Clinical trial NCT03366103
Conditions: Metastatic Malignant Solid Neoplasm Recurrent Lung Small Cell Carcinoma Recurrent Malignant Solid Neoplasm Refractory Malignant Solid Neoplasm Stage III Lung Small Cell Carcinoma, by American Joint Committee on Cancer (AJCC) v7 Stage IIIA Lung Small Cell Carcinoma AJCC v7 Stage IIIB Lung Small Cell Carcinoma AJCC v7 Stage IV Lung Small Cell Carcinoma AJCC v7 Unresectable Solid Neoplasm
Sponsor: National Cancer Institute (NCI)
Start date: 2018-03-20; Completion date: 2022-09-21
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the best dose and side effects of navitoclax and how well it works when given together with vistusertib in treating patients with small cell lung cancer and solid tumors that have come back (relapsed). Drugs used in chemotherapy, such as navitoclax, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Vistusertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving navitoclax and vistusertib may work better than navitoclax alone in treating patients with small cell lung cancer and solid tumors.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of the combination of navitoclax and vistusertib in patients with advanced solid tumors. (Phase I) II. To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and recommended phase 2 doses (RP2D) of navitoclax and vistusertib. (Phase I) III. To determine the objective response rate (ORR), defined as complete plus partial response, of the combination of navitoclax and vistusertib in patients with recurrent small cell lung cancer (SCLC). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of navitoclax and vistusertib when administered together. (Phase I) II. To observe and record anti-tumor activity. (Phase I) III. To confirm the safety and tolerability of navitoclax and vistusertib at the RP2D. (Phase II) IV. To estimate progression free survival (PFS) and overall survival (OS) of the combination of navitoclax and vistusertib at the RP2D. (Phase II) V. To estimate disease control rate (DCR) of the combination of navitoclax and vistusertib at the RP2D. (Phase II)

CORRELATIVE OBJECTIVES:

I. To assess pharmacodynamic changes in levels of phosphorylated 4EBP1 (p4EBP1) the ratio of p4EBP1 to total (p4EBP1/4EBP1) in paired pre-treatment and on-treatment biopsies at the RP2D. (Phase II) II. To correlate changes in BAX and MCL-1 with response. (Phase II) III. To estimate the baseline inter-patient variability in p4EBP1, pS6, BAX, and MCL-1. (Phase II) IV. To explore exposure-response relationships between navitoclax and vistusertib exposure and the pharmacodynamic endpoints (safety, efficacy, and laboratory correlatives). (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive navitoclax orally (PO) once daily (QD) and vistusertib PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 8-12 weeks for up to 2 years.

Arms: arm 1: Patients receive navitoclax PO QD and vistusertib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Navitoclax intervention 2: Vistusertib
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
NCI Protocol #:10070 
Version Date: 02/25/2021 
 
i 
 
DATE: 
February 25, 2021 
 
TO:  
CTEP Protocol and Information Office 
 
FROM:  
, MD 
 
SUBJECT: 
Amendment in response to review of amendment 13 comments for the 
request for amendment (RA) from Dr. 
, NCI, dated February 
1, 2021 and eligibility correction. 
 
 
SUMMARY OF CHANGES – Protocol 
 
I. Comments Requiring a Response – Major Issues including Administrative & Editorial Issues: 
# 
Section 
Comments 
1. 
3.1.3.4 
Please make the correction in proteinuria lab range from < to ≤ 1+ as 
recommended per SOC#3.    
PI Response: This correction has been made. 
2. 
8.1 
Please update navitoclax (ABT-263) pharmaceutical information as follow: 
Mode of Action: Navitoclax disrupts the interactions between antiapoptotic Bcl
2 family proteins and their counterparts. Navitoclax induces cancer apoptosis by 
inhibiting the antiapoptotic Bcl 2 family proteins Bcl XL, Bcl 2, Bcl w, and 
Bcl B. Navitoclax is an orally bioavailable BCL-2 family protein inhibitor that 
binds with high affinity to multiple antiapoptotic proteins including BCL-XL, BCL-
2, and BCL-W.  Antiapoptotic BCL-2 family members are associated with tumor 
initiation, disease progression, and drug resistance, and compelling targets for 
oncology drug development.  
 
Description: White to off white light pink powder 
 
How Supplies: 
Abbot Laboratories AbbVie supplies and the DCTD/NCI distributes navitoclax 
as 25 mg and 100 mg film coated tablets packaged in 28-Count and 30-Count 
high-density polyethylene (HDPE) bottles, respectively. 
 
Note: Navitoclax must be dispensed in its original bottle. If need to dispense the 
exact count to patient, removing extra tablet(s) from the original bottle is 
allowed. Document the extra tablet(s) as wasted in Oral DARF.  
 
Navitoclax inactive ingredients: Copovidone, Vitamin E polyethylene glycol 
succinate, colloidal silicon dioxide, croscarmellose sodium, sodium stearyl 
fumarate (coating, 25 mg: iron oxide red E172  or iron oxide yellow, polyvinyl 


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# 
Section 
Comments 
alcohol, polyethylene glycol 3350, talc, titanium dioxide; and 100 mg: iron 
oxide yellow E172 or oxide red, polyvinyl alcohol, polyethylene glycol 3350, 
talc, titanium dioxide). 
 
Approximate Solubility: Navitoclax free base is practically insoluble in water. 
and freely soluble in Phosal 53 MCT with 10 % ethanol. 
 
Patient Care Implications: Thrombocytopenia has been the primary dose
limiting toxicity in the clinical development of navitoclax. Patients must be 
careful when taking herbal products or over-the counter (57) drugs especially, 
OTC drugs that treat multisymptoms such as for cough & cold. These 
medications may contain aspirin or ibuprofen, which may affect platelets 
function 
For trials using single agent navitoclax, female patients of childbearing potential 
must agree to use highly effective methods of contraception throughout the study 
and for 30 days after the last dose of study treatment. For clinical studies with 
navitoclax in combination, use of contraception may be longer and male subjects 
may need to use contraceptive methods. 
 
It is unknown whether navitoclax is excreted in human milk; thus, breastfeeding 
is not allowed. 
PI Response: These corrections have been made. 
 
II. Request for Amendment 
 
# 
Section 
Comments 
1. 
Header, 
Title Page 
Updated protocol version date. 
2. 
7.1 
Updated Navitoclax CAEPR to Version 2.5, January 4, 2021, with the following 
changes: 
• 
Added New Risk:  
• 
Also Reported on Navitoclax Trials But With Insufficient Evidence for 
Attribution: Abdominal distension; Cardiac arrest; Chest wall pain; 
Disease progression; Edema trunk; Enterocolitis; Gastrointestinal 
disorders - Other (laryngeal hemorrhage); Gastrointestinal disorders - 
Other (pneumatosis coli); Generalized muscle weakness; Hemoglobin 
increased; Hyperkalemia; Hyperuricemia; Investigations - Other 
(elevated LFTs); Malaise; muscle weakness; Pancreatitis; Stroke; 
Syncope; Weight gain 
 
 
 


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• 
Increase in Risk Attribution: 
• 
Changed to Less Likely from Also Reported on Navitoclax Trials But 
With Insufficient Evidence for Attribution: Lymphocyte count 
decreased 
 
• 
Decreased in Risk Attribution:  
• 
Changed Also Reported on Navitoclax Trials But With Insufficient 
Evidence for Attribution from Less Likely: Abdominal pain; Anemia; 
Constipation; Dyspepsia; Electrocardiogram QT corrected interval 
prolonged; Flatulence; Headache; Hypokalemia; White blood cell 
decreased 
 
 
III. Changes requested by the PI 
 
# 
Section 
Comments 
3. 
3.1.3.4 
Corrected the typo for proteinuria from < to ≤ 1+ based on the investigator 
brochure for vistusertib. 
 
 
SUMMARY OF CHANGES – Consent Form 
 
# 
Section 
Comments 
1. 
Header 
Updated protocol version date. 
2. 
Possible Side 
Effects of 
Navitoclax 
Changes to the drug risks of Navitoclax: 
• 
Decreased in Risk Attribution:  
• 
Changed to Rare from Occasional: Infection, especially when white 
blood cell count is low 
• 
Changed to Also Reported on Navitoclax Trials But With Insufficient 
Evidence for Attribution from Occasional (i.e. removed from the 
Risk Profile): Anemia which may require blood transfusion; Belly 
pain, Constipation; Heartburn; Passing gas; Change in heart rhythm; 
Headache 


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NCI Protocol #: 10070 
 
Local Protocol #: ETCTN10070 
 
ClinicalTrials.gov Identifier:  NCT03366103 
 
TITLE:   Phase 1/2 study of navitoclax plus vistusertib in patients with relapsed small cell lung 
cancer (SCLC) and other solid tumors 
 
Phase 1 closed to accrual: 12/19/19 
Now Open for Phase 2  
 
Corresponding Organization: LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center LAO 
 
Principal Investigator: 
, MD, PhD 
 
Johns Hopkins University 
 
Viragh Building, 
 
 
201 N. Broadway 
 
Baltimore, MD 21287 
 
 
 
Participating Organizations (Phase 1) 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
 
Participating Organizations (Phase 2) 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
 
 
 




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SCHEMA 
This is a single-arm, open label, Phase 1/2 study of navitoclax plus vistusertib in patients with 
recurrent SCLC and other solid tumors. The phase 1 portion of the study is a dose escalation in 
patients with all solid tumors.  All patients will receive navitoclax in combination with 
vistusertib daily.  
 
Dose Escalation Schedule 
Dose Level 
Dose 
Navitoclax*  
by mouth, once a day 
Vistusertib 
by mouth, twice a day 
Level -1 
150 mg 
25 mg 
Level 1      
150 mg 
35 mg 
Level 2 
250 mg 
35 mg 
Level 3 
325 mg 
35 mg 
Level 4 
325 mg 
50 mg 
* To reduce the incidence of significant thrombocytopenia, all patients will receive a 7 day lead-in 
dosing of navitoclax 150mg po once a day prior to C1D1. At any time after 7 days of  navitoclax, if 
the platelet count is >50,000 and stable or increasing,  subjects can dose escalate to the navitoclax 
dose defined in the cohort level and start vistusertib. Cycle 1 day 1 is defined as the first day both 
study drugs are taken. 
 
