criteria for malignant lymphoma (Cheson et al 2014).  PFS is defined as the 
time from first dose date to documented disease progression, or death from any cause, 
whichever occurs first.  Subjects who had the event after the start of subsequent 
therapy, or who are progression-free and alive at the time of data cutoff, or have 
unknown status will be censored at the time of their last disease assessment on or 
before the start of subsequent therapy or data cut-off. Subjects with no post-baseline 
disease assessment will be censored on Day 1.  KM curves may be presented by 
histology, if appropriate.  KM estimates and corresponding two-sided 95% CIs will be 
calculated for the median and quartiles. 
5.5.4.3 
Duration of Response (DOR) 
DOR is defined as the time from the first objective response of CR or PR to the time of 
documented disease progression or death due to any cause, whichever occurs first.  
Subjects who had the event after the start of subsequent therapy, or are progression-


 
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free and alive at the time of data cutoff, or have unknown status will be censored at the 
last tumor assessment on or before the start of subsequent therapy.  Plots will be used 
to show the durations of responses.  KM curves may be presented by histology, if 
appropriate.  KM estimates and corresponding two-sided 95% CIs will be calculated for 
the median and quartiles. 
5.5.4.4 
Durable Response Rate (DRR) 
The DRR is defined as the percentage of subjects who have a complete or partial 
response lasting ≥8 weeks.  
5.5.4.5 
Overall Survival (OS) 
OS is defined as the time from first dose until the date of death from any cause.  
Subjects who have not died by the analysis data cutoff date will be censored at their last 
date known to be alive before the cutoff date.  Subjects known to be alive or dead after 
the data cutoff date will be censored at the data cutoff date.  Subjects who are lost in 
follow-up will be censored at the date the subject is last known to have been alive.  KM 
curves may be presented by histology, if appropriate.  KM estimates and corresponding 
two-sided 95% CIs will be calculated for the median and quartiles. 
5.5.5 
Pharmacokinetic Analyses 
The plasma PK of acalabrutinib and vistusertib will be characterized using 
noncompartmental analysis. The following PK parameters will be calculated, whenever 
possible, from plasma concentrations of analytes (Note: These will not be collected or 
assessed for subjects whose study participation extends past the first 12 cycles.): 
• 
AUC0-last:  Area under the plasma concentration-time curve calculated using 
linear trapezoidal summation from time 0 to time last, where “last” is the time of 
the last measurable concentration 
• 
AUC0-inf:  Area under the plasma concentration-time curve from 0 to infinity, 
calculated using the formula: AUC0-inf = AUC0-last + Clast / λz, where λz is the 
apparent terminal elimination rate constant 
• 
Cmax:  Maximum observed plasma concentration 
• 
Tmax:  Time of the maximum plasma concentration (obtained without interpolation) 
• 
t½:  Terminal elimination half-life (whenever possible) 
• 
λz:  Terminal elimination rate constant (whenever possible) 
• 
CL/F:  Oral clearance 
• 
Vz/F:  Oral volume of distribution 


 
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5.5.6 
Additional PK and PD Analyses 
Additional PD and PK analyses may be performed, as deemed appropriate. 
6.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording DLTs, AEs, SAEs and AEs 
leading to discontinuation of study drug(s); measurements of protocol-specified 
hematology, clinical chemistry, and other laboratory variables; measurement of protocol-
specified vital signs and ECGs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study drug(s). 
6.1 
DEFINITIONS 
6.1.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product, regardless of 
attribution. 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol 
specified AE reporting period, including signs or symptoms associated with 
lymphoma that were not present before the AE reporting period (see 
Section 6.2.1). 
• 
Preexisting medical conditions (other than the condition being studied) judged by 
the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period. 
• 
Abnormal laboratory values considered clinically significant by the investigator 
should be reported as an AE.   
The following are NOT considered an AE: 
• 
Pre-existing condition that has not worsened: A pre-existing condition 
(documented on the medical history eCRF) is not considered an AE unless the 
severity, frequency, or character of the event worsens during the study period. 
• 
Preplanned hospitalization: A hospitalization planned before signing the ICF is 
not considered an SAE, but rather a therapeutic intervention.  However, if during 
the preplanned hospitalization an event occurs, which prolongs the 


 
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hospitalization or meets any other SAE criteria, the event will be considered an 
SAE.  Surgeries or interventions that were under consideration, but not 
performed before signing the ICF, will not be considered serious if they are 
performed after signing the ICF for a condition that has not changed from its 
baseline level.  Elective hospitalizations for social reasons, solely for the 
administration of chemotherapy, or due to long travel distances are also not 
SAEs.  
• 
Diagnostic testing and procedures: Testing and procedures should not be 
reported as AEs or SAEs, but rather the cause for the test or procedure should 
be reported.  If a test or procedure is done to rule out a diagnosis, the sign or 
symptom leading to the test/procedure should be the event term, and the event 
term should only be updated to the diagnosis if/when the diagnosis is confirmed.  
Testing and procedures performed solely as screening measures (eg, routine 
screening mammography or colonoscopy) should not be reported as AEs or 
SAEs.  
• 
Abnormal laboratory results that the investigator considers to not be clinically 
significant: Abnormal laboratory results are not AEs unless they are clinically 
significant.  For example, a clinically significant laboratory results is one that 
requires treatment (for example a blood transfusion for low hemoglobin) or 
requires a change in study drug (eg, lowering the dose or withholding study drug 
while the laboratory finding resolves or stabilizes). 
• 
Progression of underlying malignancy:  Progression of underlying malignancy will 
not be reported as an AE if it is clearly consistent with the suspected progression 
of the underlying cancer.  Hospitalization due solely to the progression of 
underlying malignancy should NOT be reported as an SAE.  Clinical symptoms of 
progression may be reported as AEs if the symptoms cannot be determined as 
exclusively due to the progression of the underlying malignancy, or if they do not 
fit the expected pattern of progression for the disease under study. 
If there is any uncertainty about an AE being due only to the disease under 
study, it should be reported as an AE or SAE. 
6.1.2 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of an AE (see below).  “Serious” is a regulatory definition and is based on 


 
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subject or event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations from the sponsor to applicable regulatory 
authorities. 
An AE should be classified as an SAE if it meets any 1 of the following criteria: 
• 
It results in death (ie, the AE actually causes or leads to death). 
• 
It is life-threatening (ie, the AE, in the view of the investigator, places the 
subject at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the subject’s ability to conduct normal life 
functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the investigational product. 
• 
It is considered a significant medical event by the investigator based on 
medical judgment (eg, may jeopardize the subject or may require 
medical/surgical intervention to prevent 1 of the outcomes listed above). 
 
6.1.3 
Severity 
Definitions found in the CTCAE version 5.0 or higher will be used for grading the severity 
(intensity) of AEs.  The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each referenced AE.  Should a subject experience any AE 
not listed in the CTCAE, the following grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no 
special treatment, and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of 
inconvenience or concern to the subject, and which may interfere with daily 
activities, but are usually ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, 
significantly interrupt the subject’s usual daily activity, and require systemic 
drug therapy or other treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the 
subject to be in imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death 
 


 
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6.2 
DOCUMENTING AND REPORTING OF ADVERSE AND 
SERIOUS ADVERSE EVENTS 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, as outlined in the prior sections, are recorded on the eCRF.  
All SAEs must be reported on the SAE form or clinical database. 
6.2.1 
Adverse Event Reporting Period 
After the signing of the ICF, all SAEs must be reported.  After the first dose of study 
drug(s), all AEs/SAEs, irrespective of attribution of causality, must be reported.  
AE reporting, irrespective of seriousness, ends 30 days after the last dose of study 
drug(s). 
SAEs considered related to study drug(s) or study procedures occurring after the end of 
the AE reporting period (as defined above) must be reported.   
If an SAE is present at the last study visit, the SAE should be followed to resolution or 
until the investigator assesses the subject as stable, or the subject is lost to follow-up or 
withdraws consent.  Resolution/stable means the subject has returned to baseline state 
of health or the investigator does not expect any further improvement or worsening of 
the event. 
6.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation 
timepoints during the study.  All AEs and SAEs whether volunteered by the subject, 
discovered by study personnel during questioning, or detected through physical 
examination, or other means, will be recorded in the subject’s medical record and on the 
AE eCRF.  
Disease progression itself is not considered an AE. 
Each recorded AE or SAE will be described by its diagnostic term, duration (eg, start and 
end dates), severity, regulatory seriousness criteria, if applicable, suspected relationship 
to the study drug (see following guidance), and any actions taken.  The causality of AEs 
to the study drug will be assessed by means of the question: ‘Is there a reasonable 
possibility that the event may have been caused by the study drug?’ per FDA guidance 
on safety reporting requirements (Food and Drug Administration Guidance 2012).  
See Appendix 8 for more detail on assessing causality. 


 
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6.2.3 
Pregnancy 
The investigator should report pregnancies in female subjects or in the partners of male 
subjects within 24 hours using the Pregnancy Report Form.  This form should be faxed 
or emailed to Acerta Pharma Drug Safety.  Any pregnancy-associated SAE must be 
reported to Acerta Pharma, according to the usual timelines and directions for SAE 
reporting (see Section 6.2.4). 
Any uncomplicated pregnancy that occurs during this study will be reported.  All 
pregnancies that are identified during or after this study, wherein the estimated date of 
conception is determined to have occurred from the time of consent to 2 days after the 
last dose of acalabrutinib or 16 weeks after the last dose of vistusertib, whichever is 
longer, will be reported, followed to conclusion, and the outcome reported, as long as the 
subject or subject’s partner is willing to participate in follow up.  Upon completion of the 
pregnancy, additional information on the mother, pregnancy, and baby will be collected 
and sent to 
. 
A pregnancy itself is not regarded as an AE unless there is suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Likewise, elective abortions without complications are not 
considered AEs.  Any SAEs associated with pregnancy (eg, congenital 
abnormalities/birth defects/spontaneous miscarriage or any other serious events) must 
additionally be reported as such using the SAE report form. 
Subjects should be instructed to immediately notify the investigator of any pregnancies.   
6.2.4 
Expedited Reporting Requirements for Serious Adverse 
Events 
All SAEs must be reported within 24 hours of discovery.  All initial SAE reports and 
follow-up information will be reported using the protocol-specific electronic data capture 
system.  If electronic SAE reporting is not available, paper SAE forms must be emailed 
or faxed to Acerta Pharma Drug Safety, or designee.  Acerta Pharma may request 
follow-up and other additional information from the investigator (eg, hospital 
admission/discharge notes and laboratory results). 
Whenever possible, AEs/SAEs should be reported by diagnosis term not as a 
constellation of symptoms. 
Death due to disease progression should be recorded on the appropriate form in the 
EDC system.  If the primary cause of death is disease progression, the death due to 
CCI


 
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disease progression should not be reported as an SAE.  If the primary cause of death is 
something other than disease progression, then the death should be reported as an SAE 
with the primary cause of death as the event term, as death is typically the outcome of 
the event, not the event itself.  The primary cause of death on the autopsy report should 
be the term reported.  Autopsy and postmortem reports must be forwarded to Acerta 
Pharma Drug Safety, or designee, as outlined above. 
If study drug is discontinued because of an SAE, this information must be included in the 
SAE report. 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE is attributable to the investigational product (or if a causality assessment is not 
provided for the SAE, in which case a default of ‘related’ may be used for expedited 
reporting purposes) and the SAE is not listed in the current Investigator Brochure (ie, an 
unexpected event).  In this case, Acerta Pharma Drug Safety/Designee will forward a 
formal notification describing the suspected unexpected serious adverse reaction 
(SUSAR) to all investigators.  Each investigator must then notify his or her IRB/IEC of 
the SUSAR. 
Drug Safety Contact Information 
Fax: 
 (United States)  
 (for outside United States) 
Email: 
 
 
6.2.5 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the subject as stable,  
or the subject is lost to follow-up or withdraws consent. 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Acerta Pharma retains the right to terminate the study and remove all study materials 
from a study site at any time.  Specific circumstances that may precipitate such 
termination are: 
PPD
PPD
PPD


 
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• 
Unsatisfactory subject enrollment with regard to quality or quantity 
• 
Significant or numerous deviations from study protocol requirements, such as 
failures to perform required evaluations on subjects and maintain adequate study 
records 
• 
Inaccurate, incomplete and/or late data recording on a recurrent basis 
• 
The incidence and/or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment 
 
7.1 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the informed consent, Investigator Brochure, 
and any other relevant supporting information (eg, all advertising materials) to the 
appropriate IRB/IEC for review and approval before study initiation.  A signed protocol 
approval page; a letter confirming IRB/IEC approval of the protocol and informed 
consent; and a statement that the IRB/IEC is organized and operates according to Good 
Clinical Practice (GCP) guidelines and the applicable laws and regulations; must be 
forwarded to Acerta Pharma before screening subjects for the study.  Additionally, sites 
must forward a signed Form FDA 1572 (Statement of Investigator) to Acerta Pharma 
before screening subjects for study enrollment.  Amendments to the protocol must also 
be approved by the IRB/IEC and local regulatory agency, as appropriate, before the 
implementation of changes in this study. 
7.2 
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH 
INFORMATION AUTHORIZATION 
A copy of the IRB/IEC-approved informed consent must be forwarded to Acerta Pharma 
for regulatory purposes.  The investigator, or designee (designee must be listed on the 
Study Personnel Responsibility/Signature Log, see Section 7.11), must explain to each 
subject the purpose and nature of the study, the study procedures, the possible adverse 
effects, and all other elements of consent as defined in § 21 Code of Federal 
Regulations (CFR) Part 50, and other applicable national and local regulations governing 
informed consent form.  Each subject must provide a signed and dated informed consent 
before enrollment into this study.  If allowed by the protocol, a legal representative may 
sign the informed consent form for a subject incapable of giving consent.  Signed 
consent forms must remain in each subject’s study file and be available for verification 
by study monitors at any time. 


 
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In accordance to individual local and national patient privacy regulations, the investigator 
or designee must explain to each subject that for the evaluation of study results, the 
subject’s protected health information obtained during the study may be shared with 
Acerta Pharma and its designees, regulatory agencies, and IRBs/IECs.  As the study 
sponsor, Acerta Pharma will not use the subject’s protected health information or 
disclose it to a third party without applicable subject authorization.  It is the investigator’s 
or designee’s responsibility to obtain written permission to use protected health 
information from each subject, or if appropriate, the subject’s legal guardian.  If a subject 
or subject’s legal guardian withdraws permission to use protected health information, it is 
the investigator’s responsibility to obtain the withdrawal request in writing from the 
subject or subject’s legal guardian and to ensure that no further data will be collected 
from the subject.  Any data collected on the subject before withdrawal will be used in the 
analysis of study results. 
7.3 
SUBJECT SCREENING LOG 
The investigator must keep a record that lists all subjects considered for enrollment 
(including those who did not undergo screening) in the study.  For those subjects 
subsequently excluded from enrollment, record the reason(s) for exclusion. 
7.4 
CASE REPORT FORMS 
Authorized study site personnel (see Section 7.11) will complete eCRFs designed for 
this study according to the completion guidelines that will be provided within the clinical 
database.  The investigator will ensure that the eCRFs are accurate, complete, legible, 
and completed promptly.  Refer to Section 7.7 for record retention requirements.  
7.5 
STUDY MONITORING REQUIREMENTS 
Representatives of Acerta Pharma or its designee will monitor this study until 
completion.  The purpose of monitoring is to ensure compliance with the protocol and 
the quality and integrity of the data.  This study is also subject to reviews or audits. 
Every effort will be made to maintain the anonymity and confidentiality of all subjects 
during this clinical study.  However, because of the experimental nature of this 
treatment, the investigator agrees to allow the IRB/IEC, representatives of Acerta 
Pharma, its designated agents, and authorized employees of the appropriate regulatory 
agencies to inspect the facilities used in this study and, for purposes of verification, allow 
direct access to the hospital or clinic records of all subjects enrolled into this study.  This 


 
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includes providing by fax, email, or regular mail de-identified copies of radiology, 
pathology, and/or laboratory results when requested by the sponsor.  A statement to this 
effect will be included in the informed consent and permission form authorizing the use 
of protected health information. 
7.6 
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY 
Study drug must be kept in a locked limited access cabinet or space.  The study drug 
must not be used outside the context of the protocol. 
Study drug accountability records must be maintained and readily available for 
inspection by representatives of Acerta Pharma and are open to inspections by 
regulatory authorities at any time.  
All study supplies and associated documentation will be regularly reviewed and verified 
by the monitor. 
7.7 
RECORD RETENTION 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Mandatory documentation includes copies of study 
protocols and amendments, each Form FDA 1572, IRB/IEC approval letters, signed 
ICFs, drug accountability records, SAE information transmitted to Acerta Pharma, 
subject files (source documentation) that substantiate entries in eCRFs, all relevant 
correspondence and other documents pertaining to the conduct of the study. 
An investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified.  The investigator must notify Acerta Pharma and obtain 
written approval from Acerta Pharma before destroying any clinical study records at any 
time.  Acerta Pharma will inform the investigator of the date that study records may be 
destroyed or returned to Acerta Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express 
written approval of, any change in the maintenance of the foregoing documents if the 
investigator wishes to move study records to another location or assign responsibility for 
record retention to another party.  If the investigator cannot guarantee the archiving 
requirements set forth herein at his or her study site for all such documents, special 


 
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arrangements must be made between the investigator and Acerta Pharma to store such 
documents in sealed containers away from the study site so that they can be returned 
sealed to the investigator for audit purposes. 
7.8 
PROTOCOL AMENDMENTS 
Acerta Pharma will initiate any change to the protocol in a protocol amendment 
document.  The amendment will be submitted to the IRB/IEC together with, if applicable, 
a revised model ICF.  If the change in any way increases the risk to the subject or 
changes the scope of the study, then written documentation of IRB/IEC approval must 
be received by Acerta Pharma before the amendment may take effect.  Additionally 
under this circumstance, information on the increased risk and/or change in scope must 
be provided to subjects already actively participating in the study, and they must read, 
understand, and sign any revised ICF confirming willingness to remain in the trial. 
7.9 
PUBLICATION OF STUDY RESULTS 
Authorship, in general, will follow the recommendations of the International Committee of 
Medical Journal Editors (2015). 
7.10 
CLINICAL TRIAL INSURANCE 
Clinical trial insurance has been undertaken according to the laws of the countries where 
the study will be conducted.  An insurance certificate will be made available to the 
participating sites at the time of study initiation. 
7.11 
GENERAL INVESTIGATOR RESPONSIBILITIES 
The principal investigator must ensure that: 
1. He or she will personally conduct or supervise the study. 
2. His or her staff and all persons who assist in the conduct of the study clearly 
understand their responsibilities and have their names included in the Study 
Personnel Responsibility/Signature Log. 
3. The study is conducted according to the protocol and all applicable regulations. 
4. The protection of each subject’s rights and welfare is maintained. 
5. Signed and dated informed consent and, when applicable, permission to use 
protected health information are obtained from each subject before conducting 
nonstandard of care study procedures.  If a subject or subject’s legal guardian 
withdraws permission to use protected health information, the investigator will 
obtain a written request from the subject or subject’s legal guardian and will 
ensure that no further data be collected from the subject. 


 
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6. The consent process is conducted in compliance with all applicable regulations 
and privacy acts. 
7. The IRB/IEC complies with applicable regulations and conducts initial and 
ongoing reviews and approvals of the study. 
8. Any amendment to the protocol is submitted promptly to the IRB/IEC. 
9. Any significant protocol deviations are reported to Acerta Pharma and the 
IRB/IEC according to the guidelines at each study site. 
10. eCRF pages are completed promptly. 
11. All IND Safety Reports/SUSAR Reports are submitted promptly to the IRB/IEC. 
12. All SAEs are reported to Acerta Pharma Drug Safety/Designee within 24 hours of 
knowledge via the clinical database and to the IRB/IEC per their requirements. 


 
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8.0 
REFERENCES 
Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al.  Bruton tyrosine 
kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with 
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Ayers EC, Mato AR.  Richter’s transformation in the era of kinase inhibitor therapy: a 
review.  Clin Lymphoma Myeloma Leuk 2017;17:1-6. 
Bakan I, Laplante M.  Connecting mTORC1 signaling to SREBP-1 activation.  Curr Opin 
Lipidol 2012;23:226-34. 
Baselga J, Campone M, Piccart M, Burris HA, Hope S, Rugo HS.  Everolimus in 
postmenopausal hormone-receptor–positive advanced breast cancer. NEJM 
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pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor 
AZD2014.  Clin Cancer Res 2015;21:3412-9. 
Betz C, Hall MN.  Where is mTOR and what is it doing there?  J Cell Biol 2013;203:563-
74. 
Blum KA.  B-cell receptor pathway modulators in NHL.  Hematology Am Soc Hematol 
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Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, et al.  Acalabrutinib 
(ACP-196) in relapsed chronic lymphocytic leukemia.  NEJM 2016;374:323-32. 
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Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al.  
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Chiarini F, Evangelisti C, McCubrey JA, Martelli AM.  Current treatment strategies for 
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Coiffier B, Altman A, Pui CH, Younes A, Cairo MS.  Guidelines for the management of 
pediatric and adult tumor lysis syndrome: an evidence-based review.  JCO 
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Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al.  
Outcomes in refractory diffuse large B-cell lymphoma: results from the international 
SCHOLAR-1 study.  Blood 2017;130:1800-08. 
De Jésus Ngoma P, Kabama B, Dhalqvist G, Sempoux C, Lanthier N, Shindano T, et al.  
Occult HBV reactivation induced by ibrutinib treatment: a case report. Acta Gastroenterol 
Belg 2015;78:424-6. 
Extermann M, Overcash J, Lyman GH, Parr J, Balducci L. Comorbidity and functional 
status are independent in older cancer subjects. J Clin Oncol 1998;16:1582-87. 
Ezell SA, Mayo M, Bihani T, Tepsuporn S, Wang S, Passino M, et al. Synergistic 
induction of apoptosis by combination of BTK and dual mTORC1/2 inhibitors in diffuse 
large B cell lymphoma. Oncotarget 2014;5:4990-5001. 
Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as 
anticancer agents.  Nat Rev Cancer 2006;5:671-88. 
Food and Drug Administration. Guidance for industry and investigators: Safety reporting 
requirements for INDs and BA/BE studies (December 2012). Available at: 
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Services, Food and Drug Administration; 2012 [cited 2015 June 24]. Available from: 
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nces/UCM227351.pdf 
Guichard SM, Curwen J, Bihani T, D’Cruz CM, Yates JWT, Grondine M, et al. AZD2014, 
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administered using intermittent or continuous schedules. Mol Cancer Thera 
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Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al.  
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from the International Workshop on Chronic Lymphocytic Leukemia updating the 
National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446-56. 
Hillmen P, Schuh A, Eyre TA, Pagel JM, Brown JE, Ghia P, et al.  Acalabrutinib 
monotherapy in patients with Richter transformation from the Phase 1/2 ACE-CL-001 
clinical study.  ASH Annual Meeting 2016 Abstract #60. 
Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al.  The Bruton 
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of autoimmune disease and B-cell malignancy. PNAS 2010;107:13075-80. 
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome. NEJM 2011;364:1844-54. 


 
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of the oncogenic mTOR pathway reveals druggable addiction to translational control via 
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Br J Clin Pharmacol 2016;82:1213-28. 
Magnuson B, Ekim B, Fingar DC.  Regulation and function of ribosomal protein S6 
kinase (S6K) within mTOR signalling networks.  Biochem J 2012;441:1-21. 
Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E.  PI3K/AKT signaling pathway 
and cancer: an updated review. Ann Med 2014;46:372-83. 
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2.2016.   
Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. 
Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: 
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patients with breast cancer. Breast Care. 2014;9:232–7. 
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al.  
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Stern A, Green H, Paul M, et al. Prophylaxis for Pneumocystis pneumonia (PCP) in non-
HIV immunocompromised patients. Cochrane Database Syst Rev. 2014 Oct 
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Su B, Jacinto E.  Mammalian TOR signaling to the AGC kinases.  Crit Rev Biochem Mol 
Biol 2011;46:527-47. 
Thorpe LM, Yuzugullu H, Zhao JJ.  PI3K in cancer: divergent roles of isoforms, modes of 
activation and therapeutic targeting.  Nat Rev Cancer 2015;15:7-24. 
UK CLL Forum.  Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and 
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Wang M, Rule S, Zinzani PL, Goy A, Casanovas O, Smith SD, et al.  Acalabrutinib in 
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phase 2 trial.  Lancet 2017 Dec 11. pii: S0140-6736(17)33108-2. doi: 10.1016/S0140-
6736(17)33108-2. [Epub ahead of print]. 
Willemsen AE, Grutters JC, Gerritsen WR, van Erp NP, van Herpen CM, Tol J. mTOR 
inhibitor-induced interstitial lung disease in cancer patients: Comprehensive review and 
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2014;39(6):268-276. 
 


 
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9.0 
APPENDICES 
 
 


 
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Appendix 1.  Schedule of Assessments (Acalabrutinib + Vistusertib) 
Assessment 
Screena 
 
Cycle 1 
(28 Days) 
Cycles 
2-6 
(28 Days) 
Cycles 7–
12 cc 
(28 Days) 
Extended 
Study 
Treatment cc, 
>12 cycles 
(every 12 
weeks) 
Assess 
Disease 
Every 
12 weeks 
(~3 
Cycles) 
30-Day 
SFUdd 
Days 
Days 
Day 
Day 
1 
8 
15 
22 
1 
15 
1 
1 
 
(±2 Day) 
(±2 Days) 
(±7 Days) 
(±7 Days) 
(±7 Days) 
(+7 days) 
Informed consentb 
X 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
Physical examinationc 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
ECOG performance status 
X 
X 
 
X 
 
X 
 
 
X 
Vital signsd and weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Cumulative Illness Rating 
Scale (Geriatric) 
X 
 
 
 
 
 
 
12-lead ECGe 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Cardiac troponin 
X 
X 
 
X 
 
X 
 
 
 
 
X 
ECHO/MUGAf 
X 
 
 
 
 
 
X 
Hematologyg 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Serum chemistryh 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Pregnancy test (women of 
childbearing potential) 
X 
X 
 
X 
 
X 
 
 
X 
Urinalysisi 
X 
X 
 
X 
 
X 
 
 
X 
Coagulation (PT/INR/PTT) 
X 
 
 
 
 
 
 


 
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Assessment 
Screena 
 
Cycle 1 
(28 Days) 
Cycles 
2-6 
(28 Days) 
Cycles 7–
12 cc 
(28 Days) 
Extended 
Study 
Treatment cc, 
>12 cycles 
(every 12 
weeks) 
Assess 
Disease 
Every 
12 weeks 
(~3 
Cycles) 
30-Day 
SFUdd 
Days 
Days 
Day 
Day 
1 
8 
15 
22 
1 
15 
1 
1 
 
(±2 Day) 
(±2 Days) 
(±7 Days) 
(±7 Days) 
(±7 Days) 
(+7 days) 
Hepatitis serology j 
X 
 
 
 
 
 
 
HBV PCR k 
X 
 
X 
 
QM 
 
 
X 
HCV PCR l 
X 
 
C6 
 
 
 
 
 
CMV testing m 
X 
 
C6 
 
C12 
 
 
 
T/B/NK cell count 
 
X 
 
C2; 
C3; 
C6 
 
 
C9; 
C12 
 
 
X 
Serum Ig 
 
X 
 
C2; 
C3; 
C6  
 
C9,C12 
 
 
X 
Archival tumor sample n 
X 
 
 
 
 
 
 
Concomitant 
medication/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse event evaluation o 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vistusertib PK p 
 
X 
 
X 
 
 
 
 
 
 
Acalabrutinib PK Part 1q 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Assessment 
Screena 
 
Cycle 1 
(28 Days) 
Cycles 
2-6 
(28 Days) 
Cycles 7–
12 cc 
(28 Days) 
Extended 
Study 
Treatment cc, 
>12 cycles 
(every 12 
weeks) 
Assess 
Disease 
Every 
12 weeks 
(~3 
Cycles) 
30-Day 
SFUdd 
Days 
Days 
Day 
Day 
1 
8 
15 
22 
1 
15 
1 
1 
 
(±2 Day) 
(±2 Days) 
(±7 Days) 
(±7 Days) 
(±7 Days) 
(+7 days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scan of thorax x 
X 
 
 
 
 
 
 
Tumor assessments 
CT/MRI/PET scans y 
X 
 
 
 
 
X 
Xdd 
Bone marrow biopsy & 
aspirate z 
X 
 
 
 