The phase 2 portion of this study is now open and includes patients with recurrent small cell lung 
cancer only. Patients will receive navitoclax plus vistusertib at the RP2D established in the dose 
escalation portion of the study. The RP2D determined from the Phase 1 portion was Level 1: 
navitoclax 150 mg by mouth once a day plus vistusertib 35 mg by mouth twice a day. 
 
Mandatory biopsies and blood samples will be collected for correlative studies. Approximately 
37 patients will be enrolled in the phase 2 portion of this study. 
 
 
Phase 2 Dose 
Navitoclax*  
by mouth, once a day 
Vistusertib 
by mouth, twice a day 
150 mg 
35 mg 
* To reduce the incidence of significant thrombocytopenia, all patients will receive a 7 day lead-in 
dosing of navitoclax 150 mg po once a day prior to C1D1. At any time after 7 days of navitoclax, 
if the platelet count is > 50,000 and stable or increasing, subjects can dose escalate to the 
navitoclax dose defined in the cohort level and start vistusertib. Cycle 1 day 1 is defined as the first 
day both study drugs are taken. 
 
Per the drug manufacturer AstraZeneca, clinical supply of Vistusertib (AZD2014) will expire on 
August 31, 2021 (based on the planned expiration date extension), and there will be no additional 
drug available for clinical use after that date.  All patients must complete their last treatment on 


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or before August 31, 2021, and the study will be closed to accrual and treatment to coincide with 
this expiration date.


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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Phase 1 .....................................................................................................................7 
1.2 
Phase 2 .....................................................................................................................7 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Small Cell Lung Cancer ...........................................................................................9 
2.2 
CTEP IND Agent (Navitoclax) ..............................................................................12 
2.3 
Other Agent (Vistusertib) ......................................................................................20 
2.4 
Correlative Studies Background ............................................................................27 
3. 
PATIENT SELECTION ....................................................................................................30 
3.1 
Eligibility Criteria ..................................................................................................30 
3.2 
Exclusion Criteria ..................................................................................................32 
3.3 
Inclusion of Women and Minorities ......................................................................34 
4. 
REGISTRATION PROCEDURES ...................................................................................35 
4.1 
Investigator and Research Associate Registration with CTEP ..............................35 
4.2 
Site Registration .....................................................................................................36 
4.3 
Patient Registration ................................................................................................38 
4.4 
General Guidelines.................................................................................................39 
5. 
TREATMENT PLAN ........................................................................................................40 
5.1 
Agent Administration.............................................................................................40 
5.2 
Dose Escalation and Definition of Dose-Limiting Toxicity ..................................42 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................43 
5.4 
Duration of Therapy ...............................................................................................46 
5.5 
Duration of Follow Up ...........................................................................................46 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................47 
6.1 
Phase 1 ...................................................................................................................47 
6.2 
Phase 2 ...................................................................................................................51 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................55 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................55 
7.2 
Adverse Event Characteristics ...............................................................................59 
7.3 
Expedited Adverse Event Reporting ......................................................................59 
7.4 
Routine Adverse Event Reporting .........................................................................61 
7.5 
Secondary Malignancy...........................................................................................62 
7.6 
Second Malignancy ................................................................................................62 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................63 


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8.1 
CTEP IND Agents .................................................................................................63 
8.2 
Agent Ordering, Accountability and Investigator Brochure Availability ..............65 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................67 
9.1 
Overview ................................................................................................................67 
9.2 
Integrated Correlative Studies................................................................................68 
9.3 
Exploratory/Ancillary Correlative Studies ............................................................74 
10. 
STUDY CALENDAR .......................................................................................................76 
11. 
MEASUREMENT OF EFFECT........................................................................................81 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................81 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................88 
12.1 
Study Oversight .....................................................................................................88 
12.2 
Data Reporting .......................................................................................................88 
12.3 
CTEP Multicenter Guidelines ................................................................................91 
12.4 
Collaborative Agreements Language .....................................................................91 
13. 
STATISTICAL CONSIDERATIONS...............................................................................94 
13.1 
Study Design/Endpoints.........................................................................................94 
13.2 
Sample Size/Accrual Rate ......................................................................................95 
13.3 
Analysis Populations ..............................................................................................96 
13.4 
Analysis of Primary Endpoints ..............................................................................97 
13.5 
Analysis of Secondary Endpoints ..........................................................................97 
13.6 
Safety monitoring and early stopping rules for safety .........................................100 
13.7 
Analysis of Correlative Endpoints .......................................................................100 
13.8 
Reporting and Exclusions ....................................................................................101 
APPENDIX A. PERFORMANCE STATUS CRITERIA ...........................................................107 
APPENDIX B. PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD ..............................................................................................................................108 
APPENDIX C. Drug Diary for Navitoclax Lead-in Dosing........................................................110 
APPENDIX D. Drug Administration Diary for Navitoclax and Vistusertib ...............................111 
 
 
 


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1. OBJECTIVES 
 
1.1 
Phase 1  
 
1.1.1 Primary Objectives 
 
1.1.1.1 
To evaluate the safety and tolerability of the combination of navitoclax 
and vistusertib in patients with advanced solid tumors 
1.1.1.2 
To determine the maximum tolerated dose (MTD), dose limiting 
toxicities (DLT), and recommended phase 2 doses (RP2D) of 
navitoclax and vistusertib 
 
1.1.2 Secondary Objectives 
 
1.1.2.1 
To evaluate the pharmacokinetics of navitoclax and vistusertib when 
administered together 
1.1.2.2 
To observe and record anti-tumor activity.  Although the clinical 
benefit of these drugs has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit, and 
thus the patient will be carefully monitored for tumor response and 
symptom relief in addition to safety and tolerability. 
 
1.2 
Phase 2  
 
1.2.1 Primary Objective 
 
1.2.1.1 
To determine the objective response rate (ORR), defined as complete 
plus partial response, of the combination of navitoclax and vistusertib 
in patients with recurrent SCLC 
 
1.2.2 Secondary Objectives 
 
1.2.2.1 
To confirm the safety and tolerability of navitoclax and vistusertib at 
the RP2D  
1.2.2.2 
To estimate progression free survival (PFS) and overall survival (OS) 
of the combination of navitoclax and vistusertib at the RP2D 
1.2.2.3 
To estimate disease control rate (DCR) of the combination of 
navitoclax and vistusertib at the RP2D. The DCR is defined as the sum 
of CR, PR, and SD divided by the total number of patients in the phase 
2 part of the study. 
 
1.2.3 Correlative Objectives 
 
1.2.3.1 
To assess pharmacodynamic changes in levels of phosphorylated 
4EBP1 (p4EBP1) the ratio of p4EBP1 to total (p4EBP1/4EBP1) in 
paired pre-treatment and on-treatment biopsies at the RP2D 


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1.2.3.2 
To correlate changes in BAX and MCL-1 with response 
1.2.3.3 
To estimate the baseline inter-patient variability in p4EBP1, pS6, 
BAX, and MCL-1. 
1.2.3.4 
To explore exposure-response relationships between navitoclax and 
vistusertib exposure and the pharmacodynamic endpoints (safety, 
efficacy, and laboratory correlatives). 
 
 
 


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2. BACKGROUND 
 
2.1 
Small Cell Lung Cancer 
 
Small cell lung cancer (SCLC) represents 15% of all lung cancers and accounts for nearly 
30,000 deaths in the US annually (2). Etoposide plus cisplatin was established as the 
standard of care for SCLC in the 1980s and can confer high response rates as initial 
therapy (3). Recurrence and death, however, is nearly universal; the overall survival of 
patients diagnosed with advanced SCLC is 8-10 months, a statistic that has not changed 
significantly in over 30 years (4). New therapies are critically needed.  
 
2.1.1 BCL-2 inhibition in SCLC 
 
Over-expression of the anti-apoptotic protein, BCL-2, is observed in > 60% of SCLC 
cases and correlates with therapy resistance (5, 6). ABT-737 and its orally bioavailable 
derivative, navitoclax, are high affinity BH3 mimetics that bind to BCL-2, BCL-xL and 
BCL-w (but spare MCL-1) and displace proteins bound to the BH3 domains of these anti-
apoptotic proteins. We and others have demonstrated that ABT-737 can induce dramatic 
responses in BCL-2 expressing SCLC cell lines in vitro and in vivo (7, 8). In phase I/II 
clinical trials, however, navitoclax, had only limited single-agent activity in patients with 
relapsed SCLC (9, 10) and was difficult to combine with cytotoxic chemotherapy due to 
myelosuppression. The dose limiting toxicity of navitoclax was thrombocytopenia due to 
on-target inhibition of BCL-xL in circulating platelets (11), which could be attenuated by 
graduated lead-in dosing (9).  
 
2.1.2 Combined BCL-2 and mTOR inhibition in SCLC PDX models 
 
There is increasing evidence that co-targeting survival and growth pathways is effective 
in multiple tumor types. Combinatorial activity of PI3K/AKT/mTOR and BCL-2 
inhibitors has been demonstrated preclinically in several tumor types including 
lymphoma, leukemia, breast cancer and SCLC (12-16). In two recent manuscripts we 
have reported that the combination of BCL-2/BCL-xL inhibitors, ABT-737 or navitoclax, 
with mTOR inhibitors led to potent induction of cell death and tumor regression in 
multiple preclinical in vivo models of SCLC including cell line xenografts, patient-
derived xenografts (PDXs) and a genetically engineered mouse model (GEMM) (15, 16).   
 
Gardner et al., modeled ABT-737 resistance in SCLC PDXs and demonstrated that the 
mTOR inhibitor, rapamycin, can enhance ABT-737 activity in BCL-2 expressing SCLC 
models (15). In this study, several PI3K/mTOR inhibitors, including rapamycin, 
everolimus and AZD8055, were synergistic with ABT-737 in SCLC cell lines in vitro.  
Furthermore, rapamycin enhanced ABT-737 cytotoxicity in vivo resulting in rapid and 
durable tumor regressions in BCL-2 expressing PDXs derived from patients with 
chemotherapy-naïve (LX47, Fig. 1A) and recurrent (LX48, Fig. 1B) SCLC. In contrast, 
in a BCL-2 low PDX (LX33) treatment with rapamycin resulted in tumor growth 
inhibition (15); ABT-737 did not add significantly to the effect of rapamycin (Fig. 1C).  