 
To 
confirm 
CR 
 
Vistusertib (oral) aa 
 
twice daily continuous 
or 2 days on/5 days 
off 
 
 
 
 
 
Acalabrutinib (oral) bb 
 
twice daily continuous 
 
 
 
 
 
Study drug compliance 
 
X 
X 
X 
X 
 
 
Abbreviations:  C = cycle; CMV = cytomegalovirus; CR = complete remission; CT = computed tomography; ctDNA = circulating tumor DNA; D = day; ECG = 
electrocardiogram, ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; HBV = hepatitis B virus; HCV = hepatitis C virus; Ig = immunoglobulin; 
INR = international normalization ratio; LTF = long-term follow-up; MCL = mantle cell lymphoma; magnetic resonance imaging; MUGA = multigated acquisition; NK = 
natural killer; PCR = polymerase chain reaction; PET = positron-emission tomography; PK = pharmacokinetics; PT = prothrombin time; PTT = partial thromboplastin 
time; Q3M = every 3 months; QM = every month; SFU = safety follow-up; SOC = standard of care. 
 
a. 
Screening tests should be performed within 30 days before the first administration of study drug, unless otherwise indicated. 
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b. 
Informed consent muVWEHREWDLQHG days before any protocol-defined screening procedures and before the first dose of study drug(s). 
c. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only), and examination of the skin, eyes, 
ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed physical exams are 
done thereafter.   
d. 
Vital signs (blood pressure, oxygen saturation, pulse, and temperature) will be assessed after the subject has rested in the sitting position for at least 5 minutes. 
e. 
Subjects should be in suSLQHSRVLWLRQDQGUHVWLQJIRU10 minutes before the ECGs.  Triplicate ECGs are required at screening and Cycle 6 only, or if clinically 
indicated, at all other visits, single ECGs are required.  If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, and 
potassium) must be done to coincide with the ECG testing. 
f. 
In addition to screening, an ECHO should be done 14 days after an abnormal ECG finding (T wave inversion/flattening), or when clinically indicated.  If an ECHO 
cannot be taken, a multigated acquisition (MUGA) scan to assess left ventricular ejection fraction (LVEF) will be done.  In case of any T wave abnormality, the 
ECHO (or MUGA) should be repeated at the 30-day follow up visit to address the question of recovery, during the off-treatment period. 
g. 
Hematology includes complete blood count (CBC) with differential including, but not limited to white blood cell count, hemoglobin, hematocrit, platelet count, 
absolute neutrophil count (ANC), and absolute lymphocyte count (ALC). 
h. 
Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), 
calcium, chloride, cholesterol, C-peptide, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, potassium, sodium, triglycerides, 
total bilirubin, total protein, and uric acid.  If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, and potassium) must be 
done to coincide with the ECG testing. 
i. 
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. 
j. 
Hepatitis serology must include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and hepatitis C 
(HCV) antibody.  In addition, any subjects testing positive for any hepatitis serology, must have polymerase chain reaction (PCR) testing. 
k. 
Subjects who are anti-HBc positive (or have a known history of HBV infection) should have a quantitative PCR test for HBV DNA performed during screening and 
monthly thereafter.  Monthly monitoring should continue until 12 months after last dose of study drug(s).  Any subject with a rising viral load (above lower limit of 
detection) should discontinue study drug and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B.  As 
intravenous immunoglobulins (IVIG) may cause false positive hepatitis serology, monthly PCR testing is not required in subjects who are currently receiving or 
received prophylactic IVIG within 3 months before study enrollment and have a documented negative anti-HBc test before the initiation of IVIG therapy.  PCR 
testing should be performed when clinically indicated (eg, in the setting of rising transaminase levels). 
l. 
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should have quantitative PCR testing for HCV RNA performed during 
screening and Cycle 6.  No further testing beyond Cycle 6 is necessary if PCR results are negative. 
m. CMV testing at screening must include serology testing for CMV immunoglobulin G (IgG), CMV IgM, and CMV PCR testing.   
n. 
Formalin-fixed tumor tissue embedded in paraffin blocks are to be retrieved for all subjects (see Section 4.1.23).   
o. 
A formal assessment of adverse events (AEs) will occur at the visits marked in this table, but AEs reported at any time other time will also be recorded in the 
electronic case report form (eCRF).   
p. 
Vistusertib pharmacokinetic (PK) blood sampling (2 mL per sample) will be collected at predose and at approximately 1, 2, 4 and 6 hours postdose on Cycle 1 
Day 1 and Cycle 1 Day 22 for all subjects in Part 1. 
q. 
Acalabrutinib PK blood sampling (2 mL per sample) will be collected.  For Part 1, samples will be collected from all subjects on Cycle 1 Day 1 and Cycle 1 Day 22 
predose and at approximately 1, 2, 4 and 6 hours postdose.   
r. 
Acalabrutinib PK blood sampling (2 mL per sample) will be collected. 
s. 
 
t. 
Fresh tumor biopsies will be collected from subjects who opt in and have accessible tumors.  Biopsies will be collected between screening and at least 3 days 
before the first dose of study drug (ie, predose sample), 1 hour after dosing on Cycle 1 Day 1, any time on Cycle 1 Day 8 (preferred timepoint) or Cycle 1 Day 22 (if 
tumor still accessible) and, when possible, at disease progression (which may be at the 30-day SFU visit). 
u. 
 
 
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v. 
 
 
 
x. 
A baseline thorax CT scan must be available for all subjects treated with vistusertib, for retrospective analysis and comparison with a high-resolution CT scan, 
should it be required, if symptoms of interstitial lung disease occur during study conduct.  A separate thorax CT scan is not required if a CT scan is done for 
baseline tumor assessment as described in footnote y. 
y. 
Baseline tumor assessments will be performed using radiologic imaging by CT with contrast and PET-CT covering neck, chest, abdomen, and pelvis at a 
minimum within 28 days before the first dose of study drug.  Radiologic scans (ie, contrast CT) will be repeated every 3 cycles (ie, approximately every 
12 weeks ± 7 days).  PET-CT also will be repeated on the same schedule, when required, per Section 4.3 of the protocol.  For subjects with baseline 
hepatosplenomegaly, the cranial-caudal measurement of the spleen and longest diameter of the liver will be assessed at screening and all subsequent response 
evaluations. 
z. 
Bone marrow biopsy and aspirate with flow cytometry analysis at baseline will be performed locally to show any bone marrow involvement.  A further bone marrow 
biopsy and aspirate is required to confirm a complete response (CR), if the baseline sample is positive.   
aa. Refer to the protocol for the dose/schedules of vistusertib evaluated in this protocol. 
bb. Acalabrutinib will be taken twice daily beginning with Cycle 1 Day 1.  On days of vistusertib dosing, both drugs will be taken simultaneously. 
cc. Subjects showing clinical benefit and who are tolerating study treatment may remain on study for up to a total of 12 cycles of treatment.  Subjects who have 
received 12 cycles of treatment (ie, been on study for approximately 12 months) and are deriving clinical benefit from acalabrutinib monotherapy or the 
combination of acalabrutinib and vistusertib may remain on study treatment beyond the first 12 months until disease progression occurs or be eligible to enroll in 
either a rollover study of acalabrutinib monotherapy or a rollover study of the combination of acalabrutinib and vistusertib, respectively. 
dd. The SFU visit will be performed 30 days (+7 days) after the last dose of all study drug(s).  Tumor assessments will be repeated at this visit, if they have not been 
performed within the past 12 weeks. 
 
 
 
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Appendix 2.  Schedule of Assessments (Acalabrutinib Monotherapy) 
 
Treatment Phase j 
Extended Study 
Treatment >12 cycles j 
Safety Follow- up 
Visitk 
 
Every 3 months (±7 
days) 
Every 12 weeks 
30 days  
(+7 days) after last dose 
 
 
 
PEa/Vital signsb/Weight 
X 
 
X 
ECOG status 
X 
 
X 
Lab assessments: 
 
 
 
Hematologyc 
X 
 
X 
Serum chemistryd 
X 
 
X 
HBV PCRe 
QM 
 
 
T/B/NK cell count 
Every 6 mos 
 
 
Serum Ig 
Every 6 mos 
 
X 
Pregnancy testing (women of childbearing 
potential) 
QM 
 
X 
Tumor samplef 
At disease progression 
 
 
 
 
 
 
Bone marrow (aspirate/biopsy)g  
Investigator discretion & 
to confirm CR 
 
 
Pharmacodynamics 
 
 
X 
Acalabrutinib dispensed 
X 
X 
 
Study drug compliance 
X 
X 
 
Tumor assessmenth 
X 
 
X 
Radiologic assessmenti 
X 
 
X 
Concomitant medications 
X 
X 
X 
Adverse events 
X 
X 
X 
Disease progression/new anticancer therapy 
follow-up 
 
 
 
Survival 
 
 
 
Abbreviations:  CR = complete remission; CT = computed tomography; DFU = discontinuation follow-up; ECOG = Eastern Cooperative Oncology Group; HBV = 
hepatitis B virus; Ig = immunoglobulin; LTF = long-term follow-up; mos = months; PE = physical exam; NK = natural killer; PCR = polymerase chain reaction; Q3M = 
every 3 months; QM = every month; SOC = standard of care 
 
a. 
Symptom-directed physical exams will be performed.  
b. 
Vital signs (blood pressure, pulse, and body temperature) will be assessed after the subject has rested in the sitting position.   
c. 
Hematology must include complete blood count (CBC) with differential, including, but not limited to white blood cell count, hemoglobin, hematocrit, platelet count, 
absolute neutrophil count (ANC), and absolute lymphocyte count (ALC).   
d. 
Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), 
calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total protein, and uric 
acid.   
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e. 
Subjects who are hepatitis B core antibody (anti-HBc) positive (or have a known history of HBV infection) should have a monthly quantitative polymerase chain 
reaction (PCR) test for HBV DNA.  Monthly monitoring should continue until 12 months after last dose of study drug(s).  Any subject with a rising viral load (above 
lower limit of detection) should discontinue study drug(s) and have antiviral therapy instituted and a consultation with a physician with expertise in managing 
hepatitis B.  As intravenous immunoglobulins (IVIG) may cause false positive serology, monthly PCR testing is not required in subjects who are currently receiving 
or received prophylactic IVIG within 3 months before study enrollment and have a documented negative anti-HBc before the initiation of IVIG therapy, unless 
clinically indicated (eg, in the setting of rising transaminase levels). 
f. 
Provide tissue slides from a newly obtained tumor sample at the time of disease progression for exploratory correlative studies.  
g. 
Bone marrow aspirate and biopsy to be done at investigator discretion, per standard of care.  Bone marrow and positron-emission tomography/computed 
tomography (PET/CT) are only required for confirmation of complete remission (CR) per clinical guidelines (see Section 4.3). When possible extra bone marrow 
tissue may be used for pharmacodynamic evaluation.   
h. 
On-treatment computed tomography (CT) scans will be done every 12 weeks (~3 cycles) or more frequently at the investigator’s discretion.   
i. 
PET/CT is only required for confirmation of CR per clinical guidelines (see Section 4.3).   
j. 
Subjects showing clinical benefit and who are tolerating study treatment may remain on study for up to a total of 12 cycles of treatment.  Subjects who have 
received 12 cycles of treatment (ie, been on study for approximately 12 months since first dose of study drug) and are deriving clinical benefit from acalabrutinib 
monotherapy may remain on study treatment beyond the first 12 months until disease progression occurs or be eligible to enroll in a rollover study of acalabrutinib 
monotherapy. 
k. 
The safety follow-up visit will be performed 30 days (+7 days) after the last dose of all study drug(s).  Tumor assessments will be repeated at this visit, if they have 
not been performed within the past 12 weeks. 
 
 


 
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Appendix 3.  Performance Status Scores  
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, eg, light house 
work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care. Totally 
confined to bed or chair 
5 
Dead 
As published in Am J Clin Oncol: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982. 
Credit: Eastern Cooperative Oncology Group Chair: Robert Comis, MD 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed 23 August 2013. 
 
 
 
 


 
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Appendix 4.  Restricted CYP and Transporter-Related Comedications 
Before study start, use of potent or moderate inhibitors or inducers of CYP3A4/5, P-gp 
and BCRP or substrates of the drug transporters P-gp and BCRP is not permitted within 
the appropriate washout periods for each drug before the first dose of study treatment 
until at least after Cycle 1. 
Examples of such substances and the corresponding minimum washout periods are 
presented in Table 13. 
Short term administration of such substances during a study may be permitted after the 
end of Cycle 1 under the following circumstances: 
• 
If a subject requires short-term administration of a restricted CYP3A4/5, P-gp or 
BCRP inhibitor (see Table 13), vistusertib must be withheld for 3 days before the 
first dose and not restarted until at least the concomitant therapy has been 
discontinued for the appropriate washout period. 
• 
If a subject requires short-term administration of a restricted CYP3A4/5, P-gp or 
BCRP inducer (see Table 13) this should be clearly documented in the eCRF 
and may be permitted, but this could lead to lower levels of vistusertib and a 
potential reduction in clinical efficacy. 
• 
If a subject requires short-term administration of restricted substrates of 
OATP1B1, OATP1B3, MATE1 and MATE2K transporters (see Table 14), 
vistusertib treatment must be withheld for 3 days prior to the first dose and not 
restarted until the concomitant therapy has been discontinued for the appropriate 
washout period (at least 5 times the elimination half-life). 
The lists of CYP and transporter inhibitors/inducers and transporter substrates in 
Table 13 and Table 14 are not exhaustive and the absence of a drug from these lists 
does not imply that its combination with the study drug(s) is safe. 