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to anti-apoptotic proteins is associated with cell survival (28-30). 
 
In contrast to other known oncogenes, Bcl-2 does not stimulate cellular proliferation, but 
rather inhibits programmed cell death by protecting cells from a wide variety of pro-
apoptotic stimuli, including cytokine withdrawal, irradiation, cytotoxic drugs, heat, and 
deregulated oncogenes (31).  Anti-apoptotic Bcl-2 family members are associated with 
tumor initiation, disease progression, and drug resistance, and are therefore compelling 
targets for antitumor therapy.  Overexpression of certain anti-apoptotic Bcl-2 proteins is 
associated with increased tumor resistance to chemotherapy; thus, inhibition of these 
proteins might enhance response to such therapies and overcome resistance. 
 
2.2.1.1 
Nonclinical Efficacy Studies 
 
Preclinical models of therapy-resistant lymphoma support the biologic relevance of 
the Bcl-2 family of proteins in the pathogenesis of B-cell lymphomas.  In three flank 
models of B-cell lymphoma (DoHH-2, WSU-DLCL2, and GRANTA-519) known to 
express high levels of Bcl-2, significant monotherapy activity was noted when 
navitoclax was administered at an oral dose of 100 mg/kg/day, once daily (QD) × 17 
days (ABT-263 Investigator’s Brochure, 2011).  Tumor growth inhibition in these 
models ranged from 40% to 54% as compared to vehicle treated controls.  The WSU-
DLCL2 line had been isolated from a patient whose disease progressed following 
chemotherapy, radiation therapy, and bone marrow transplantation, and is reputed to 
be a model of therapy-resistant lymphoma.   
 
Navitoclax has been tested in vitro against 68 cell lines spanning diverse tumor types 
and was found to display potent (concentration achieving 50% effect [EC50] <1 μM) 
single-agent activity against small cell lung cancer (SCLC), follicular lymphoma, and 
leukemia-derived cell lines (ABT-263 Investigator’s Brochure, 2011).  These 
included 10 of 22 cell lines representing multiple leukemia and lymphoma types 
spanning both B-cell and T-cell malignancies, and 7 of 22 SCLC cell lines.  In a panel 
(n=23) of cell lines examined by the Pediatric Preclinical Testing Program (PPTP), 
IC50 values of <1 μM were observed in 9 cell lines, including 3 acute lymphoblastic 
leukemia (ALL), 2 rhabdomyosarcoma, and 1 Ewing’s sarcoma cell line (32).  In 
addition, strong synergism was observed with DNA-damaging and antimitotic agents 
across multiple cell lines and tumor types (ABT-263 Investigator’s Brochure, 2011).   
 
Strong synergism with DNA-damaging agents (etoposide, carboplatin) as well as with 
the proteasome inhibitor bortezomib was observed in the A549 non-small cell lung 
cancer (NSCLC) cell line.  Interestingly, in some cases, the degree of synergism was 
dependent on the ratio of the two compounds.  For example, the synergism between 
navitoclax and carboplatin increased as the ratio of navitoclax to carboplatin 
decreased. 
 
To assess the ability of navitoclax to directly induce apoptosis, the time course of 
caspase-3 activation was monitored in H146 cells as a function of navitoclax 
concentration (ABT-263 Investigator’s Brochure, 2011).  Navitoclax induced a 


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concentration-dependent increase in caspase-3 activation with an EC50 of 
approximately 100 nM.  Caspase-3 activity is rapidly induced in response to 
navitoclax treatment with near maximum activity by 6 hours.  This is consistent with 
the time course for which cytotoxicity is observed in this cell line.  Other apoptotic 
markers (cytochrome c release, phosphatidylserine externalization) were elevated in a 
navitoclax-dose-dependent manner, further supporting the hypothesis that navitoclax 
induces apoptosis, likely mediated through Bcl-2 family proteins. 
 
Navitoclax was found to be active in 8 of 9 xenograft models of established SCLC, in 
which tumors were allowed to grow to an average volume of 200 to 250 mm3 prior to 
initiation of therapy (ABT-263 Investigator’s Brochure, 2011).  When delivered at a 
dose of 100 mg/kg/day orally (PO) for 21 consecutive days, navitoclax exhibited 
highly significant activity in 3 models (H1963, H889, and H146).  Complete tumor 
regression was observed in half of the mice bearing H146 tumors and all of the mice 
bearing either H889 or H1963 tumors.  Significant antitumor activity, including 
partial responses (PRs; ≥50% shrinkage), was observed in an additional 5 models 
(H1417, H128, H211, H510, and H345).  Using the same dose and schedule, 
navitoclax was also active against larger (440 mm3), more vascular H146 tumors, 
inducing complete tumor regression in 3 of 10 mice and 1 confirmed tumor cure. 
 
In panels of murine tumor xenograft models examined by the PPTP, single-agent 
navitoclax prolonged the event-free survival (33) period in 5 of 6 ALL models as well 
as in 9 of 35 solid tumor xenograft models examined (32).  Complete responses (CRs) 
were seen in a B-precursor ALL xenograft and in both T-cell xenografts.  Solid 
tumors that showed improved EFS included 2 of 5 rhabdomyosarcoma, 2 of 5 
osteosarcoma, 2 of 6 neuroblastoma, 1 of 5 Ewing sarcoma, and 1 of 3 Wilms’ tumor 
models, as well as the only ependymoma model tested. 
 
Efficacious doses of navitoclax were determined from dose-response studies in the 
H146 SCLC flank tumor model after daily (Days 1-21) PO dosing of navitoclax.  A 
dose of 50 mg/kg/day elicited tumor regression in 6 of 9 mice (2 CRs, 4 PRs) and was 
defined as the minimally efficacious dose.  A dose of 100 mg/kg/day induced a high 
percentage of complete tumor regressions and was identified as the target dose.  At 
the 200 and 300 mg/kg/day doses, 20% of the mice were cured, as no tumor was 
evident by histopathological examination at 125 days after inoculation.  Plasma and 
tissue drug concentrations were determined following multiple (n = 3) QD PO dosing 
in the same strain of mouse utilized in the efficacy study.  From this study, the 
minimally efficacious plasma exposure for navitoclax in mice, as expressed by area 
under the concentration-time curve (AUC), was 53 μg•hr/mL, and the target AUC 
was 88 μg•hr/mL.  Based on these data and on PK modeling, the predicted efficacious 
plasma exposure in humans is a maximum plasma concentration (Cmax) of 6.5 μg/mL. 
 
2.2.1.2 
Nonclinical Toxicology  
 
The primary effects of navitoclax on the hematopoietic systems of both rats and dogs 
were decreased circulating platelets and lymphocytes (ABT-263 Investigator’s 


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Brochure, 2011).  These effects were dose-dependent and reversible, as were any 
effects secondary to platelet depletion.  The decreased circulating lymphocytes 
consisted of CD4 and CD8 T cells in rats and dogs, with a primary effect seen on B 
cells in dogs.  Other observed hematopoietic effects included reversible decreases in 
total white blood cell count and eosinophil count, primarily in the rat. 
 
Macroscopic and microscopic changes indicative of lymphoid depletion occurred in 
lymphoid tissues at ≥30 mg/kg/day in rats and at ≥3 mg/kg/day in dogs, and were 
consistent with reductions in circulating lymphocytes (ABT-263 Investigator’s 
Brochure, 2011).  Affected lymphoid organs included lymph nodes and spleen (rats 
and dogs), thymus (rats only), and Peyer's patch (dogs only).  Partial to complete 
reversibility of all effects on lymphoid tissue was noted. 
 
Navitoclax had no clear adverse CNS effects in the rat and mouse at an 
intraperitoneally (IP) injected dose of 5 mg/kg (ABT-263 Investigator’s Brochure, 
2011).  At doses of 10 mg/kg IP and higher, mild to moderate sedation occurred and 
latency to sleep increased after barbital injection.  At doses of 25 mg/kg IP and 
higher, body temperature decreased as sedation became more pronounced.  At 100 
mg/kg IP, loss of traction was observed.  Navitoclax produced no relevant effects on 
neurobehavioral function through the highest dose of 15 mg/kg (plasma 
concentrations of 137.9 ± 27.5 μg/mL). 
 
Navitoclax does not pose a genotoxic risk, as it was negative in all genetic toxicity 
studies, and no effect on embryo-fetal development in rats or rabbits was observed 
(ABT-263 Investigator’s Brochure, 2011). 
 
In the Segment I male rat fertility study, navitoclax-related changes were limited to 
small and/or soft testes, decreased testis and epididymis weights, 
hypospermatogenesis, and reduced sperm motility and sperm counts at 30 mg/kg/day 
(top dose) following approximately 70 days of once daily oral dosing (ABT-263  
 
Investigator’s Brochure, 2011).  In addition, time- and dose-dependent navitoclax-
related effects were observed on the rat ovary.  Ovarian atrophy (associated with 
~58% decreased ovarian weights) was observed at the highest dose of 100 mg/kg in 
the 6-month study, characterized by reduction or absence or corpora lutea and 
reduction in number of developing follicles.  Decreases in ovarian weights (up to 
~29%) were observed at the lower doses in the 6-month study and in the shorter 
duration studies of 2 and 13 weeks in duration.  These weight changes were 
considered not to be adverse due to the absence of associated histopathologic 
findings.  However, no effect on reproductive performance was observed in male or 
female rats.  No impairment of fertility was observed in the female rat Segment I 
study at up to 100 mg/kg/day (high dose).  In Segment II embryo-fetal development 
studies, once daily oral doses of navitoclax in time-mated female rats (high dose, 100 
mg/kg/day) and rabbits (high dose, 200 mg/kg/day) were not teratogenic and did not 
have any effect on the embryo/fetal viability of offspring.   
 


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2.2.1.3 
Clinical Safety Profile 
 
Navitoclax is being investigated as a single agent and as a component of combination 
therapy.  Trial M10-454, a biocomparison study, is fully enrolled.  Additionally, three 
phase 1/2a studies have completed and published safety and tolerability data from the 
phase 1 dose-escalation portions of the studies, and have transitioned to the phase 2a 
portions of the study: 
 
• M06-814, in patients with relapsed or refractory lymphoid malignancies (34).   
• M06-822, in patients with small-cell lung cancer (SCLC), pulmonary 
carcinoid, and other solid tumors (phase 1), and in patients with SCLC (phase 
2a) (9, 10).   
• M06-873, in patients with relapsed or refractory chronic lymphocytic 
leukemia (CLL) (35). 
 
Thrombocytopenia has been the primary dose-limiting toxicity (DLT) in the clinical 
development of navitoclax.  This has been observed nonclinically and is thought to be 
due to the pharmacodynamic effect of drug action (inhibition of the platelet-expressed 
homolog Bcl-XL, leading to apoptosis) (ABT-263 Investigator’s Brochure, 2011).  
Grade 3/4 thrombocytopenia was observed in 29 out of 55 patients in trial M06-814 
(34); 5 out of 47 patients in the phase 1 portion of trial M06-822 and 16 out of 39 
SCLC patients in the phase 2a portion (9, 10); and 8 out of 29 patients in trial M06-
873 (35).  Grade 4 thrombocytopenia and neutropenia were reversible via temporary 
suspension or dose reduction of navitoclax, and filgrastim for persistent grade 4 
neutropenia.   
 
In all three trials, platelet count decreases occurred both on an intermittent dosing 
schedule (navitoclax administered PO QD on 14 consecutive days of a 21-day cycle) 
and on a continuous schedule (21 out of 21 days).  Platelet counts reached their nadir 
soon (1-3 days) after the first dose of navitoclax, but with a rebound occurring even 
during the dosing period (9, 34).  This recovery is thought to be due to a 
compensatory upregulation of megakaryocyte platelet production.  As a result, 
clinical studies now employ a 7-day lead-in period at a reduced dose of navitoclax 
prior to administration of the full dose in Cycle 1.  Use of the lead-in dose before a 
continuous dosing schedule has helped to reduce acute platelet nadirs and the 
incidence of grade 4 thrombocytopenia during the first cycle, allowing higher doses 
than were obtainable on the intermittent (14/21) schedule (34, 35).  However, severe 
thrombocytopenia was observed during later cycles in 4 of 7 patients in the 250 mg 
and 300 mg continuous-dosing cohorts; as with thrombocytopenia observed in Cycle 
1, these events were reversible with dose reduction or granulocyte colony-stimulating 
factor (G-CSF) administration (35).   
 
Other frequently reported AEs include anemia, neutropenia, infection, diarrhea, 
nausea, and fatigue (ABT-263 Investigator’s Brochure, 2011) (9, 34, 35).  Although 
decreases in circulating neutrophils were not observed in nonclinical toxicity studies, 


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neutropenia has been noted in some patients both early (Cycles 1-5) and late (Cycles 
7-14) in the CLL monotherapy study M06-873 (35).  Preliminary analysis of early 
clinical data demonstrates an apparent trend in decreasing baseline-normalized ANC 
nadirs with increasing navitoclax dose, Cmax, or AUC.  As such, neutropenia is 
considered an adverse drug reaction, attributed to navitoclax administration; in the 
CLL study it was reversible with dose reduction or G-CSF administration. Grade 1 
and 2 gastrointestinal AEs may be due to the vehicle used in the liquid formulation; 
nausea and vomiting have been managed with antiemetics, and diarrhea with 
diphenoxylate and atropine (34).  Anorexia is also considered an adverse drug 
reaction as it is consistent with the other identified gastrointestinal toxicities. 
Other AEs of interest include elevation in liver enzymes, which has limited some 
subjects' dosing.  As such, liver function tests should be routinely monitored during 
the conduct of navitoclax studies.   
 
Some investigators have reported QTc prolongation as nonserious adverse events 
(ABT-263 Investigator’s Brochure, 2011).  Many of these subjects were heavily 
pretreated with cardiotoxic drugs.  Based on nonclinical evaluation, it is unknown or 
unlikely that QTc prolongation is related to navitoclax administration; however, 
further clinical QTc investigation is planned.  Additionally, metabolic changes such 
as hyperuricemia, hyperkalemia, and increased lactate dehydrogenase values have 
been reported and are consistent symptoms of tumor lysis syndrome (TLS).  One 
serious adverse event of TLS was reported; however, with continued treatment with 
prophylaxis, no further events of TLS have been reported.   
 
The following recommended phase 2 doses (RP2D) were independently determined 
based on their respective safety and tolerability results:  
• M06-814 (lymphoid malignancies):  7-day lead-in dose of 150 mg/day followed 
by 325 mg QD (21/21 days) (34).   
• M06-822 (SCLC and other solid tumors):  7-day lead-in dose of 150 mg/day 
followed by 325 mg QD (21/21 days) (9).   
• M06-873 (CLL):  7-day lead-in dose of 100 mg/day followed by 250 mg QD 
(21/21 days) (36). 
 
2.2.1.4 
Clinical Pharmacokinetics 
 
Pharmacokinetic (PK) data were obtained for the intermittent (14/21) dosing 
schedules in trials M06-814, M06-822, and M06-873, and for the continuous (21/21) 
dosing schedule in trial M06-873.  M06-814 also tested for food effects on PK 
parameters. Overall, the absorption of navitoclax after oral dosing was relatively 
slow, with Cmax achieved around 6-9 hours after first dose. Exposure (Cmax and AUC0-
24) was approximately dose-proportional over a range of doses from 10 mg/day 
through 475 mg/day. There were no significant differences in PK values between 
disease groups (general lymphoid malignancies, SCLC, and CLL) (ABT-263 
Investigator’s Brochure, 2011). Individual study results are summarized below. 
 


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Trial M06-814: Peak concentration was observed approximately 9 hours after dosing, 
with a terminal plasma half-life (t1/2) of approximately 17 hours, with first-order 
elimination kinetics (34). Exposure was dose-proportional over a range of 10 mg/day 
to 440 mg/day, with an interpatient variability in exposure of 40%. The dose-
normalized Cmax and AUC0-24 of a non-fasting dose was about 20% higher than a 
fasting dose among subjects in the 10 mg through 440 mg cohorts. Dosages ≥315 
mg/day met the minimum plasma exposure predicted to be in the therapeutic range 
based on animal models. After a fasting dose, the oral clearance of navitoclax 
averaged about 4.4 L/h across all dose levels (ABT-263 Investigator’s Brochure, 
2011). Navitoclax was not detected in urine, indicating little to no renal excretion. 
 
Trial M06-822:  Peak concentration was observed approximately 7 hours after dosing, 
with a t1/2 of approximately 15 hours (9).  Exposure (Cmax and AUC0-24) was dose-
proportional over a range of 10 mg/day to 475 mg/day. Interpatient variability in 
dose-normalized Cmax and AUC0-24 was about 40%, and values were similar between 
fasting and non-fasting conditions.  Peak-to-trough plasma concentration ratio was 
close to twofold at steady state.  Dosages ≥225 mg/day met the minimum plasma 
exposure predicted to be in the therapeutic range based on animal models. 
 
Trial M06-873:  Peak concentration was observed approximately 6-8 hours after 
dosing in both the intermittent and continuous dosing cohorts (35).  Exposure was 
dose-proportional over a range of 10 mg/day to 250 mg/day in the intermittent cohort, 
and interpatient variability in AUC was 46% for intermittent and continuous cohorts.  
No consistent trend was observed in dose-normalized steady-state trough 
concentrations over time. Navitoclax exposure did not demonstrate any correlation 
with age, sex, body weight, body surface area, renal function, or total bilirubin levels. 
 
2.2.1.5 
Clinical Efficacy 
 
Trial M06-814:  Overall, 21 of 46 patients with assessable adenopathy showed some 
reduction in tumor size (34).  Ten of these patients achieved a PR of at least a 50% 
reduction in tumor size, and these responders had median progression-free survival 
(PFS) of 455 days.  Responses occurred over the entire range of doses, with the 
exception of 20 and 200 mg/day, and in several tumor types.  Responses were 
recorded after a median of 3.5 cycles (range 2–10).   
 
CLL and small lymphocytic lymphoma (SLL), diseases of B-cell accumulation, 
showed the greatest sensitivity to treatment (34).  Seven patients with leukemic 
counts of >5000 cells/μL achieved at least a 50% reduction in their leukemia cells, 
and eight of 16 patients with measurable adenopathy, including bulky adenopathy, 
achieved a PR of at least a 50% reduction in lymph-node size.  For all 20 patients 
with CLL or SLL, median PFS was 246 days, and median overall survival had not 
been reached at time of the report.  Measurable tumor reduction was also noted in six 
of 16 patients with follicular lymphoma.  Overall, the 16 patients with FL had a 
median PFS of 88 days, and no patient with FL had died at time of the report. 
 


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Trial M06-822:  Of the 38 patients who were evaluable for response in the phase 1 
portion (23 with SCLC or pulmonary carcinoid), eight had stable disease (SD; five 
SCLC and three atypical pulmonary carcinoid) and one patient with SCLC remained 
on study for 13 months (9). One patient with SCLC had a PR that was sustained for 
longer than 35 months (at the time of report); this patient had a localized recurrence 
after first-line treatment with progressive disease on second-line therapy before study 
entry. Overall, among patients with disease control, the median number of prior 
therapies was three (range, 1–5 prior therapies). The majority of patients with disease 
control were those treated at the highest dose levels and the median duration of 
disease control was 5 months (range, 2–35 months). 
 
In the phase 2a portion of the trial, out of 39 SCLC patients, only 1 PR (ORR 2.6%) 
and 9 SD were observed (10).  Thirteen patients were not evaluable for response.  
Median PFS was 1.5 months (95% confidence interval [CI], 1.4–1.7) and median OS 
was 3.2 months (95% CI, 2.3–8.1). 
 
Trial M06-873:  Nine of 29 CLL patients achieved a PR (objective response rate 
[ORR] 31%), five on the intermittent-dosing (14/21) cohort and four on the 
continuous-dosing cohort (35).  SD was the best response in 18 patients and was 
sustained for at least 6 months in eight patients.  Among the 26 patients who received 
doses of navitoclax sufficient to achieve sustained exposure of biologically active 
concentrations (≥110 mg/day), the ORR was 35%.  Clinical benefit appeared durable, 
since seven patients had SD features for more than 12 months from commencement 
of therapy.  The median PFS and the median time to disease progression were both 25 
months.   
 