 
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Table 13.  Cytochrome P450 enzyme inhibitors/inducers and transporters 
restrictions 
Category 
Examples of drugs 
Minimum drug washout 
period 
CYP3A4/5 
Potent competitive 
inhibitors 
 
grapefruit juice, indinavir, 
itraconazole, ketoconazole, 
nefazodone, nelfinavir, saquinovir, 
telithromycin and troleandomycin 
and voriconazole 
 
1 week 
 
 
 
idelalisib 
2 weeks 
CYP3A4/5 
Potent 
Time dependent inhibitors 
 
bocepravir, clarithromycin, 
cobicistat, danoprevir, elvitegravir, 
LCL161, lopinavir, mibefradil*, 
posaconazole, ritonavir, telaprevir 
and tipranivir 
 
2 weeks 
 
 
CYP3A4/5 
Potent inhibitors 
(classification unknown) 
 
conivaptan 
 
1 week 
CYP3A4/5 
Moderate 
competitive inhibitors 
 
amprenavir, aprepitant, 
atazanavir, cimetidine, 
cyclosporine, fluconazole, imatinib 
and netupitant 
 
1 week 
CYP3A4/5 
Moderate 
Time dependent inhibitors 
ACT-178882, casopitant, 
crizotinib, darunavir, diltiazem 
erythromycin, ledipasvir, 
lomitapide, tofisopam and 
verapamil 
 
2 weeks 
FK1706 
half-life not found 
CYP3A4/5 
Moderate inhibitors 
(classification 
not known) 
 
ciprofloxacin and dronedarone 
1 week 
schisandra sphenanthera 
half-life not found 
CYP3A4/5 
Potent inducers 
carbamazepine, phenytoin, 
rifabutin, rifampicin and St John 
Wort 
 
3 weeks 
enzalutamide and phenobarbital 
 
5 weeks 
mitotane 
114 weeks 
avasimibe 
half-life not found 
CYP3A4/5 
Moderate inducers 
bosentan, genistein, lersivirine, 
lopinavir, modafinil, nafcillin, 
ritonavir, semagacestat,  
thioridazine and tipranavir 
1 week 


 
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Table 13.  Cytochrome P450 enzyme inhibitors/inducers and transporters 
restrictions 
Category 
Examples of drugs 
Minimum drug washout 
period 
etravirine 
 
2 weeks 
efavirenz 
 
3 weeks 
talviraline 
half-life not found 
P-gp inhibitors 
dronedarone, erythromycin, 
indinavir, itraconazole, 
ketoconazole, lapatinib, lopinavir, 
ritonavir, quinidine and verapamil 
 
1 week 
 
 
vorapaxer 
10 weeks 
valspodar (PSC 833) 
half-life not found 
P-gp  
inducers 
 
carbamazepine and rifampin 
 
3 weeks 
 
BCRP inhibitors 
 
atazanavir, cyclosporine, 
lopinavir, ritonavir and tipranavir 
 
1 week 
 
Reference:  University of Washington database 
* discontinued 
Strong inhibitor (yielding area under the curve [AUC] ratio ≥5) 
Moderate inhibitor (yielding AUC ratio ≥2 and <5) 
Strong inducer (AUC decreased by ≥80% or CL increased by more than 5-fold [400%]) 
Moderate inducer (AUC decreased by 50% to 80% or CL increased by more than 2- to 5-fold 
[100% to 400%]) 
 
Table 14.  Transporter substrate restrictions 
Transporters 
Examples of substrates 
OATP1 (B1 or B3) 
bosentan, fexofenadine, glyburide, pitavastatin, pravastatin, 
repaglinide, rosuvastatin 
MATE (1 or 2K) 
cisplatin 
Substrates in bold type have a narrow therapeutic index. 
Reference:  Expert Opin.  Drug Metab.  Toxicol.  (2013) 9(6):737-751.  Washout period should be 
5 times reported terminal half-life. 
 
 


 
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Appendix 5.  Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law 
INTRODUCTION 
This Appendix describes the process to be followed to identify and appropriately report 
potential Hy’s law (PHL) cases and Hy’s law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.  
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a subject meets 
PHL criteria at any point during the study.  All sources of laboratory data are appropriate 
for the determination of PHL and HL events; this includes samples taken at scheduled 
study visits and other visits, including central and all local laboratory evaluations, even if 
collected outside of the study visits (eg, PHL criteria could be met by an elevated ALT 
from a central laboratory and/or elevated total bilirubin from a local laboratory).  The 
investigator will also review adverse event (AE) data (eg, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events. 
The investigator participates with the sponsor in the review and assessment of cases 
meeting PHL criteria to agree whether HL criteria are met.  HL criteria are met if there is 
no alternative explanation for the elevations in liver biochemistry other than drug-induced 
liver injury (DILI) caused by the investigational medicinal product (IMP).  The investigator 
is responsible for recording data pertaining to PHL/HL cases and for reporting AEs and 
serious adverse events (SAEs) according to the outcome of the review and assessment 
in line with standard safety-reporting processes. 
DEFINITIONS 
Potential Hy’s Law  
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN at any point during the study 
after the start of study drug, irrespective of an increase in alkaline phosphatase.  
Hy’s Law 
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN, where no reason other than 
the IMP can be found to explain the combination of increases (eg, elevated alkaline 
phosphatase indicating cholestasis, viral hepatitis, or another drug).   
For PHL and HL, the elevation in transaminases must precede or be coincident with (i.e., 
on the same day) the elevation in total bilirubin, but there is no specified timeframe 
within which the elevations in transaminases and total bilirubin must occur. 


 
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IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
Laboratory data must be comprehensively reviewed by the investigator for each subject 
to identify laboratory values meeting the following criteria: 
• 
ALT ≥3 x ULN 
• 
AST ≥3 x ULN 
• 
Total bilirubin ≥2 x ULN 
When the identification criteria are met from central or local laboratory results, the 
investigator will perform the following: 
• 
Notify the sponsor representative/Medical Monitor by telephone and report the case 
as an SAE of Potential Hy’s law; seriousness criteria “Important medical event” and 
causality assessment “yes/related” or in accordance with the clinical study protocol 
as appropriate. 
• 
Request a repeat of the test (new blood draw) without delay 
• 
Complete the appropriate unscheduled laboratory electronic Case Report Form 
(eCRF) module(s)  
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the clinical study protocol, as applicable 
 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed by the investigator for all cases where 
PHL criteria are met. 
As soon as possible after the biochemistry abnormality is initially detected, the study 
Medical Monitor and the Investigator will review available data, to agree whether there is 
an alternative explanation for meeting PHL criteria other than DILI caused by the IMP 
and to ensure that timely analysis and reporting to health authorities within 15 calendar 
days from the date PHL criteria were met.    
Where there is an agreed alternative explanation for the ALT or AST and total bilirubin 
elevations, a determination of whether the alternative explanation is an AE will be made 
and, subsequently, whether the AE meets the criteria for an SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 


 
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• 
If the alternative explanation is an AE/SAE, update the previously submitted PHL 
SAE accordingly with the new information (reassessing event term, causality, and 
seriousness criteria) following the sponsor’s standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and total 
bilirubin elevations other than the IMP, then: 
• 
Send updated SAE (report term “Hy’s law”) according to the sponsor’s standard 
processes:  
o The “Medically Important” serious criterion should be used if no other serious 
criteria apply. 
o Because there is no alternative explanation for the HL case, a causality 
assessment of “related” should be assigned. 
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until an informed decision can be made: 
• 
Provide any further update to the previously submitted SAE of PHL (report term now 
“Hy’s law case”), ensuring causality assessment is related to IMP and seriousness 
criteria are medically important, according to clinical study protocol process. 
• 
Continue follow-up and review according to the agreed plan.  After the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are still met.  Update the previously submitted PHL 
SAE report following the clinical study protocol process, according to the outcome of 
the review. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
This section is applicable when a subject meets PHL criteria while receiving study 
treatment and has already met PHL criteria at a previous on-study treatment visit.  The 
requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous 
occurrence.   


 
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The investigator should determine the cause for the previous occurrence of PHL and 
answer the following question: 
Was the alternative cause for the previous occurrence of PHL determined to be 
the disease under study (eg, chronic or progressing malignant disease, severe 
infection, or liver disease)? 
• 
If the answer is No: 
Follow the process described in “Potential Hy’s Law Criteria Met” in this 
Appendix for reporting PHL as an SAE. 
• 
If the answer is Yes:  
Determine whether there has been a significant change in the subject’s 
condition compared with the previous occurrence of PHL.  Note:  A 
“significant” change in the subject’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST, 
or total bilirubin) in isolation or in combination or a clinically relevant 
change in associated symptoms.  The determination of whether there has 
been a significant change will be at the discretion of the investigator; this 
may be in consultation with the study medical monitor if there is any 
uncertainty. 
o If there is no significant change, no action is required. 
o If there is a significant change, follow the process described in 
“Potential Hy’s Law Criteria Met” in this Appendix for reporting 
PHL as an SAE. 
 
LABORATORY TESTS 
The list below represents a comprehensive list of follow-up tests that may aid in 
assessing PHL/HL.   
Test results used to assess PHL/HL should be recorded on the appropriate eCRF. 
Additional standard chemistry and 
coagulation tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
IgM and IgG anti-HBc 
HBsAg 
HBV DNA 
IgM and IgG anti-HCV 
HCV RNA 
IgM anti-HEV 
HEV RNA 


 
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Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin 
(CD-transferrin) 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab 
(Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin 
Transferrin saturation 
 
Reference 
FDA Guidance for Industry (issued July 2009). Drug-induced liver injury: Premarketing 
clinical evaluation 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM174090.pdf 
 
 
 


 
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CCI


 
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CCI


 
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CCI


 
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Appendix 7.  Cumulative Illness Rating Scale-Geriatric (CIRS-G) Calculator 
Web-based CIRS-G calculator link:  
http://eforms.moffitt.org/cirsgScore.aspx 
 


 
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Appendix 8.  Adverse Event Assessment of Causality 
 
Is there a reasonable possibility that the event may have been caused by study drug?  
No___ Yes___ 
The descriptions provided below will help guide the principal investigator in making the 
decision to choose either “yes” or “no”: 
No = There is no reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
• 
may be judged to be due to extraneous causes such as disease or environment 
or toxic factors 
• 
may be judged to be due to the subject’s clinical state or other therapy being 
administered 
• 
is not biologically plausible 
• 
does not reappear or worsen when study drug is re-administered 
• 
does not follow a temporal sequence from administration of study drug 
Yes = There is a reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
• 
follows a temporal sequence from administration of study drug 
• 
is a known response to the study drug based on clinical or preclinical data 
• 
could not be explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapy administered to the subject 
• 
disappears or decreases upon cessation or reduction of dose of study drug 
• 
reappears or worsens when study drug is re-administered 
 
 


 
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Appendix 9.  Response Criteria for NHL 
 


Recommendations for Initial Evaluation, Staging, and
Response Assessment of Hodgkin and Non-Hodgkin
Lymphoma: The Lugano Classiﬁcation
Bruce D. Cheson, Richard I. Fisher, Sally F. Barrington, Franco Cavalli, Lawrence H. Schwartz,
Emanuele Zucca, and T. Andrew Lister
See accompanying article on page 3048
Bruce D. Cheson, Georgetown Univer-
sity Hospital, Lombardi Comprehensive
Cancer Center, Washington, DC; Rich-
ard I. Fisher, Fox Chase Cancer Center,
Philadelphia, PA; Sally F. Barrington, St
Thomas’ Hospital; T. Andrew Lister, St
Bartholomew’s Hospital, London,
United Kingdom; Franco Cavalli and
Emanuele Zucca, Oncology Institute of
Southern Switzerland, Bellinzona, Swit-
zerland; and Lawrence H. Schwartz,
Columbia University, New York, NY.
Published online ahead of print at
www.jco.org on August 11, 2014.
Processed as a Rapid Communication
manuscript.
Written on behalf of the following
groups: Alliance, Australasian Leukae-
mia and Lymphoma Group, Eastern
Cooperative Oncology Group, European
Mantle Cell Lymphoma Consortium,
Italian Lymphoma Foundation, Euro-
pean Organisation for Research and
Treatment of Cancer/Dutch Hemato-
Oncology Group, Grupo Espan˜ol de
Linfomas y Trasplantes de Me´dula
O´ sea, German High-Grade Lymphoma
Study Group, German Hodgkin’s Study
Group, Japanese Lymphoma Study
Group, Lymphoma Study Association,
NCIC Clinical Trials Group, Nordic
Lymphoma Study Group, Southwest
Oncology Group, and United Kingdom
National Cancer Research Institute.
Presented in part at the 12th Interna-
tional Conference on Malignant
Lymphoma, Lugano, Switzerland, June
19-22, 2013.
Authors’ disclosures of potential con-
ﬂicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Bruce D.
Cheson, MD, Georgetown University
Hospital, Lombardi Comprehensive
Cancer Center, 3800 Reservoir Rd, NW,
Washington, DC 20007; e-mail:
bdc4@georgetown.edu.
© 2014 by American Society of Clinical
Oncology
0732-183X/14/3227w-3059w/$20.00
DOI: 10.1200/JCO.2013.54.8800
A
B
S
T
R
A
C
T
Abstract
The purpose of this work was to modernize recommendations for evaluation, staging, and response
assessment of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). A workshop
was held at the 11th International Conference on Malignant Lymphoma in Lugano, Switzerland, in
June 2011, that included leading hematologists, oncologists, radiation oncologists, pathologists,
radiologists, and nuclear medicine physicians, representing major international lymphoma clinical trials
groups and cancer centers. Clinical and imaging subcommittees presented their conclusions at a
subsequent workshop at the 12th International Conference on Malignant Lymphoma, leading to
revised criteria for staging and of the International Working Group Guidelines of 2007 for response.
As a result, ﬂuorodeoxyglucose (FDG) positron emission tomography (PET)–computed tomogra-
phy (CT) was formally incorporated into standard staging for FDG-avid lymphomas. A modiﬁcation
of the Ann Arbor descriptive terminology will be used for anatomic distribution of disease extent,
but the sufﬁxes A or B for symptoms will only be included for HL. A bone marrow biopsy is no
longer indicated for the routine staging of HL and most diffuse large B-cell lymphomas. However,
regardless of stage, general practice is to treat patients based on limited (stages I and II, nonbulky)
or advanced (stage III or IV) disease, with stage II bulky disease considered as limited or advanced
disease based on histology and a number of prognostic factors. PET-CT will be used to assess
response in FDG-avid histologies using the 5-point scale. The product of the perpendicular
diameters of a single node can be used to identify progressive disease. Routine surveillance scans
are discouraged. These recommendations should improve evaluation of patients with lymphoma
and enhance the ability to compare outcomes of clinical trials.
J Clin Oncol 32:3059-3067. © 2014 by American Society of Clinical Oncology
INTRODUCTION
The availability of more effective therapies for
lymphoma and the increasingly sensitive and spe-
ciﬁc technologies for disease assessment provide
rationale for updated patient evaluation, staging,
and response criteria. These should be unambig-
uous and universally applicable and facilitate the
comparison of patients and results among studies
and the evaluation of new therapies by regula-
tory agencies.
Staging deﬁnes disease location and extent,
suggests prognostic information, allows compari-
sons among studies, and provides a baseline against
which response or disease progression can be com-
pared. Initial staging criteria were designed primar-
ily for Hodgkin lymphoma (HL)1-3 and were
superseded by the Ann Arbor classiﬁcation,4 which
subdividedHLpatientsintofourstagesandsubclas-
siﬁcation A and B based on the presence of fevers to
greater than 101°F (38.3°C), weight loss, and night
sweats and which has been the most widely used
classiﬁcation since its introduction. The Cotswold
classiﬁcation5 ﬁrst formally incorporated computed
tomography (CT) scans and introduced “X” for
bulky disease and complete remission unconﬁrmed
(CRu) to describe patients with a residual mass after
treatment that was most likely ﬁbrous tissue.
The ﬁrst universally accepted response criteria
for non-Hodgkin lymphoma (NHL), used also for
HL, were published in 1999 by the National Cancer
InstituteWorkingGroup6andrevisedin2007bythe
International Working Group (IWG)7 to incorpo-
ratepositronemissiontomography(PET)andbone
marrow immunohistochemistry and ﬂow cytom-
etry in response assessment, eliminating CRu.
JOURNAL OF CLINICAL ONCOLOGY
S P E C I A L
A R T I C L E
VOLUME
32