Among seven patients with fludarabine-refractory disease receiving ≥110 mg/day, 
one achieved a PR and five had overall SD while demonstrating some antitumor 
efficacy with either a more than 50% reduction in peripheral blood lymphocytosis 
and/or a substantial reduction in lymphadenopathy. The median PFS of fludarabine-
refractory patients was 25 months. Among nine patients with bulky lymphadenopathy 
receiving navitoclax at doses ≥110 mg/day, three achieved a PR and six had SD while 
demonstrating some tumor reduction. Similarly, three of nine patients with del(17p) 
CLL treated with navitoclax at ≥110 mg/day achieved a PR, and their median PFS 
has not been reached. 
 
2.2.1.6 
Planned starting dose for Phase 1 
 
For this combination trial with vistusertib, the initial dose of navitoclax will be 
150mg daily, which is less than 50% of the phase 2 dose of 325mg daily. The 150mg 
daily dose was the starting dose in the combination trial of trametinib and navitoclax. 
If this is found to be tolerable when combined with 35mg of dose level 1 of 
vistusertib, the dose of navitoclax will then be escalated to 250mg, and 325mg daily. 
A lead-in dose of 150mg daily will be used for the first week in all dosing cohorts. 
 
 


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2.3 
Other Agent (Vistusertib) 
 
2.3.1 Vistusertib (AZD 2014)  
 
Vistusertib is an inhibitor of the kinase activity of mammalian Target of Rapamycin 
(mTOR) serine threonine kinase, which plays a critical role in regulating cellular energy 
sensing, growth and metabolism.  Deregulation of mTOR signaling is observed in many 
tumor types (37, 38), and mutations or loss of function of several upstream regulators, 
have been reported in most types of human tumor (39, 40). 
 
The mTOR kinase forms two distinct multiprotein complexes called mTORC1 and 
mTORC2.  Rapamycin and its analogues (rapalogs) are potent inhibitors of mTORC1 and 
have shown to be clinically effective in certain cancer types, such as endometrial cancer, 
mantle cell lymphoma, renal cell carcinoma and breast cancer.  However, resistance to 
rapamycin and its analogues have been shown to limit their response rates in clinical 
studies.  Vistusertib is a selective inhibitor of mTOR kinases and unlike rapalogs inhibits 
signaling of both mTORC1 and mTORC2 complexes (41).  Vistusertib is therefore 
molecularly differentiated from rapamycin and its analogues.   
 
2.3.1.1 
Preclinical Studies 
 
In addition to its dual inhibition of mTORC1 and mTORC2, vistusertib achieves a 
more profound inhibition of mTORC1 and shows a broader range of growth 
inhibitory activity in vitro across tumor types compared to rapalogs.  Additionally, 
vistusertib has been found to be particularly effective in estrogen receptor-positive 
(ER+) breast cancer cell lines. Vistusertib delivers efficacy in a number of different 
tumor types in pre-clinical mouse models, particularly in breast cancer models which 
are sensitive or resistant to endocrine therapy.   
 
2.3.1.2 
Key Safety Findings 
 
At the data cut-off (DCO) October 5, 2015 (Investigator’s Brochure AZD2014, 
Version 7), clinical data were available for the clinical study program for vistusertib 
from 3 Phase 1 and 1 Phase 2a AstraZeneca sponsored studies. These were designed 
to assess the safety, tolerability, PK and preliminary efficacy of vistusertib. There 
were also 10 ongoing ESR studies.  
 
As of DCO of October 5, 2015, 547 patients have been enrolled in studies with 
vistusertib; 252 in AZ-sponsored studies, and 295 in externally sponsored 
collaborative research (ESCR) studies.  A total of 465 patients have received 
vistusertib; 252 in AZ-sponsored studies, and approximately 213 in ESCR studies.   
 
Two AstraZeneca-sponsored Phase 1 studies were designed to assess the safety, 
tolerability, pharmacokinetics and preliminary efficacy of vistusertib. Several doses 
and dosing schedules of vistusertib have been explored in both the monotherapy and 
combination studies including:  


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• D2270C00001: monotherapy in patients with advanced cancer. This study is 
now complete and Clinical Study Report (CSR) is available. 
• D2270C00005: in combination with fulvestrant in patients with metastatic 
breast cancer.  
• D2270C00008 (Japan PK) monotherapy in patients with advanced solid 
malignancies  
• D2274C00001 (STORK) in combination with paclitaxel to patients with 
relapsed or refractory squamous non-small cell lung cancer (sqNSCLC) after 
at least one line of therapy 
• D2270C00011 (TAX-TORC) in combination with paclitaxel in patients with 
solid tumors 
 
Monotherapy 
In Study D2270C00001 the following dosing was explored: 
 
Dosing schedule 
Doses explored 
Defined MTD 
Intermittent weekly BD 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 BD dosing 
25 mg, 50 mg, 70 mg, 
100 mg  
50 mg  
Continuous QD dosing 
75 mg, 100 mg, 125 
mg, 175 mg  
100 mg  
BD- twice daily dosing, QD- once daily dosing, MTD- maximum tolerated dose. 
 
86.7 % of patients experienced at least 1 adverse event (AE) considered related to 
vistusertib by the reporting investigator.  The most common AEs related to study 
treatment (occurring in ≥15% patients overall across all cohorts) were fatigue 
(58.5%), nausea (48.1%), mucositis (29.6%), diarrhea (28.1%), rash (27.4%), 
decreased appetite (22.2%), vomiting (21.5 %) and hyperglycemia (15.6%).  Dose 
limiting toxicities (DLTs) reported at non-tolerated doses were fatigue, diarrhea, 
mucositis, nausea, vomiting and rash.  During the study, 55/135 (40.7%) patients had 
a serious adverse event (SAE), and 24/135 (17.8%) had a treatment-related SAE.  
One patient died due to an AE of pulmonary embolism during the study; this was 
deemed unrelated to treatment by the investigator.  26 patients (19.3%) reported at 
least 1 AE leading to discontinuation.  The most common AEs leading to 
discontinuation of vistusertib (reported in ≥4 patients overall) were fatigue (7.4%), 
nausea (4.4%), decreased appetite (3.0%), diarrhea (3.0%), mucositis (3.0%), rash 
(3.0 %), and vomiting (3.0%). 
 
Although most patients experienced an AE, the drug was considered to be well 
tolerated with easily manageable side effects by the investigators. A total of 68 
patients (50.4%) experienced an AE of Common Terminology Criteria for Adverse 


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Events (CTCAE) grade 3, 1 patient (1.3%) had a CTCAE grade 4 AE, and 1 patient 
(1.3%) had a CTCAE grade 5 AE (incidence rates include DLTs at non-tolerated 
doses).  15 (12%) patients on doses below the MTD experienced AEs that led to the 
discontinuation of vistusertib and no patients 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 
non-tolerability were generally reversible within a week of stopping treatment with 
vistusertib.  105 patients (77.8%) had a duration of treatment (including periods of 
dose interruption) of >3 months.  1 patient had duration of treatment of 18 months. 
 
The change from the continuous dosing at a dose of 50 mg BD to the intermittent (2 
consecutive days, 2 days on, 5 days off) dosing of vistusertib at a dose of 125 mg BD 
was accompanied by an increase in the incidence of nausea from 20/41 (48.8%) to 
9/13 (69.2 %) and diarrhea from 18/41 (44.0%) to 9/13 (69.2 %), however, it reduced 
the incidence of rash from 20/41 (48.8%) to 2/13 (15.4%)] and mucositis from 18/41 
(43.9%) to 4/13 (30.8%). The 125 mg 2 consecutive days, 2 days on, 5 days off 
schedule did not have any AE’s associated with discontinuation with vistusertib, 
compared to the continuous 50 mg BD schedule, for which 18/41(43.9 %) patients 
discontinued treatment as a result of an AE.   
 
T wave changes on ECG have been observed in 9 selected patients of the total 135 
included in study D2270C00001: 4 patients had AE of T wave inversion reported by 
Investigator. Additional 5 patients’ ECG were assessed by GSP/MSD as potentially 
significant as the T wave changes were persistent on treatment and did not resolve at 
end of study. However, the above mentioned ECG findings do not indicate a 
clinically significant ECG abnormality when the pre-clinical CV safety profile of the 
study compound and the clinical context of the observed ECG changes are taken into 
the final clinical consideration. 
 
Study D2270C00005: Combination with Fulvestrant (42) 
 
In Study D2270C00005 in the following vistusertib dosing was explored: 
 
Dosing schedule 
Doses explored 
Recommended dose/ defined 
MTD 
Intermittent BD 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 BD dosing 
35 mg, 50 mg 
50 mg 
Continuous QD dosing 
75 mg, 100 mg 
75 mg 
BD- twice daily dosing, QD- once daily dosing, MTD- maximum tolerated dose 
 
At the MTD doses the most frequently reported AEs related to vistusertib (reported in 
≥15% patients overall) were fatigue, nausea, rash, diarrhea, decreased appetite, 


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vomiting, hyperglycemia, mucositis, pruritus, headache, anemia, asthenia, dry skin, 
constipation, dizziness and skin hyperpigmentation. Due to low numbers in Study 
D2270C00005 50 mg BD continuous dosing with fulvestrant group, headache, 
asthenia, constipation, dizziness and skin hyperpigmentation are included in this list 
despite only affecting 2 patients (2/13, 15.4% of the group). The most frequently 
reported AEs of CTCAE Grade 3 or higher (reported in >1 patient at an MTD, 
irrespective of causality) were rash, fatigue, nausea, infections, mucositis, vomiting, 
anemia, diarrhea, hyperglycemia, and hypophosphatemia. 
 
At MTD doses, no SAE MedDRA term was reported in more than 1 patient. The 
SAEs in the continuous dosing groups of 50 mg BD 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 BD plus fulvestrant were vomiting, nausea, hypercalcemia, diarrhea, infections, 
colitis, enteritis and subdural hematoma. Two patients had causally-related SAEs: 1 
patient (75 mg QD) had CTCAE Grade 4 febrile neutropenia; and 1 patient (125 mg 
BD) had CTCAE Grade 3 nausea, Grade 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 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.   
 
Combination with Paclitaxel 
 
Study D2270C00011 (TAX-TORC) Vistusertib is being explored in combination 
with paclitaxel in patients with squamous cell lung cancer and epithelial ovarian 
cancer in an Externally Sponsored Collaborative Research (ESCR) study.  The 
paclitaxel dose is 80 mg/m2 administered weekly for six consecutive weeks followed 
by a one week treatment interruption. In order to maximize exposure to vistusertib at 
the same time as paclitaxel, the dose of 50 mg BD vistusertib, 3 days on, 4 days off, 
in combination with 80 mg/m2 weekly paclitaxel (6 weeks on, 1 week off) was 
selected for further exploration.    
 
In Study D2270C00011 22 patients had an SAE ≥CTCAE Grade 3; diarrhea (reported 
in 4 patients), and fatigue, pneumothorax, sepsis, small intestinal obstruction, and 
urinary tract infection (each reported in 2 patients) were the only CTCAE ≥Grade 3 
SAEs that were reported in more than 1 patient. Ten patients had at least 1 SAE that 
was considered to be related to study treatment (1 patient with fatigue, 1 patient with 
fatigue and mucosal inflammation, 1 patient with rash macular and rash maculopapular 
[both considered to be related to vistusertib only], 1 patient with febrile neutropenia 
and diarrhea, 3 patients with diarrhea [2 events considered to be related to vistusertib 
only], 1 patient with urinary tract infection, gastrointestinal toxicity and pneumonitis, 
and 2 patients with bronchitis). Seven patients had SAEs that resulted in 
discontinuation of study drug: 1 patient (25 mg BD) with pneumothorax and 


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cerebrovascular accident; 1 patient (25 mg BD) with dyspnea; 1 patient (50 mg BD, 3 
days on and 4 days off) with device-related sepsis; 1 patient (50 mg BD, 3 days on and 
4 days off) with pulmonary edema, urinary tract infection, gastrointestinal toxicity and 
pneumonitis; 1 patient with bronchitis (50 mg BD); 1 patient with hemoptysis (25 mg 
BD); and 1 patient with bronchitis, small intestinal obstruction, and ascites (50 mg BD 
3 days on 4 days off). 
 
Three patients died due to AEs in Study D2270C00011.  One patient died as a result of 
bronchitis which was thought to be related to both vistusertib and to paclitaxel. One 
patient died following chest sepsis and pneumonia, thought to be related to paclitaxel 
only. One patient died as a result of hemoptysis and disease progression, thought to be 
unrelated to either drug. 
 
Study D2274C00001 (STORK) Only 4 patients of the 5 patients dosed (n=5) had 
reported AEs. Abdominal pain and peripheral neuropathy (each reported in 2 patients) 
are the only MedDRA preferred terms to have been reported in more than 1 patient.  
The AEs at CTCAE Grade 3 and above were mucositis, diarrhea, and acute respiratory 
failure.  AEs thought to be causally-related to vistusertib were fatigue, diarrhea, 
mucositis, pruritus, asthenia, abdominal pain, and anemia.  There were two SAEs 
(chronic obstructive pulmonary disease and acute respiratory failure) and these 
occurred in the same patient, neither of these was thought to be causally-related to 
vistusertib. There have been no deaths in this study. This study was terminated early. 
 
Summary of Safety Findings 
 
Vistusertib Monotherapy and in combination with Fulvestrant 
The overall safety findings at vistusertib MTDs in small numbers of patients in non-
randomized 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. However, at intermittent dosing schedules, 
vistusertib showed a different safety profile compared to continuous dosing 
schedules. At intermittent dosing schedules (125 mg BD 2 days on and 5 days off) the 
main AEs reported, which also led to dose discontinuation in 1 patient, were nausea 
and vomiting. There was also a marked reduction in rash at intermittent dosing 
schedules (from 69.2% to 16.2% in combination and 48.8% to 15.4% in 
monotherapy), pruritus (61.5% to 13.5% in combination and 34.1% to 0% in 
monotherapy) and mucositis (from 69.2% to 29.7% in combination therapy and 
43.9% to 30.8% in monotherapy). Interestingly, there were no cases of pneumonitis 
observed with this intermittent monotherapy schedule (compared with 2.4% and 7.7% 
in the continuous monotherapy and combination therapies respectively). Thus, the 
intermittent dosing schedules, showing similar efficacy at least in combination with 
fulvestrant offer an important new development option for a mTOR kinase inhibitor 
with a different safety profile, especially for combinations with other agents. 
 
 


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Vistusertib in combination with Paclitaxel 
AstraZeneca recently reviewed preliminary unvalidated safety and efficacy data from 
these two studies (D2274C00001 (STORK) and D2270C00011 (TAX-TORC)). In the 
STORK study there were no new safety signals or significant changes to the expected 
safety profile of vistusertib. However, data from both of these studies in sqNSCLC 
patients, who commonly have a large number of comorbidities, suggested that the 
vistusertib 50 mg BD (3 days on 4 days off per week) in combination with weekly 
paclitaxel (6 weeks on, 1 week off) dose level did not appear to be an acceptable 
regimen because of discontinuations due to rapid disease progression and/or AEs. In 
addition, data suggested that the vistusertib 50 mg BD in combination with weekly 
paclitaxel dose level of the STORK study did not demonstrate acceptable efficacy in 
sqNSCLC patients, with only stable disease observed (for between approximately 2 to 
6 months) as best response in 4/11 patients (no objective response was observed).  
 
AstraZeneca considered these data to represent a change in the benefit:risk profile of 
the vistusertib 50 mg BD (3 days on 4 days off per week) in combination with weekly 
paclitaxel (6 weeks on, 1 week off) dose level in sqNSCLC patients. Therefore, 
AstraZeneca decided not to further evaluate the 50 mg BD in combination with 
weekly paclitaxel dose level in sqNSCLC patients. 
 
2.3.1.3 
Key Efficacy Findings 
 
In D2270C00001 (monotherapy in patients with advance cancer) at the 50 mg BD 
dose in a total of 40 patients, 2 patients had an objective response; 1 patient with 
pancreatic acinar cell type cancer and 1 patient with ER+ breast cancer had confirmed 
RECIST PR and received vistusertib treatment for 175 and 206 days, respectively.  In 
addition, 12 patients in the 50 mg BD group, and 4 patients each in the 100 mg QD 
and 125 mg intermittent cohort achieved stable disease.  
 
In D2270C00005 (combination with fulvestrant), as of the DCO (October 5, 2015) 
vistusertib in combination with fulvestrant has demonstrated encouraging response 
rate data in this Phase I setting at MTDs for both the continuous and intermittent 
dosing schedules (42). There were partial responses (confirmed and unconfirmed) at 
every MTD dose group, 3/11 (27.3%) with a confirmed response rate of 2/11 (18.2%) 
in the 50 mg BD continuous dosing group, 3/13 (23.1%) with a confirmed response 
rate of 2/13 (15.4%) in the 75 mg QD continuous dosing group, and 3/20 (15.0%) 
with a confirmed response rate of 1/20 (5.0%) in the 125 mg BD intermittent dosing 
group.  
Additional information on the best objective responses in all patients and patients 
with measurable disease at baseline, is included in Table 20 in Section 5 of the IB 
edition 7.   
 
2.3.1.4 
Clinical Pharmacokinetics 
 
The pharmacokinetics of vistusertib has been studied following single and repeat 
administration of a solution and tablet formulation in cancer patients.  QD, BD and 


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intermittent dosing (2 consecutive days, 2 days on, 5 days off) have been investigated.   
 
Solution: The single dose PK data showed that vistusertib administered as a solution 
formulation was orally available and rapidly absorbed, with median time to reach 
maximum plasma concentration (Tmax) between 0.50 h and 1.0 h (range 0.27 h to 2.1 
h) across the 25 mg to 125 mg dose range. Plasma levels declined in a biphasic 
manner and terminal half-life (t½,λz) was short and variable between patients (mean 
between 2.5 h and 3.8 h across the 25 mg to 125 mg dose range; individual range 0.82 
h to 8.0 h). Single dose exposure (AUC) increased greater than proportionally to dose 
across the range investigated, with a 5-fold increase in dose from 25 mg to 125 mg 
giving approximately a 13-fold increase in AUC and a 9-fold increase in Cmax.  
 
Tablets: Single dose PK data following administration of the tablet formulation 
showed that absorption of the tablet was slower relative to the solution. This was 
shown by a comparatively lower Cmax and a slightly longer Tmax (median between 1.0 
h and 3 h and range from 0.5 h to 6.2 h) across the 50 mg to 225 mg dose range 
investigated (more information is available in the AZD 2014 IB version 7, Figure 2 
and Table 5).  
 
In summary, vistusertib is orally available, rapidly absorbed when administered as a 
tablet and has a short terminal half-life.  There is a greater than dose proportional 
increase in exposure (AUC) to vistusertib across the dose range investigated with a 
corresponding decrease in oral clearance (CL/F).  At higher doses (>100 mg) the 
apparent clearance decreases (CLss/F < CL/F for the same dose) following repeat 
dosing, with a corresponding increase in terminal half-life.  The mechanism for this 
and clinical relevance has not been fully elucidated.  Absorption of vistusertib is 
delayed following administration with food (delayed Tmax and reduction in Cmax) 
relative to the fasted state, but the extent of exposure (AUC) appears comparable.    
 
Pharmacokinetics and drug metabolism in humans 
 
Vistusertib is a substrate and weak inhibitor of various cytochrome P450 isoenzymes 
and drug transporters in vitro.  In addition, vistusertib is a weak inducer of CYP3A4 
in vitro.  The clinical relevance of these findings has not been fully evaluated.  There 
are specific exclusion criteria and co-medication guidance in place to avoid potential 
pharmacokinetic drug interactions (the AZD 2014 Investigator’s Brochure, version 7, 
and section 5.3.2 for further information). 
 
2.3.1.5 
Pharmacodynamics 
 
In study D2270C00001, phosphorylation of markers of S6 and 4EBP1 (TORC1) was 
reduced in 8/8 and 3/7 evaluable tumor biopsies respectively and phosphorylation of 
the marker of AKT (TORC2) was reduced in 3/4 evaluable tumor biopsies, following 
vistusertib treatment. 
 