NUMBER
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20
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Afterextensiveexperiencewiththesecriteria,andrecognizingthe
progress made after their publication, particularly in imaging tech-
niques, a workshop was held at the 11th International Conference
on Malignant Lymphoma in Lugano, Switzerland, in June 2011,
which was attended by leading hematologists, oncologists, radia-
tion oncologists, pathologists, radiologists, and nuclear medicine
physicians, representing major lymphoma clinical trials groups
and cancer centers in North America, Europe, Japan, and Austral-
asia. The aim was to develop improved staging and response
criteria for HL and NHL, relevant for community physicians,
investigator-led trials, cooperative groups, and registration trials.
Subcommittees focused on clinical and imaging issues, and a sub-
sequent workshop at the 12th International Conference on Malig-
nant Lymphoma in 2013 led to the following revisions.
INITIAL EVALUATION
Diagnosis
Lymphoma diagnosis depends on morphology, immunohisto-
chemistry,andﬂowcytometryreviewedbyanexperiencedlymphoma
pathologist and, where appropriate, molecular studies to accurately
categorize the lymphoma.8 A ﬁne-needle aspirate is inadequate for
initial diagnosis. An incisional or excisional biopsy is preferred to
provide adequate tissue for these examinations, but a core-needle
biopsy can be considered when excisional biopsy is not possible9,10
and to document relapse; however, a nondiagnostic sample must be
followed by an incisional or excisional biopsy. With consent, addi-
tional parafﬁn-embedded, fresh-frozen tissue, or cell suspensions
should be stored for future research.
Patient Evaluation
Clinical evaluation requires a comprehensive history including
age; sex; absence/presence of fevers to more than 101°F (38.3°C),
chills, drenching night sweats, or unexplained weight loss more than
10% of body mass over 6 months; and history of malignancy. Fatigue,
pruritus, and alcohol-induced pain in patients with HL should also be
noted. Whereas these factors rarely direct treatment, their recurrence
may herald disease relapse.
Physical examination includes measurement of accessible nodal
groups and the size of the spleen and liver in centimeters below their
respective costal margins in the midclavicular line. However, the sen-
sitivity of physical examination is variable among observers. There-
fore, organomegaly is formally deﬁned by CT imaging (Table 1).
Laboratory tests and other investigations necessary for the deter-
mination of the prognostic indices for the different lymphoma sub-
types and general patient management, including assessment of
comorbidities, must be recorded.
Anatomic Staging
Historical series and prospective clinical trials have used the
Ann Arbor staging system5 to select patients and report outcomes.
Now, stage is only one component of factors in prognostic indices
increasingly used for pretreatment risk stratiﬁcation and selection
of therapy.11-15
PET-CT scanning has become the standard for assessment of
response in most lymphomas.7 For HL and ﬂuorodeoxyglucose
(FDG) -avid NHL subtypes, PET and PET-CT improve the accuracy
of staging compared with CT scans for nodal and extranodal sites.16
PET-CTleadstochangeinstagein10%to30%ofpatients,moreoften
upstaging, although alteration in management occurs in fewer pa-
tients, with no demonstrated impact on overall outcome. However,
improving staging accuracy ensures that fewer patients are under-
treated or overtreated.16 PET-CT is particularly important for staging
before consideration of radiation therapy.17,18 Although most lym-
phomas are FDG avid, because of greater variability in FDG uptake,
metabolic imaging is less reliable in other lymphomas.19-24 Whereas
mantle-celllymphomaisroutinelyFDGavid,limiteddatasuggestthat
thesensitivityandspeciﬁcityofidentifyingbowelinvolvementarelow
and should not replace other investigative measures.25,26
RECOMMENDATION FOR REVISIONS TO STAGING CRITERIA
PET-CT is already widely used for pretreatment assessment, often
outside of clinical trials, to assign stage and has already been incorpo-
rated into response assessment.7 Although physical examination re-
mainsimportant,anddespiteconcernsthatmoresensitivestagingcan
Table 1. Criteria for Involvement of Site
Tissue Site
Clinical
FDG Avidity
Test
Positive Finding
Lymph nodes
Palpable
FDG-avid histologies
PET-CT
Increased FDG uptake
Nonavid disease
CT
Unexplained node enlargement
Spleen
Palpable
FDG-avid histologies
PET-CT
Diffuse uptake, solitary mass, miliary lesions, nodules
Nonavid disease
CT
 13 cm in vertical length, mass, nodules
Liver
Palpable
FDG-avid histologies
PET-CT
Diffuse uptake, mass
Nonavid disease
CT
Nodules
CNS
Signs, symptoms
CT
Mass lesion(s)
MRI
Leptomeningeal inﬁltration, mass lesions
CSF assessment
Cytology, ﬂow cytometry
Other (eg, skin, lung, GI tract,
bone, bone marrow)
Site dependent
PET-CT, biopsy
Lymphoma involvement
Abbreviations: CSF, cerebrospinal ﬂuid; CT, computed tomography; FDG, ﬂuorodeoxyglucose; MRI, magnetic resonance imaging; PET, positron emission tomography.
PET-CT is adequate for determination of bone marrow involvement and can be considered highly suggestive for involvement of other extralymphatic sites. Biopsy
conﬁrmation of those sites can be considered if necessary.
Cheson et al
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result in stage migration, impairing the use of historically controlled
data, PET-CT is critical as a baseline measurement before therapy to
increase the accuracy of subsequent response assessment27,28 (Table
1). Therefore, the consensus was that PET-CT should be recom-
mended for routine staging of FDG-avid, nodal lymphomas (essen-
tially all histologies except chronic lymphocytic leukemia/small
lymphocytic lymphoma, lymphoplasmacytic lymphoma/Walden-
stro¨m’s macroglobulinemia, mycosis fungoides, and marginal zone
NHLs, unless there is a suspicion of aggressive transformation) as the
gold standard.24
The following recommendations are intended for lymphomas
withprimarilynodalinvolvement,althoughtheyarealsoapplicableto
primaryextranodaldiffuselargeB-celllymphoma(DLBCL).Separate
criteria have been proposed for primary extranodal29,30 and cutane-
ous lymphomas.31
Imaging
PET-CT is preferred for staging of FDG-avid lymphomas, and
CT scan is preferred in the other lymphomas. A chest x-ray is no
longer required in lymphoma staging because it less accurate than
CT.32 Moreover, CT identiﬁes more hilar nodes and may better
discriminate between a single large nodal mass and an aggregate of
individual nodes. Bulk is a negative prognostic factor,11,13-15 but
there is little agreement on its deﬁnition, which is disease, stage,
and treatment speciﬁc.
These criteria strongly recommend PET-CT for staging of
routinely FDG-avid histologies, especially in clinical trials. A contrast-
enhanced CT scan should be included for a more accurate measure-
mentofnodalsizeifrequiredfortrials;ifnecessary,tomoreaccurately
distinguish bowel from lymphadenopathy; and in the setting of com-
pression/thrombosis
of
central/mediastinal
vessels.
Contrast-
enhanced CT is also preferred for radiation planning. Variably FDG-
avid histologies should be staged with a CT scan.
For patients staged with PET-CT, focal uptake in nodal and
extranodal sites that is in keeping with lymphoma, according to the
distributionand/orCTcharacteristics,isconsideredinvolvementwith
lymphoma, including spleen, liver, bone, thyroid, and so on. For
patients staged with CT, up to six of the largest target nodes, nodal
masses, or other lymphomatous lesions that are measurable in two
diameters (longest diameter [LDi] and shortest diameter) should
be identiﬁed from different body regions representative of the
patient’s overall disease burden and include mediastinal and retro-
peritoneal disease, if involved. A measurable node must have an
LDi greater than 1.5 cm. Measurable extranodal disease (eg, he-
patic nodules) may be included in the six representative, measured
lesions. A measurable extranodal lesion should have an LDi greater
than 1.0 cm. All other lesions (including nodal, extranodal, and
assessable disease) should be followed as nonmeasured disease (eg,
cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial
effusions, ascites). In patients in whom a discordant histology or
malignant transformation is suspected, a PET-CT may identify the
optimal site to biopsy for conﬁrmation.20,21
Tumor Bulk
A single nodal mass, in contrast to multiple smaller nodes, of 10
cm or greater than a third of the transthoracic diameter at any level of
thoracic vertebrae as determined by CT is retained as the deﬁnition of
bulky disease for HL.5 A chest x-ray is not required to determine bulk
because of its high concordance with CT.32 However, a variety of sizes
have been suggested for NHL,15,33 with limited evidence suggesting 6
cm as best for follicular lymphoma15 and 6 to 10 cm in the rituximab
era for DLBCL.34 However, none of the proposed sizes have been
validated in the current therapeutic era. Therefore, the recommenda-
tion for HL and NHL is to record the longest measurement by CT
scan, with the term X no longer necessary.
Spleen Involvement
A wide range of normal spleen sizes has been reported,35-37 re-
lated to race, body size, and height.38 A spleen may be of normal size
andstillcontainlymphomaormaybeenlargedasaresultofvariations
in blood volume, use of hematopoietic growth factors, or lymphoma-
unrelated causes. Splenic involvement is best determined by PET-CT
and may be characterized by homogeneous splenomegaly, diffuse
inﬁltration with miliary lesions, focal nodular lesions, or a large soli-
tary mass.39 There is no agreement on whether single, multiple, or
volumetric measurements should be used to measure spleen size35 or
what cutoff to use for splenomegaly. For simplicity, a single measure-
mentthatcorrelateswellwithvolume40,41ispreferabletoavolumetric
measurementorestimationbyequations,withspecialsoftware,which
are unlikely to be used routinely.
Most studies use 10 to 12 cm for vertical length. Our recommen-
dation is to use a cutoff for splenomegaly of more than 13 cm.
Liver Involvement
Given variability in body habitus and the impact of numerous
medical conditions, liver size by physical examination or CT scan is
not a reliable measure of hepatic involvement by lymphoma. Similar
to splenic involvement, diffusely increased or focal uptake, with or
without focal or disseminated nodules, supports liver involvement.
Bone Marrow Involvement
Bone marrow biopsy (BMB) has been standard in lymphoma
staging,5 although it is often performed even when the likelihood of
involvement is low. The high sensitivity of PET-CT for bone mar-
row involvement has recently called into question the continued
use of BMB in several common histologies.42-46 In one study in HL,
18% of patients had focal skeletal lesions on PET-CT, but only 6%
had positive BMB,46 all with advanced disease on PET-CT. None of
the patients would have been allocated to another treatment based
on BMB results. Patients with early-stage disease rarely have in-
volvement in the absence of a suggestive PET ﬁnding, and those
with advanced-stage disease rarely have involvement in the ab-
sence of disease-related symptoms or other evidence of advanced-
stage disease. Thus, if a PET-CT is performed, a bone marrow
aspirate/biopsy is no longer required for the routine evaluation of
patients with HL.
InDLBCL,PET-CTisalsomoresensitivethanBMBbuthasbeen
reported to miss low-volume diffuse involvement of 10% to 20% of
the marrow.42,47-49 Nevertheless, patients with clinical early-stage dis-
ease rarely have involvement in the absence of a suggestive PET ﬁnd-
ing. In one study in DLBCL, 27% of patients were found to have
marrow involvement (94% by PET-CT and only 40% by BMB). BMB
wasnegativein21of28patientswithfocaldiseaseonPET-CTanddid
not upstage any patients. Two cases (1.5%) of bone marrow involve-
ment went undetected by PET-CT, with a 10% inﬁltrate of large cells.
Thus, a PET-CT scan indicating bone or marrow involvement is
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usually sufﬁcient to designate advanced-stage disease, and a BMB is
not required. Patients with a positive BMB generally have other fac-
tors consistent with advanced stage or poor prognosis.49,50 If the scan
is negative, a BMB is indicated to identify involvement by discordant
histology if relevant for a clinical trial or patient management.51
The data in all other lymphoma histologies are insufﬁcient to
change the standard practice, and a 2.5-cm unilateral BMB is recom-
mended, along with immunohistochemistry and ﬂow cytometry.
PROGNOSTIC GROUPS AND TREATMENT ALLOCATION
The increased use of systemic and multimodality approaches has
made Ann Arbor stage less relevant in directing the choice of therapy.
Nevertheless, we recommend a modiﬁcation of the Ann Arbor classi-
ﬁcation(Table2)foranatomicdescriptionofdiseaseextent.However,
regardlessofstage,generalpracticeistotreatpatientsbasedonlimited
(stages I and II, nonbulky) or advanced (stages III or IV) disease, with
stageIIbulkydiseaseconsideredlimitedoradvancedasdeterminedby
histology and a number of prognostic factors. The designation E for
extranodaldiseaseisrelevantonlyforlimitedextranodaldiseaseinthe
absence of nodal involvement (IE) or in patients with stage II disease
and direct extension to a non-nodal site. E is not relevant to patients
with advanced-stage disease.
TheAnnArborclassiﬁcationsubdividespatientsaccordingtothe
absence (A) or presence (B) of disease-related symptoms. However,
thesefeaturesarefrequentlyneitherrecordednoraccurate.Moreover,
in the International Prognostic Index,12 Follicular Lymphoma Inter-
national Prognostic Index,13 Follicular Lymphoma International
Prognostic Index 2,15 Mantle Cell International Prognostic Index,14
andInternationalPrognosticScore,11constitutionalsymptomsdonot
confer an unfavorable outcome. Thus, only patients with HL need be
assigned the designations A or B because symptoms only direct treat-
ment in that disease.
Summary
Excisionalbiopsyispreferredfordiagnosis,althoughcore-needle
biopsy may sufﬁce when not feasible.
Clinical evaluation includes careful history, relevant laboratory
tests, and recording of disease-related symptoms.
PET-CTisthestandardforFDG-avidlymphomas,whereasCTis
indicated for nonavid histologies.
A modiﬁed Ann Arbor staging system is recommended; how-
ever, patients are treated according to prognostic and risk factors.
Sufﬁxes A and B are only required for HL.
The designation X for bulky disease is no longer necessary; in-
stead, a recording of the largest tumor diameter is required.
IfaPET-CTisperformed,aBMBisnolongerindicatedforHL;a
BMB is only needed for DLBCL if the PET is negative and identifying
a discordant histology is important for patient management.
ASSESSMENT OF RESPONSE AFTER TREATMENT
End-of-treatment assessment is more accurate with PET-CT, espe-
ciallyforpatientswithradiologic(CT)CRuorpartialresponse(PR)in
HL, DLBCL, and follicular lymphoma.7,52-55 PET-CT–based criteria
eliminate CRu and improve the prognostic value of PR. In early- and
advanced-stagepatientswithHL,anegativepredictivevalueof95%to
100% and positive predictive value of more than 90% have been
reported.56,57 In aggressive NHL, studies have reported a negative
predictive value of 80% to 100% but a lower positive predictive value,
rangingfrom50%to100%.58-61Iffurthertreatmentbasedonresidual
metabolically active disease on PET-CT is being considered, either
biopsy or follow-up scan is advised. In these lymphoma subtypes,
response assessment with PET-CT may be preferred.
The IWG criteria for reviewing PET scans were based on visual
interpretation and intended for end-of-treatment evaluation,62 using
mediastinalbloodpoolasthecomparator.Thecurrentrecommenda-
tionistousethe5-pointscale,bothforclinicaltrialsincludinginterim
analysis and for end-of-treatment assessment (Table 3).24 Interim
PET-CT is used to assess early treatment response and, at end of
treatment, to establish remission status. A score of 1 or 2 is considered
to represent complete metabolic response at interim and end of treat-
ment.FDGuptakedeclinesduringtherapyinchemotherapy-sensitive
disease, and residual FDG uptake higher than normal liver uptake is
frequentlyseenatinteriminpatientswhoachievecompletemetabolic
response at the end of treatment. More recent data also suggest that
most patients with uptake higher than mediastinum but less than or
equivalent to liver (score of 3) have good prognosis at the end of
treatment with standard therapy in HL,63 DLBCL,61 and follicular
lymphoma.54 However, in response-adapted trials exploring treat-
mentde-escalation,amorecautiousapproachmaybepreferred,judg-
ingascoreof3tobeaninadequateresponsetoavoidundertreatment.
Therefore, interpretation of a score of 3 depends on the timing of
assessment, the clinical context, and the treatment. A score of 4 or 5 at
interimsuggestschemotherapy-sensitivedisease,provideduptakehas
reduced from baseline, and is considered to represent partial meta-
bolic response. At the end of treatment, residual metabolic disease
with a score of 4 or 5 represents treatment failure even if uptake has
reduced from baseline. A score of 4 or 5 with intensity that does not
change or even increases from baseline and/or new foci compatible
Table 2. Revised Staging System for Primary Nodal Lymphomas
Stage
Involvement
Extranodal (E) Status
Limited
I
One node or a group of adjacent
nodes
Single extranodal lesions
without nodal
involvement
II
Two or more nodal groups on the
same side of the diaphragm
Stage I or II by nodal
extent with limited
contiguous extranodal
involvement
II bulky
II as above with “bulky” disease
Not applicable
Advanced
III
Nodes on both sides of the
diaphragm; nodes above the
diaphragm with spleen
involvement
Not applicable
IV
Additional noncontiguous
extralymphatic involvement
Not applicable
NOTE. Extent of disease is determined by positron emission tomography–
computed tomography for avid lymphomas and computed tomography for
nonavid histologies. Tonsils, Waldeyer’s ring, and spleen are considered
nodal tissue.
Whether stage II bulky disease is treated as limited or advanced disease
may be determined by histology and a number of prognostic factors.
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with lymphoma represents treatment failure at interim and at the
end-of-treatment assessment.
In most cases, lack of signiﬁcant response can be interpreted
visually. Although ideally a quantitative cutoff might improve consis-
tency, there is insufﬁcient evidence to quantify precisely the reduction
in uptake that predicts adequate response using FDG-PET for lym-
phoma, which is dependent on disease type, timing, and treatment
given.RecentdatasuggestthattheCTscanmayplayacomplimentary
role in patients with HL who have either a positive interim or post-
treatment PET-CT, with a greater reduction in tumor mass correlat-
ing with an improved outcome.64,65 How best to use this information
remains to be determined.
CT-based response is preferred for histologies with low or vari-
ableFDGavidityandinregionsoftheworldwherePET-CTisunavail-
able. However, in the absence of a PET-CT scan, a mass that has
decreasedinsizebutpersistsisconsideredatbestaPRintheabsenceof
biopsydocumentingabsenceoflymphoma,andtheformertermCRu
is not to be considered.7 In trials exploring new agents in multiply
relapsed disease where data are lacking regarding PET-CT and where
assessment of disease control is more important than likelihood of
cure, CT-based response may also be more relevant (Table 3).
At interim or end of therapy, tests that were abnormal before
treatment should be repeated, including assessment of extranodal
sites. Response assessment is detailed in Table 3 and in the follow-
ing sections.
Nodes or Extranodal Lesions That Split When Disease
Is Responding
If a conﬂuent nodal mass splits into several discrete nodes, the
individual product of the perpendicular diameters (PPDs) of the
nodes should be summed together to represent the PPD of the split
lesion; this PPD is added to the sum of the PPDs of the remaining
lesionstomeasureresponse.Ifsubsequentgrowthofanyorallofthese
discrete nodes occurs, the nadir of each individual node is used to
determine progression (as if each individual node was selected as a
target lesion at baseline).
Nodes or Extranodal Lesions That Become Conﬂuent
When Disease Is Progressing
If a group of target lymph nodes becomes conﬂuent, the PPD of
the current conﬂuent mass should be compared with the sum of the
PPDs of the individual nodes, with more than 50% increase in the
PPD of the conﬂuent mass compared with the sum of individual
nodes necessary to indicate progressive disease. The LDi and shortest
diameter are no longer needed to determine progression.
Additional Response Assessment Guidelines
The presence of residual symptoms in the absence of detectable
disease by imaging does not preclude the designation CR. In the
context of an agent associated with a ﬂare reaction, caution must be
exercised not to confuse the possible tumor ﬂare with progressive
disease. It is recommended that either a biopsy be performed or the
lesion be reassessed in at least 2 weeks, and if there is continued
evidence of tumor progression, the date of progressive disease is the
previous evaluation.
FOLLOW-UP EVALUATIONS
Good clinical judgment, a careful history, and physical examination
are the cornerstones of patient follow-up. The IWG, National Com-
prehensive Cancer Network, and European Society for Medical On-
cology published recommendations for follow-up that vary by
histology(curablevincurable),whetherapatientisonaclinicaltrialor
managed with standard of care, or the clinical setting (eg, initial v
relapsed/refractory disease; complete response v PR to treat-
ment).7,66,67 For example, for curable histologies such as HL and
DLBCL, the likelihood of relapse decreases over time; thus, the fre-
quency of follow-up should decrease, with visits being reduced from
every 3 months during the ﬁrst 2 years, to every 6 months for the next
3 years, and then annually thereafter to monitor for late relapse and
treatment-related adverse effects. In contrast, in follicular lymphoma,
mantle-celllymphoma,andotherincurablehistologies,thelikelihood
of recurrence continues or increases over time, and patients should be
observed every 3 to 6 months, determined by pretreatment risk fac-
tors, whether the patient is being managed conservatively, and
whether treatment has achieved a complete or less than complete
response. In addition, a CBC, metabolic panel, and serum lactate
dehydrogenase are recommended.
Published studies fail to support routine surveillance scans, and
they are discouraged.68-70 The false-positive rate with PET scans is
greater than 20%, leading to unnecessary investigations, radiation
exposure, biopsies, expense, and patient anxiety. Follow-up scans
should be prompted by clinical indications. In clinical trials with
time-dependent end points (eg, progression-free survival, event-free
survival), a CT scan is determined by the study-designated interval. In
theindolentlymphomas,asymptomaticintra-abdominalorretroper-
itoneal disease progression may be a concern in patients with residual
disease in those areas after therapy. In such patients, judicious use of
scans can be considered. In clinical practice and in clinical trials,
attempts should be made to limit the number of scans to which a
patient is exposed.
Summary
PET-CT should be used for response assessment in FDG-avid
histologies, using the 5-point scale; CT is preferred for low or variable
FDG avidity.
A complete metabolic response even with a persistent mass is
considered a complete remission.
A PR requires a decrease by more than 50% in the sum of the
product of the perpendicular diameters of up to six representative
nodes or extranodal lesions.
Progressive disease by CT criteria only requires an increase in the
PPDs of a single node by  50%.
Surveillance scans after remission are discouraged, especially for
DLBCL and HL, although a repeat study may be considered after an
equivocal ﬁnding after treatment.
Judicious use of follow-up scans may be considered in
indolent lymphomas with residual intra-abdominal or retro-
peritoneal disease.
MEASUREMENT OF OUTCOME
Deﬁnitions are consistent with the IWG deﬁnitions.7
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Table 3. Revised Criteria for Response Assessment
Response and Site
PET-CT–Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all of the following)
Lymph nodes and
extralymphatic sites
Score 1, 2, or 3 with or without a residual mass on 5PS†
Target nodes/nodal masses must regress to  1.5 cm in LDi
It is recognized that in Waldeyer’s ring or extranodal sites
with high physiologic uptake or with activation within
spleen or marrow (eg, with chemotherapy or myeloid
colony-stimulating factors), uptake may be greater than
normal mediastinum and/or liver. In this circumstance,
complete metabolic response may be inferred if uptake at
sites of initial involvement is no greater than surrounding
normal tissue even if the tissue has high physiologic
uptake
No extralymphatic sites of disease
Nonmeasured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if indeterminate, IHC negative
Partial
Partial metabolic response
Partial remission (all of the following)
Lymph nodes and
extralymphatic sites
Score 4 or 5† with reduced uptake compared with baseline
and residual mass(es) of any size
 50% decrease in SPD of up to 6 target measurable nodes
and extranodal sites
At interim, these ﬁndings suggest responding disease
When a lesion is too small to measure on CT, assign 5 mm  5
mm as the default value
At end of treatment, these ﬁndings indicate residual disease
When no longer visible, 0  0 mm
For a node  5 mm  5 mm, but smaller than normal, use
actual measurement for calculation
Nonmeasured lesions
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by  50% in length beyond
normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in normal marrow but
reduced compared with baseline (diffuse uptake
compatible with reactive changes from chemotherapy
allowed). If there are persistent focal changes in the
marrow in the context of a nodal response, consideration
should be given to further evaluation with MRI or biopsy
or an interval scan
Not applicable
No response or stable disease
No metabolic response
Stable disease
Target nodes/nodal masses,
extranodal lesions
Score 4 or 5 with no signiﬁcant change in FDG uptake from
baseline at interim or end of treatment
 50% decrease from baseline in SPD of up to 6 dominant,
measurable nodes and extranodal sites; no criteria for
progressive disease are met
Nonmeasured lesions
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive disease
Progressive metabolic disease
Progressive disease requires at least 1 of the following
Individual target nodes/nodal
masses
Score 4 or 5 with an increase in intensity of uptake from
baseline and/or
PPD progression:
Extranodal lesions
New FDG-avid foci consistent with lymphoma at interim or
end-of-treatment assessment
An individual node/lesion must be abnormal with:
LDi  1.5 cm and
Increase by  50% from PPD nadir and
An increase in LDi or SDi from nadir
0.5 cm for lesions  2 cm
1.0 cm for lesions  2 cm
In the setting of splenomegaly, the splenic length must
increase by  50% of the extent of its prior increase
beyond baseline (eg, a 15-cm spleen must increase to
 16 cm). If no prior splenomegaly, must increase by at
least 2 cm from baseline
New or recurrent splenomegaly
Nonmeasured lesions
None
New or clear progression of preexisting nonmeasured
lesions
(continued on following page)
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CONCLUDING REMARKS
Accurate pretreatment evaluation and response assessment are
critical to the optimal management of patients with lymphoma.
With increasing knowledge of the disease, new prognostic factors,
and a better understanding of tumor biology comes a need to
update prior systems. Despite the importance of a physical exam-
ination, imaging studies have become the standard. The present
recommendations are directed primarily at initial staging and as-
sessment, and their role in the multiply relapsed setting and early
clinical trials remains to be conﬁrmed. A major departure from the
Ann Arbor system and the IWG criteria is that PET-CT is included
in staging for FDG-avid lymphomas, because it is more sensitive
than CT and provides a baseline against which response is more
accurately assessed. Patients should be treated based on prognostic
factors. Subclassiﬁcation of A and B is now only indicated if prog-
nostically important (ie, HL). Patients, including those with HL
and most with DLBCL, can be spared a staging BMB,71 and a
routine chest x-ray is unnecessary for staging, although it may be
useful for monitoring select patients with HL. Although the cur-
rent deﬁnition of bulk is retained for HL, further correlations
between maximum tumor diameter and outcome are needed to
provide a clinically meaningful deﬁnition of bulk with current
treatment approaches for NHL. Response assessment is preferred
for FDG-avid lymphomas where possible, using the 5-point scale,
whereas CT-based response remains important in lymphomas
with low or variable FDG avidity, and in multiply relapsed disease,
CT criteria for progressive disease can be based on an increase of a
single lesion. The better we are able to exploit the biology of
lymphomas for therapeutic beneﬁt, the more our treatment strat-
egies will be determined by relevant receptors and pathways, with
even less reliance on Ann Arbor staging. Hopefully, the current
recommendations will provide the necessary standardization of
clinical trial conduct and interpretation that leads to improved
therapies for patients with lymphoma.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) and/or an author’s immediate family member(s) indicated a
ﬁnancial or other interest that is relevant to the subject matter under
consideration in this article. Certain relationships marked with a “U” are
those for which no compensation was received; those relationships marked
with a “C” were compensated. For a detailed description of the disclosure
categories, or for more information about ASCO’s conﬂict of interest policy,
please refer to the Author Disclosure Declaration and the Disclosures of
Potential Conﬂicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Bruce D. Cheson, Gilead (C), Celgene (C), Genentech (C),
Pharmacyclics (C), AstraZeneca (C), Spectrum (C); Lawrence H.
Schwartz, Novartis (C), BioImaging (C), Icon Medical (C); Emanuele
Zucca, Roche (C), Mundipharma (C), Celgene (C), Janssen (C) Stock
Ownership: None Honoraria: Emanuele Zucca, Roche,
Mundipharma, Celgene, Janssen Research Funding: Bruce D.
Cheson, Gilead, Celgene, Genentech, Pharmacyclics; Emanuele
Zucca, Roche, Mundipharma, Novartis Expert Testimony: None
Patents, Royalties, and Licenses: None Other Remuneration: Bruce
D. Cheson, Gilead, Celgene, Genentech, Pharmacyclics; Emanuele
Zucca, Roche, Mundipharma, Janssen; T. Andrew Lister, Millennium
AUTHOR CONTRIBUTIONS
Conception and design: All authors
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Table 3. Revised Criteria for Response Assessment (continued)
Response and Site
PET-CT–Based Response
CT-Based Response
New lesions
New FDG-avid foci consistent with lymphoma rather than
another etiology (eg, infection, inﬂammation). If
uncertain regarding etiology of new lesions, biopsy or
interval scan may be considered
Regrowth of previously resolved lesions
A new node  1.5 cm in any axis
A new extranodal site  1.0 cm in any axis; if  1.0 cm in
any axis, its presence must be unequivocal and must be
attributable to lymphoma
Assessable disease of any size unequivocally attributable to
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, ﬂuorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse diameter of a lesion;
MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular
to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions.
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant
lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes should
preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those
in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not
selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal masses,
and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well
as truly assessable disease, which is any site of suspected disease that would be difﬁcult to follow quantitatively with measurement, including pleural
effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be conﬁrmed and followed by imaging. In
Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic
response, but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid
growth factors).
†PET 5PS: 1, no uptake above background; 2, uptake  mediastinum; 3, uptake  mediastinum but  liver; 4, uptake moderately  liver; 5, uptake markedly higher
than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.
Staging and Response Assessment in Lymphoma
www.jco.org
© 2014 by American Society of Clinical Oncology
3065
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■■■
Staging and Response Assessment in Lymphoma
www.jco.org
© 2014 by American Society of Clinical Oncology
3067
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&RS\ULJKW$PHULFDQ6RFLHW\RI&OLQLFDO2QFRORJ\$OOULJKWVUHVHUYHG