 


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2.3.1.6 
Planned starting dose for Phase 1 
 
Vistusertib is available for administration as a tablet for use in clinical studies and is 
presented as three strengths: 10, 25 or 50 mg.  Continuous and intermittent dosing 
schedules have been explored and the intermittent schedule has shown an improved 
safety profile compared to the continuous dosing schedule in non-randomized studies.  
For this combination trial with navitoclax, the initial dose of vistusertib will be 35mg 
BID; based on the preclinical data presented in section 2.4, continuous dosing of 
vistusertib was recommended.  If a continuous BID regimen of vistusertib is not 
tolerated even at the 25 mg dose level, then an alternative schedule of BID for 2 days 
on/5 days off will be explored as suggested by AstraZeneca.  
 
2.4 
Correlative Studies Background 
 
2.4.1 Navitoclax and Vistusertib Pharmacokinetics 
 
In cancer patients, navitoclax exposure is dose proportional over the dose range proposed 
in this trial (34).  Navitoclax pharmacokinetics is best described by a two-compartment 
model with slow absorption (i.e., a lag-absorption with a one transit compartment) and 
linear elimination between doses of 10 and 475 mg (43). The Tmax occurs at 9 hr with a 
17 hr half-life.  Age has a significant effect on apparent clearance with an estimated value 
of 5.5, 3.7, and 3.0 L/hr for a 30, 60, or 90 yo patient.  Lastly, the pharmacokinetics were 
linked with thrombocytopenia (pharmacodynamics effect) by an Emax model utilizing a 
semiphysiological model with a progenitor compartment with maturation to a circulating 
platelet thus linking the known DLT of navitoclax to the drug exposure.  A mass balance 
study demonstrated ~90% of the navitoclax is excreted in the feces with ~50% being 
metabolites (7 metabolites have been identified) (44). Navitoclax is metabolized by 
CYP3A4 and is a moderate inhibitor of CYP2C8 and a strong inhibitor of CYP2C9 
(ABT-263 Investigator’s Brochure, 2011).  Navitoclax is also reported to be a P-
glycoprotein (ABCB1) substrate (45). Despite being primarily metabolized by CYP3A4, 
the pharmacokinetic of navitoclax were not altered when administered with the strong 
CYP3A4 inhibitor, ketoconazole (46). However, when administered with the strong 
CYP3A4 inducer rifampin, navitoclax AUC was decreased by 40% but the half-life was 
not altered (44).  
 
Vistusertib (AZD2014 Investigator's Brochure version 7, 2016) was selected from a 
series of dual mTORC1 and mTORC2 inhibitors due to its superior pharmacokinetic 
profile in rodents and minimal metabolism via human hepatocytes (47). Vistusertib is 
metabolized by CYP3A4 and CYP3A5 and is substrate for and inhibited by the P-
glycoprotein (ABCB1) and BCRP (ABCG2) transporters (AZD2014 Investigator's 
Brochure version 7, 2016).  Vistusertib is a weak inhibitor of CYP2C8, CYP 2C9, 
CYP2C19, and CYP2D6 but unlikely to cause clinically relevant drug-drug interactions 
(AZD2014 Investigator's Brochure version 7, 2016). Vistusertib induced CYP3A4 
mRNA in a concentration-dependent manner in human hepatocytes but the clinical 
relevance has not been determined or estimated (AZD2014 Investigator’s Brochure 
version 7, 2016). Patients on moderate to strong inducers and/or inhibitors of CYP3A4/5 


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and P-glycoprotein (ABCB1) and BCRP (ABCG2) are excluded in other trials 
(mTORC1/mTORC2 Kinase Inhibitor AZD2014 in Previously Treated Glioblastoma 
Multiforme https://clinicaltrials.gov/ct2/show/NCT02619864).   
 
There is a potential for a drug-drug interaction between CYP3A4 with navitoclax as a 
substrate and vistusertib as a weak inducer. Since navitoclax will need to be given for 1 
week prior to the combination to attenuate thrombocytopenia, a formal drug-drug 
interaction trial design will not be performed.  A full pharmacokinetic profile of 
navitoclax at steady-state will be proposed in this trial to assess for a drug-drug 
interaction.  Additionally, navitoclax and vistusertib trough concentrations will be 
assessed over the course of the first cycle. The navitoclax concentrations will be used to 
correlate with thrombocytopenia.  We will incorporate the expansion to a full 
pharmacokinetic profile for navitoclax and vistusertib if toxicities are frequent and severe 
with the combination. 
 
2.4.2 Reverse Phase Protein Array 
 
Our preclinical data supports a mechanism in which exposure to mTOR inhibitors results 
in changes in BCL-2 family member expression and sensitizes tumors to navitoclax. 
Specifically, we observed that mTOR inhibition resulted in increased expression of 
proapoptotic proteins (BAX and BAK) and decreased expression of the antiapoptotic 
protein, MCL-1; either of these perturbations could render cells more sensitive to the 
effects of a BCL-2 inhibitor such as navitoclax. Here we hypothesize that at the RP2D of 
navitoclax plus vistusertib, paired pre-treatment and on-treatment tumor biopsies will 
demonstrate the following pharmacodynamic responses: decreased phosphorylation of 
the TORC1 targets 4EBP1 S6K, decreased MCL-1 protein levels, increased BAX or 
BAK protein levels, and increased apoptosis.  We further hypothesize that these changes 
will correlate with response to the drug combination.  
 
As BCL-2 proteins and the mTOR pathway are generally regulated at the protein level we 
will use reverse phase protein array (RPPA) as our integrated assay for this study. RPPA 
utilizes a small amount of tissue to assess the levels of over 180 proteins and phospho-
proteins including BCL-2 family members, PI3K/AKT/mTOR proteins and proteins 
involved in cell death. The utility of RPPA has been documented in multiple studies 
based on cell lines and patient samples. The MD Anderson Cancer Center RPPA core and 
our translational science collaborator, Dr. 
,  have extensive experience in 
this technology and application in preclinical and clinical studies for a spectrum of 
cancers including SCLC.  
 
Using RPPA we will compare mTOR pathway activation and BCL2 protein levels at 
baseline then after a 2 week exposure to vistusertib and navitoclax at the RP2D.  Paired 
pre-treatment and on treatment core biopsies will be mandatory for patients on the phase 
2 portion of the trial. Fresh biopsies are optional for patients on the Phase 1 portion of the 
trial. As described above, these samples will provide the opportunity to correlate 
pharmacodynamic effects with tumor response and pharmacokinetic parameters at the 
RP2D.  Pre-treatment biopsies will be obtained during screening, and on-treatment 


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biopsies will be obtained on Cycle 1 Day 15 (+/-7days). Vistusertib is a potent ATP-
competitive inhibitor of both TORC1 and TORC2 complexes and produces dose-
dependent inhibition of phosphorylation of 4EBP1, S6K and AKT in vivo. The 
differential intensity of phospho-4EBP1 or p-S6 in pre-treatment compared with on-
treatment tissue samples may serve as marker to assess PD effect of vistusertib on 
inhibition of TORC signaling. 
 
Assessing tumor levels of these potential biomarkers in patients treated with navitoclax 
plus vistusertib will be critical for formulating a mechanistic understanding of tumor 
responses and we believe that paired tumor biopsies can be obtained safely.  In our recent 
Hopkins institutional experience ~ 50% of study biopsies for patients with advanced 
SCLC were obtained from outside the thorax at sites including liver, adrenal gland and 
lymph nodes. For patients whose tumors are localized to the lung, our endobronchial and 
transthoracic biopsy complication rates (primarily pneumothorax) are 5-10%. We feel 
that these numbers are representative of academic institutions, particularly those that 
would participate in this study. Our protocol specifies that we will only attempt to collect 
tumor samples if patients have tumor sites amenable to biopsy; the risk of pneumothorax 
will be heavily considered when determining whether a tumor site is amenable to biopsy. 
 
2.4.3 Tissue and plasma biomarkers of efficacy (exploratory biomarkers) 
 
2.4.3.1 
Tumor Tissue Studies 
 
When available, optional extra or leftover tissue samples (archival or fresh) will be 
studied to identify biomarkers associated with drug activity. Potential studies include 
analyses that would complement the results from the RPPA analyses(including gene 
expression and IHC) and whole-exome sequencing on pre-treatment tumors for 
identification of genomic correlates of response using methodologies developed by 
the Velculescu group (48-50).  High priority targets would include BCL-2 family 
members (e.g., BIM, BAX, BCL-2, BCL-all, MCL-1) and of the PI3K/mTOR 
pathway, including RICTOR amplification. 
 
2.4.3.2 
Optional Blood Studies  
 
The Velculescu group has developed non-invasive genomic approaches in order to 
determine somatic mutations that detect residual disease in the patient’s circulation 
(51-54).  Using optional blood samples collected prospectively after initiation of 
navitoclax plus vistusertib, we will determine whether measurements of cancer-
specific genomic alterations in circulating tumor DNA (ctDNA) can predict disease 
progression prior to conventional CT imaging. Tumor-specific mutations found in the 
circulation after disease progression will be compared to the genomic profile of the 
recurrent tumors and we will confirm the presence of matching resistance mutations 
in ctDNA.  
 
 
 
 


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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Phase 1 Specific Eligibility Criteria 
 
3.1.1.1 
Patients must have histologically or cytologically confirmed malignancy that is 
metastatic or unresectable and for which standard curative or palliative measures do 
not exist or are no longer effective.  
 
3.1.2 Phase 2 Specific Eligibility Criteria 
 
3.1.2.1 
Patients must have histologically or cytologically confirmed small cell lung cancer 
whose disease has relapsed or progressed after ≥ 1 prior therapy, one of which must 
have been a platinum doublet. Pathology confirmation must be done at SKCCC or at 
the local participating site. 
 
3.1.2.2 
Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for 
non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray 
or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  See Section 
11 for the evaluation of measurable disease. 
 
3.1.2.3 
Subjects must be willing to undergo 2 sets of core needle biopsies (pre-treatment and 
on-treatment), if there are lesions amenable to biopsy. An optional core biopsy will be 
requested at progression. 
 
3.1.3 General Eligibility Criteria 
 
3.1.3.1 
Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of navitoclax in combination with vistusertib in patients <18 years of age, 
children are excluded from this study, but will be eligible for future pediatric trials. 
 