Acknowledgment
We thank the following contributors to the writing of this article: Ranjana Advani, Kirit Ardeshna, Jim Armitage, Matthew Barish, Alberto
Biggi, George Canellos, Luca Ceriani, Bertrand Coifﬁer, Joe Connors, Michael Crump, Martin Dreyling, Andreas Engert, Massimo Federico,
Andrea Gallamini, Randy Gascoyne, Christian Gisselbrecht, Mary Gospodarawicz, Armando Lopez Guillermo, Ton Hagenbeek, Michael
Herold, Richard Hoppe, Martin Hutchings, Peter Johnson, Brad Kahl, Won Seog Kim, Eva Kimby, Lale Kostakoglu, John Leonard, Kelie Luby,
Elly Lugtenburg, Michel Meignan, N. George Mikhaeel, Silvia Montoto, Craig Moskowitz, Stefan Mueller, Michinori Ogura, Michael Pfreund-
schuh, Aaron Polliack, John Radford, Gilles Salles, Laurie Sehn, John Seymour, Ritsuro Suzuki, Kensei Tobinai, Judith Trotman, Wyndham
Wilson,UmbertoVitolo,JulieVose,AnasYounes,AndrewZelenetz,Jose´ Zijlstra,andPier-LuigiZinzani.WealsothankCristianaBrentanforher
invaluable administrative support.
Cheson et al
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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TABLE OF CONTENTS 
Table of Contents ............................................................................................................ 2 
Table of Abbreviations ..................................................................................................... 4 
1. 
INTRODUCTION .................................................................................................... 6 
2. 
OBJECTIVES ......................................................................................................... 6 
2.1 
PRIMARY OBJECTIVE .................................................................................. 6 
2.2 
SECONDARY OBJECTIVES: ........................................................................ 6 
2.3 
EXPLORATORY OBJECTIVES ..................................................................... 6 
3. 
STUDY OVERVIEW ............................................................................................... 7 
3.1 
Study Design .................................................................................................. 7 
3.2 
Sample Size ................................................................................................... 9 
3.3 
STUDY ENDPOINTS ................................................................................... 10 
3.3.1 
Primary Endpoints ........................................................................... 10 
3.3.2 
Secondary Endpoints ...................................................................... 10 
4. 
HYPOTHESES AND MULTIPLICITY .................................................................... 10 
5. 
ANALYSIS SETS .................................................................................................. 10 
5.1 
Safety Analysis Set ...................................................................................... 10 
5.2 
Efficacy Evaluable Analysis Set ................................................................... 10 
5.3 
Pharmacokinetic Analysis Set ...................................................................... 11 
6. 
SUBGROUP ANALYSIS ....................................................................................... 11 
7. 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES .............................. 11 
8. 
ANALYSIS TIMEPOINT AND CLINICAL STUDY REPORT .................................. 11 
9. 
MISSING VALUES ............................................................................................... 11 
10. 
STATISTICAL METHODS OF ANALYSIS ............................................................ 11 
10.1 General Principles ........................................................................................ 11 
10.2 Subject Accountability .................................................................................. 12 
10.3 Important Protocol Deviations ...................................................................... 12 
10.4 Demographic and Baseline Characteristics .................................................. 12 
10.5 Treatment and Medications .......................................................................... 12 
10.5.1 Prior Anticancer Therapies .............................................................. 12 
10.5.2 Concomitant Medications ................................................................ 12 
10.5.3 Exposure to Investigational Product ................................................ 13 
10.6 Safety Analyses ........................................................................................... 13 
10.6.1 Adverse Events ............................................................................... 13 
10.6.2 Laboratory Test Results .................................................................. 13 


 
 
 
 
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10.6.3 Vital Signs ....................................................................................... 14 
10.6.4 ECOG Performance Status ............................................................. 14 
10.6.5 12-Lead Electrocardiogram ............................................................. 14 
10.7 Efficacy Analyses ......................................................................................... 14 
10.7.1 Overall Response Rate and Complete Response Rate ................... 14 
10.7.2 Progression-Free Survival ............................................................... 14 
10.7.3 Duration of Response ...................................................................... 15 
10.7.4 Durable Response Rate .................................................................. 15 
10.7.5 Overall Survival ............................................................................... 16 
10.8 Pharmacokinetic Analyses ........................................................................... 16 
11. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES .................................... 16 
12. 
LITERATURE CITATIONS/REFERENCES .......................................................... 16 
13. 
APPENDICES....................................................................................................... 16 
13.1 Definitions .................................................................................................... 16 
13.2 Imputation Rules for Partial or Missing Dates ............................................... 17 
14. 
DETAILED CENSORING RULES FOR EFFICACY ENDPOINTS......................... 18 
14.1 PFS Events and Censoring Rules ................................................................ 18 
14.2 Overall Survival Censoring Rules ................................................................. 19 


 
 
 
 
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TABLE OF ABBREVIATIONS 
AE(s) 
adverse event(s) 
BID 
twice per day (dosing) 
CI 
confidence interval 
CR 
complete response (remission) 
CRF 
case report form  
CSR 
clinical study report  
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
diffuse large B-cell lymphoma 
DOR 
duration of response 
DRR 
durable response rate 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
U.S. Food and Drug Administration 
ICF 
informed consent form 
IPD 
important protocol deviation 
IXRK 
Interactive Voice/Web Response System 
K-M 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeter of mercury 
mTOR 
Mammalian target of rapamycin 
MTD 
maximum tolerated dose(s) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
ORR  
overall response rate 
OS 
overall survival 
PD 
pharmacodynamic, pharmacodynamics, or progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic or pharmacokinetics 
PO  
orally 
PR 
partial response (remission) 
PT 
preferred terms 
QD 
once per day (dosing) 
QTcF 
QT interval corrected by Fridericia's formula 
R/R 
relapsed/refractory 
RS 
Richter syndrome 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan  
SD 
stable disease 
SI 
International System of Units 
SMQ 
Standardized MedDRA Queries 
SOC 
system organ class 
SRC 
Safety Review Committee 


 
 
 
 
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TEAE(s) 
treatment emergent adverse event(s) 
WHODRUG 
World Health Organization Drug Dictionary 
 
 
 


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Part 1 
Part 1 of the study planned to include adult subjects with any of the following 
relapsed/refractory disease types: 
• De novo DLBCL 
• Transformed DLBCL 
• Richter syndrome (RS) 
Subjects were scheduled to take acalabrutinib BID at approximately 12-hour intervals. A 
treatment cycle was defined as 28 days. The acalabrutinib dose was 100 mg bid. 
Acalabrutinib is administered on every day of the 28-day cycle.  
 
Although acalabrutinib monotherapy has not demonstrated dose-limiting toxicities 
(DLTs) to date, the safety of the combination of acalabrutinib and vistusertib in this 
patient population was assessed. Therefore, a safety analysis was planned when 6 
subjects had been enrolled in each schedule (see below). Eligible subjects were 
randomized 1:1 to receive one of the following starting regimens of vistusertib through 
use of an Interactive Voice/Web Response System (IXRS): 
Schedule 1 (continuous dosing): Vistusertib 35 mg bid continuous dosing (1 cycle = 
28 days), n=6 
--Or-- 
Schedule 2 (intermittent dosing): Vistusertib 100 mg bid intermittent dosing (2 days 
on/ 5 days off over the 28-day cycle), n=6 
 
The following doses/schedules for vistusertib were planned to be evaluated in 
combination with acalabrutinib 100 mg bid in Part 1: 
 
Level -1 
(Starting Dose) 
Level 0 
(Target Level) 
Level +1 
Continuous 
dosing 
schedule 
(Schedule 1) 
35 mg bid 
(daily) 
n=6 
50 mg bid 
(daily) 
n=6 
75 mg bid 
(daily) 
n=6 
Intermittent 
dosing 
schedule 
(Schedule 2) 
100 mg bid 
(2 days on/ 5 days 
off) 
n=6 
125 mg bid 
(2 days on/ 5 
days off) 
n=6 
150 mg bid 
(2 days on/5 
days off) 
n=6 
Abbreviations: bid = twice per day 


 
 
 
 
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Standard DLT criteria were used to assess safety during the first cycle of treatment of 
the combination treatment. (To be evaluable for DLT, patients who have not experienced 
DLT must have received at least 75% of scheduled doses. Patients who have 
experienced DLT do not have a minimum dosing requirement.) Each schedule was 
independently assessed. Escalation to the target level could occur until the DLT review 
had occurred. If ≤1 DLTs occurred during Cycle 1 in the 6 subjects enrolled in a given 
schedule, then the dose of vistusertib was escalated as per study schema in the protocol 
and 6 new subjects were enrolled and assessed for DLT.  Detailed information on DLT 
review and toxicity monitoring was provided in Section 3.7 and Section 3.14 of the study 
protocol. 
Since the study will not proceed to Part 2, the final analysis will be conducted after all 
ongoing subjects in Part 1 have had the opportunity to complete at least 3 scheduled 
post-baseline scans. 
3.2 
Sample Size  
Under current protocol (version 2.0), the sample size for Part 1 and Part 2 were set up 
separately. Depending on dose escalation/de-escalation and enrollment in the 
expansion groups, up to 71 subjects were planned to be enrolled in this study: 
• Part 1: ≤36 subjects 
• Part 2: ≤35 subjects 
In Part 1 (dose selection), enrollment of 6 subjects per dose level limited the number of 
subjects exposed, consistent with the expected safety profiles of the study drugs, but 
included sufficient number of subjects to explore effects on PD biomarkers of BTK and 
mTOR inhibition. The trial employed the standard NCI definition of MTD (dose 
associated with DLT in <33.3% of subjects assessed during Cycle 1). In Part 1, subjects 
who did not meet the DLT review criteria were replaced. 
By the time of the decision of study closeout, two dose levels (level -1 and level 0) had 
been explored in each of the two schedules (continuous/intermittent vistusertib dosing), 
resulting in enrolling 24 patients. In the cohort of dose level -1 35 mg BID continuous, 
one subject who was not DLT evaluable was replaced. Therefore, the overall number of 
subjects is 25. 


 
 
 
 
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3.3 
STUDY ENDPOINTS  
3.3.1 
Primary Endpoints 
• The safety endpoints are the primary endpoints of this study, including type, 
frequency, severity, and relationship to either or both study drug of any 
treatment-emergent adverse events (TEAEs) or abnormalities of laboratory 
tests, serious adverse events (SAEs), AEs leading to dose modification, dose 
delay, and discontinuation of any study drug. 
3.3.2 
Secondary Endpoints 
• PK Endpoints 
• Efficacy Endpoints 
o ORR (CR + PR) 
o DRR 
o CR rate 
o DOR 
o PFS 
o OS 
4. 
HYPOTHESES AND MULTIPLICITY 
No formal statistical hypotheses will be tested and no multiplicity adjustments will be 
made. This proof-of-concept study will assess the clinical potential of acalabrutinib in 
combination with vistusertib in relapsed/refractory subsets of B-cell malignancies. 
5. 
ANALYSIS SETS 
The following definitions will be used for the safety and efficacy analysis populations. 
5.1 
Safety Analysis Set 
The safety analysis set includes all subjects who received at least one dose of any study 
drug (either acalabrutinib or vistusertib). The safety analysis set will be used for 
evaluating the safety endpoints. 
5.2 
Efficacy Evaluable Analysis Set  
The efficacy evaluable analysis set includes all subjects in the safety analysis set with a 
baseline tumor assessment. The efficacy analysis set will be used for evaluating the 
efficacy endpoints, with the exception of DOR. The analyses of DOR will be conducted 


 
 
 
 
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on the subset of the efficacy evaluable analysis set who achieve CR or PR as their best 
overall response. 
5.3 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set includes all subjects in the safety analysis set with 
evaluable PK parameters. Pharmacokinetic evaluable analysis set will be defined by 
PK/PD group. 
6. 
SUBGROUP ANALYSIS 
No subgroup analyses will be performed. 
7. 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES  
Interim analysis was planned for Part 2 of this study. Because of the closeout of this 
study at Part 1, no interim analysis will be performed. 
8. 
ANALYSIS TIMEPOINT AND CLINICAL STUDY REPORT 
Due to early closeout of the study at Part 1, the planned primary analysis (after all 
ongoing subjects have had the opportunity to complete at least 3 scheduled post-
baseline scans) will be considered as the final analysis. The clinical study report will be 
written.  
9. 
MISSING VALUES 
No imputation of values for missing data will be performed except for missing or partial 
start and end dates for AEs and concomitant medication will be imputed according to 
prespecified, conservative imputation rules. The details of imputation rules for partial or 
missing dates are listed in Appendix 13.2. 
10. 
STATISTICAL METHODS OF ANALYSIS 
10.1 
General Principles 
Descriptive statistics (including means, standard deviations, medians, minimum and 
maximum for continuous variables, and frequency, proportions, and confidence intervals 
[CIs] for discrete variables) will be used to summarize data as appropriate. 
Calculation of time to event or duration of event endpoints will be based on the study day 
of the event or censoring date rather than visit number or visit label. Missing efficacy or 
safety data will not be imputed unless otherwise specified. 


 
 
 
 
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The following rules will be used for the days to months/years conversion: 
• 
1 month= 30.4375 days; 
• 
1 year= 365.25 days. 
All summaries will be presented by treatment group. 
10.2 
Subject Accountability 
The number of subjects enrolled by site and country will be presented. Subject 
disposition will be summarized for all enrolled subjects including the following 
information: 
• 
Proportion of subjects who received study drug 
• 
Proportion of subjects with study drug discontinuation and primary reason for 
study drug discontinuation 
• 
Proportion of subjects discontinuing study and reasons for study discontinuation 
• 
Time on study 
10.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined and managed by the study 
team during the IPD reviews throughout the study before database lock. The final IPD 
list is used to produce the Summary of IPDs table and the List of Subjects with IPDs.   
10.4 
Demographic and Baseline Characteristics 
Summaries of demographic characteristics will be presented for age, age category (< 65, 
≥ 65), sex, race, ethnicity, and geographic region for each study.   
Baseline characteristics will be presented for Eastern Cooperative Oncology Group 
(ECOG) performance status, disease stage, and number of prior anticancer therapies for 
each study. 
10.5 
Treatment and Medications 
10.5.1 
Prior Anticancer Therapies 
Summary statistics will be presented for prior anticancer regimens (might include 
multiple therapies) and prior cancer-related surgery for each study. Prior cancer therapy 
categories will be adjudicated by the medical monitor. 
10.5.2 
Concomitant Medications 
Concomitant medications will be coded and tabulated according to the World Health 
Organization Drug Dictionary (WHODRUG).  


 
 
 
 
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10.5.3 
Exposure to Investigational Product  
The number of subjects who received at least one dose of acalabrutinib, vistusertib, or 
both; duration of exposure; average daily dose of acalabrutinib; average weekly dose of 
vistusertib and relative dose intensity will be summarized for each investigational product 
and by treatment group. 
Exposure parameters are defined in more detail in Appendix 13.1. 
10.6 
Safety Analyses 
The safety analysis will be performed using the safety analysis set. 
10.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA v20.1 or higher) will be used 
to code all AEs to a system organ class and a preferred term.  The severity of the AE will 
be assessed by National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5. Study drug-related AEs are those assessed by 
investigator as related.  
All AE tables will be summarized by treatment cohorts. 
TEAEs are defined as those events that occur or worsen on or after the first dose of 
study drug, through the treatment phase, and within 30 days following the last dose of 
any study treatment. 
TEAEs will be summarized by system organ class (SOC) and preferred terms in 
descending order of frequency, by CTCAE toxicity grade. Drug-related TEAEs, serious 
TEAEs, TEAEs leading to dose modifications, dose delay, and study treatment 
discontinuation will be summarized by preferred teams in descending order of frequency, 
by CTCAE toxicity grade.  
Death information is reported in the death report form (CRF) for all deaths. Incidences of 
deaths are to be reported, along with the primary cause of death. 
10.6.2 
Laboratory Test Results 
Laboratory data up to 30 days after last dose or the safety follow-up visit date, 
whichever is later, will be reported in International System of Units (SI) units. 
Applicable laboratory results will be graded according to CTCAE Version 5. For each 
laboratory parameter, the baseline laboratory value/grade is defined as the last 
laboratory value/grade collected on or prior to the date of the first dose of study 


 
 
 
 
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drug. Treatment-emergent laboratory abnormalities for selected parameters will be 
summarized. 
10.6.3 
Vital Signs 
Body temperature (C), pulse (beats/min), systolic blood pressure (mmHg), diastolic 
blood pressure (mmHg), oxygen saturation (%), height (cm), and weight (kg) will be 
collected as scheduled in the protocol. For each parameter, summary statistics (mean, 
standard deviation, median, and range) will be produced for baseline, maximum, and 
minimum value. 
10.6.4 
ECOG Performance Status  
ECOG performance status scores will be summarized for each treatment group using a 
shift table.  The shifts in scores from baseline to worst ECOG score on treatment will be 
summarized.   
10.6.5 
12-Lead Electrocardiogram  
The summary statistics (mean, standard deviation, median, and range) of QTc based on 
Fridericia’s formula (QTcF) at baseline and each assessed time point will be produced. If 
triplicate ECGs were performed (at screening and Cycle 6 only, or if clinically indicated), 
the results will be summarized using the mean of the three measurements. 
10.7 
Efficacy Analyses  
The efficacy analysis will be performed using the efficacy evaluable analysis set, with the 
exception of DOR. The analyses of DOR will be conducted on the subset of the efficacy 
evaluable analysis set who achieve CR or PR as their best overall response. 
10.7.1 
Overall Response Rate and Complete Response Rate 
The ORR is defined as the rate of subjects who achieve either a PR or CR, according to 
the revised response criteria for malignant lymphoma (Cheson et al. 2014), as assessed 
by investigators, before receiving any other anticancer therapy. The corresponding 95% 
two-sided CIs with use of the exact binomial distribution will be calculated for ORR and 
CR rate. 
10.7.2 
Progression-Free Survival 
PFS is defined as the time from first dose date to documented disease progression or 
death from any cause, whichever occurs first. Disease progression is determined by the 
investigators according to the revised response criteria for malignant lymphoma (Cheson 


 
 
 
 
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et al. 2014). Kaplan-Meier methods will be used to estimate the event-free curves and 
corresponding quantiles (including the median).   
Data from surviving, non-progressing subjects will be censored at the date of the last 
adequate disease assessment that is on or before the start date of subsequent therapy. 
Data from subjects who have disease progression or die after more than one missed 
visit will be censored at the last visit date prior to the missing assessments that lack 
objective disease assessment. The details of definition of progression events and 
censoring rules are listed in Section 14.1. 
Study treatment end date will be used as the date of progression for subjects who 
discontinued study treatment due to disease progression or death prior to their first 
disease assessment. Data for subjects who discontinued study treatment prior to their 
first disease assessment due to reasons other than disease progression or death will be 
censored at their study treatment start date.  
10.7.3 
Duration of Response 
DOR is defined as the time from the first objective response of CR or PR to the time of 
documented disease progression or death due to any cause, whichever occurs first. 
Kaplan-Meier methods will be used if appropriate to estimate the event-free curves and 
corresponding quantiles (including the median).  In case of very limited number of 
responders, the listing with duration of response and indicator of censoring might be 
used. 
Data from surviving, non-progressing subjects will be censored at the date of the last 
adequate disease assessment that is on or before the start date of subsequent therapy. 
Data from subjects who have disease progression or die after more than one missed 
visit will be censored at the last visit date before the missing assessments that lack 
objective disease assessment. The details of definition of progression events and 
censoring rules are the same as for PFS endpoint and are listed in Section 14.1. 
10.7.4 
Durable Response Rate 
The DRR is defined as the percentage of subjects who have a CR or PR lasting ≥8 
weeks. This measure was intended mainly for study Part 2 of the analysis and will not be 
summarized since study was terminated at Part 1. 


 
 
 
 
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10.7.5 
Overall Survival 
Overall survival is defined as the time from treatment start date until date of death due to 
any cause. Since we are closing the study early, subjects will not be followed for survival 
after the last subject last visit for Part 1. Subjects who are known to be alive or whose 
survival status is unknown will be censored at the date last known to be alive. Kaplan-
Meier methods will be used to estimate the survival curves and corresponding quantiles 
(including the median).  Censoring rules are defined in more detail in Section 14.2. 
10.8 
Pharmacokinetic Analyses 
A separate PK and/or PD analysis plan will be provided since those analyses will be 
performed by the vendor. 
11. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES  
The changes from protocol-specified analyses due to early closeout of the study at Part 
1 as follows:  
• 
Part 2 of the study was not conducted. 
• 
The planned primary analysis as described in the protocol (after all ongoing 
subjects have had the opportunity to complete at least 3 scheduled post-baseline 
scans) is the final analysis. 
• 
Subjects will not be followed for survival after the last subject last visit for Part 1. 
• 
The DRR analysis was intended for Part 2 of the study and will not be 
summarized. 
12. 
LITERATURE CITATIONS/REFERENCES 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol 2014;32:3059-3067. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, USDHHS, NIH, 
NCI; publish date November 27, 2017. 
13. 
APPENDICES  
13.1 
Definitions 
Study Day 
The study day will be calculated in reference to the first dose date of study drug. Study 
Day 1 is defined as the first dose date of study drug. For assessments that occur on or 


 
 
 
 
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after the first dose date of study drug, study day is defined as (date of assessment – 
first dose date of study drug + 1). For assessments that occur prior to the first dose 
date of study drug, study day is defined as (date of assessment – first dose date of 
study drug). There is no Study Day 0. 
 
Duration of Exposure 
The duration of exposure to acalabrutinib or vistusertib will be calculated in months as 
(last dose date - first dose date + 1) / 30.4375. The gaps in treatment will be included. 
The duration of exposure in days will be used for planned dose calculation. 
 
Total Dose   
Total dose received is a sum of all actual doses taken through the treatment duration 
and will be presented in grams. For scheduled drug administration visits that are 
skipped, the actual dose will be 0. 
 
Average Daily Dose (Acalabrutinib)   
Average daily dose is total dose divided by duration of exposure in days. 
 
Average Weekly Dose (Vistusertib)   
Average weekly dose is total dose divided by number of weeks for vistusertib study 
treatment. 
 
Relative Dose Intensity 
Relative dose intensity is the ratio of total dose to the protocol-specified total dose 
through the duration of exposure. 
 
13.2 
Imputation Rules for Partial or Missing Dates 
Imputation of partial dates will be made for AE onset and stop dates, start and end dates 
of concomitant medication, start date of subsequent anticancer therapy, date of initial 
diagnosis, and death date. If dates are completely missing, no imputation will be made. 
For any partial date with missing year, no imputation will be made. 
 
The general rule for imputation is: 
• 
If only day is missing, then the 15th of the month will be used. 
• 
If only year is present, then June 30th will be used. 


 
 
 
 
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If such imputation date for initial diagnosis is on or after date of first dose, then date of 
first dose – 1 will be used. If such imputed date for subsequent anticancer therapies is 
before date of last dose, then date of last dose + 1 will be used.  
If the imputed date is for an AE start date and is in the same year and month but before 
the first dose date, then the first dose date will be used; if the imputed AE start date is 
after the AE end date, then the AE end date will be used. If the imputed date is for an AE 
start date and is in the same year and month but after the last dose date + 30 days, then 
the last dose date + 30 days will be used.  
If the imputed date is for an AE end date and is after the death date, then the death date 
will be used; if the imputed AE end date is before the AE start date, then the AE start 
date will be used. 
Every effort will be made to obtain complete dates for deaths. If both month and day are 
missing for death date or a death date is totally missing, it will not be imputed; the 
subject survival time will be censored. If death year and month are available but day is 
missing, the following algorithm will be used: 
• 
If mmyyyy for last contact date = mmyyyy for death date, set death date to the 
day after the last contact date. 
• 
If mmyyyy for last contact date < mmyyyy for death date, set death date to the 
first day of the death month. 
• 
If mmyyyy for last contact date > mmyyyy for death date, data error and do not 
impute. 
14. 
DETAILED CENSORING RULES FOR EFFICACY ENDPOINTS  
14.1 
PFS Events and Censoring Rules 
 
Situation 
PFS 
Date of Progression or 
Censoring 
Outcome 
Progression documented on 
scheduled visit 
Date of scheduled visit  
Progression 
Progression documented 
between scheduled visits  
Date of unscheduled visit  
Progression 
Treatment discontinuation 
for undocumented 
progression  
Date of last visit with adequate 
assessment  
Censor 
Death before first PD 
assessment  
Date of death  
Progression 


 
 
 
 
Acerta Pharma 
Confidential 
Page 19  
 
Death between adequate 
assessment visits  
Date of death  
Progression 
Death or progression after 
only one missed visit 
Date of death  
Progression 
Death or progression after 2 
or more missed visits  
Date of last visit with adequate 
assessment  
Censor 
Death or progression after 2 
or more missed visits and 
only baseline disease 
assessment available 
Date of 1st dose of study drug 
Censor 
No baseline disease 
assessments  
Date of 1st dose of study drug  
Censor 
Baseline disease 
assessments only and no 
evidence of documented PD, 
treatment discontinuation 
due to PD or death within no 
more than one missed visit 
Date of 1st dose of study drug  
Censor 
No progression  
Date of last visit with adequate 
assessment  
Censor 
Treatment discontinuation 
for toxicity or other reason  
Date of last visit with adequate 
assessment  
Censor 
Subsequent anticancer 
treatment started  
Date of last visit with adequate 
assessment  
Censor 
 
14.2 
Overall Survival Censoring Rules 
Situation 
Date Death or Censoring 
Outcome 
Death at any timepoint 
Date of death 
Death 
Lost to follow-up immediately after 1st 
dose of study drug 
Date of 1st dose study drug 
Censored 
Not known to have died at or after the 
analysis cutoff date 
The date last known alive before data 
analysis cutoff 
Censored 
Known to have died after the analysis 
cutoff date 
Date of data analysis cutoff 
Censored