3.1.3.2 
ECOG performance status ≤ 1 (Karnofsky ≥70%, see Appendix A)  
 
3.1.3.3 
Life expectancy of greater than 12 weeks. 
 
3.1.3.4 
Patients must have normal organ and marrow function as defined below: 
− 
leukocytes 
 
≥3,000/mcL 
− 
absolute neutrophil count  
≥1,500/mcL 
− 
hemoglobin   
 
≥ 9.0 g/dL 
− 
platelets 
≥100,000/mcL 
− 
aPTT, PT 
≤ 1.2 x ULN 
− 
total bilirubin 
≤ 1.5 x ULN (patients with Gilbert’s syndrome may 
have serum bilirubin > 1.5 ULN)  
− 
AST(SGOT)/ALT(SGPT) 
≤ 2.5 × institutional ULN if no demonstrable liver 


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31 
 
metastases or ≤ 5 x ULN in the presence of liver 
metastases 
− 
creatinine 
 
≤ 1.5 x ULN and concurrent creatinine clearance 
(CrCl)  ≥ 50mL/min/1.73 m2 for patients with Cr > 
1.5 x ULN 
− 
proteinuria 
≤ 1+ on dipstick testing (if 2+ seen on first test, 
retest ≥ 24 hours later) 
 
3.1.3.5 
Patients with a history of central nervous system (CNS) metastases must have 
documentation of stable or improved status based on brain imaging for at least 2 
weeks after completion of definitive treatment and within 2 weeks prior to first dose 
of Study Drug, off or on a stable dose of corticosteroids.  
 
3.1.3.6 
Patients must have completed chemotherapy, biological or radiotherapy ≥ 3 weeks 
prior to entering the study. 
 
3.1.3.7 
Patients must have recovered to ≤ grade 1 adverse events or to  ≤ grade 2 alopecia and 
sensory neuropathy due to prior treatment.- 
 
3.1.3.8 
Patients must be able to understand and willing to sign a written informed consent 
document. 
 
3.1.3.9 
Patients must be able to swallow pills. 
 
3.1.3.10 
The effects of navitoclax and vistusertib on the developing human fetus are unknown.  
For this reason, women of child-bearing potential and men must agree to use adequate 
contraception prior to study entry, for the duration of study participation, and up to 90 
days following completion of therapy. For women this should include one highly 
effective method of contraception and one barrier method, as defined below.   
 
Highly effective methods include: 
• total abstinence from sexual intercourse (minimum one complete menstrual 
cycle prior to study drug administration); 
• vasectomized partner; 
• medroxyprogesterone acetate depot injection; 
• placement of a copper-banded intrauterine device (IUD) or intrauterine system 
(IUS); 
• bilateral tubal ligation. 
 
Barrier methods include: 
• condom; 
• occlusive cap (e.g. diaphragm or cervical/vault caps) with spermicide. 
 
Please note: use of 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. Periodic abstinence, the rhythm 


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method, and the withdrawal method are not acceptable methods of contraception. 
 
Additionally, male subjects (including those who are vasectomized) whose partners 
are pregnant or might be pregnant must agree to use condoms for the duration of the 
study and for 90 days following completion of therapy. 
 
Women of childbearing potential must have a negative urine pregnancy test within 7 
days prior to initiation of treatment.  Women will be considered not of childbearing 
potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or 
post-menopausal (amenorrheic for at least 12 months). 
 
Should a woman become pregnant or suspect she is pregnant while she or her partner 
is participating in this study, she should inform her treating physician immediately.  
Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and for 90 
days after completion of navitoclax and/or vistusertib administration. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Phase 2 Specific Exclusion Criteria 
 
3.2.1.1 
Prior treatment with a TORC1, dual TORC1/2 inhibitor, or BCL-2/xL inhibitor 
 
3.2.1.2 
Patients with active malignancies other than SCLC or patients with prior curatively 
treated malignancy at high risk of relapse during the study period with the exception 
of localized squamous or basal cell skin cancers. 
 
3.2.2 Phase 1 and General Exclusion Criteria 
 
3.2.2.1 
Major surgery within 21 days of starting protocol treatment. 
 
3.2.2.2 
Patients who are receiving any other investigational agents. 
 
3.2.2.3 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to navitoclax or vistusertib  
 
3.2.2.4 
Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk 
of thrombocytopenia with navitoclax.  
• Excluded agents include heparin or low molecular weight heparin, warfarin, 
clopidogrel, ibuprofen and other NSAIDS, tirofiban, and other anticoagulants, 
drugs, or herbal supplements that affect platelet function.  
• Administration of heparin to keep subject's infusion lines patent is allowed. 
Low-dose anticoagulation medications that are used to maintain the patency of 
a central intravenous catheter are allowed.  
• Aspirin will not be allowed within 7 days prior to the first dose of navitoclax 
or during navitoclax administration. However, subjects who have previously 


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33 
 
received aspirin therapy for thrombosis prevention, may resume a low dose 
(i.e., maximum 100 mg QD) of aspirin if platelet counts are stable 
(≥50,000/mm3) through 6 weeks of navitoclax administration.  
• All decisions regarding treatment with aspirin therapy will be determined by 
the investigator in conjunction with the medical monitor.  
 
3.2.2.5 
Patients with an underlying condition predisposing them to bleeding or currently 
exhibiting signs of clinically significant bleeding.  
 
3.2.2.6 
Patients with a recent history of non-chemotherapy-induced thrombocytopenic-
associated bleeding within 1 year prior to the first dose of study drug.  
 
3.2.2.7 
Patients with a significant history of cardiovascular disease or procedures within the 
preceding 6 months (e.g., MI, coronary artery bypass graft placement, angioplasty, 
vascular stent, angina pectoris, ventricular arrhythmias requiring continuous therapy, 
congestive heart failure New York Heart Association (NYHA) Grade ≥ 2, thrombotic 
or thromboembolic event).  
 
3.2.2.8 
Any of the following cardiac criteria: 
• Mean resting corrected QT interval (QTc using Fredericia’s formula (QTcF)) 
> 470 msec obtained from 3 electrocardiograms  
• Congenital or family history of long or short QT syndrome, Brugada 
syndrome, known history of QTc prolongation or Torsades de Pointes within 
12 months of entering the study 
• Abnormal echocardiogram at baseline (left ventricular ejection fraction 
[LVEF] < 40% and shortening fraction [SF] < 15%.  
 
Drugs which have an increased risk for QTc prolongation should be avoided; for a list 
of these drugs, please refer to  http://crediblemeds.org/ 
 
3.2.2.9 
Patients with uncontrolled Type 1 or Type 2 diabetes. Vistusertib belongs to a class of 
drugs that causes hyperglycemia. In order to assess toxicity, patients with an elevated 
risk of hyperglycemia should be excluded from study. 
 
3.2.2.10 
Patients currently receiving medications or herbal supplements of the classes below 
are ineligible. Patients are eligible if they stop use of these compounds at least 1 week 
prior to receiving any treatment on this protocol or as specified in protocol section 
5.3.1.1, 5.3.2.1 and 5.3.2.2. 
• potent inhibitors or inducers of CYP3A4/5 (CYP3A4 inhibitors such as 
ketoconazole and clarithromycin are not allowed 7 days prior to the first dose 
of navitoclax and during navitoclax administration) 
• strong or moderate inhibitors of Pgp or BRCP1 
• sensitive substrates of CYP2C9 (i.e. phenytoin and warfarin) 
• substrates of certain drug transporters (OATP1B1, OATP1B3, MATE1 or 
MATE2K)  
 


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34 
 
 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as Facts and Comparisons or Lexicomp; 
medical reference texts such as the Physicians’ Desk Reference may also provide this 
information.   
 
3.2.2.11 
Pregnant women are excluded from this study because navitoclax and vistusertib have 
the potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the 
mother with navitoclax and vistusertib breastfeeding should be discontinued if the 
mother is treated with navitoclax and vistusertib 
 
3.2.2.12 
Patients positive for human immunodeficiency virus (HIV) are not excluded from this 
study, but HIV-positive patients must have:  
• A stable regimen of highly active anti-retroviral therapy (HAART) that does 
not include strong or moderate CYP3A4 inducers or inhibitors 
• No requirement for concurrent antibiotics or antifungal agents for the 
prevention of opportunistic infections  
• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on 
standard PCR-based test 
 
3.2.2.13 
Any hematopoietic growth factors (e.g., filgrastim [granulocyte colony-stimulating 
factor; G-CSF], sargramostim [granulocyte-macrophage colony-stimulating factor; 
GM-CSF]) within 14 days prior to receiving study treatment. 
 
3.2.2.14 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.2.15 
Patients who have received a live, attenuated vaccines within 4 weeks of first dose of 
drug 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their 
subpopulations be included in all NIH-supported biomedical and behavioral research 
projects involving NIH-defined clinical research unless a clear and compelling rationale 
and justification establishes to the satisfaction of the funding Institute & Center (IC) 
Director that inclusion is inappropriate with respect to the health of the subjects or the 
purpose of the research.  Exclusion under other circumstances must be designated by the 
Director, NIH, upon the recommendation of an IC Director based on a compelling 
rationale and justification.  Cost is not an acceptable reason for exclusion except when 
the study would duplicate data from other sources.  Women of childbearing potential 
should not be routinely excluded from participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 




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36 
 
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, 
or as the CI on the DTL must be rostered at the enrolling site with a participating 
organization (i.e., Alliance).  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval   
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must 
submit the Study Specific Worksheet for Local Context (SSW) to the CIRB using 
IRBManager to indicate their intent to open the study locally.  The NCI CIRB’s approval 
of the SSW is automatically communicated to the CTSU Regulatory Office, but sites are 
required to contact the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to 
establish site preferences for applying NCI CIRB approvals across their Signatory 
Network.  Site preferences can be set at the network or protocol level.  Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office by emailing 
the email address above or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website.  Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation, 
• IRB-signed CTSU IRB Certification Form, and/or 
• Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must 
meet the following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol. 
 
 
 


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Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Asssurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization, and  
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website.  Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment.  To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a Participating Organization on the protocol.  
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, 
or 
o Click on the By Lead Organization folder to expand, then select LAO- 
LAO-MD017, and protocol number 10070, 
• Click on Documents, select Site Registration, and download and complete the 
forms provided.  (Note:  For sites under the CIRB initiative, IRB data will load 
automatically to the CTSU as described above.)  
 
4.2.2 Requirements For 10070 Site Registration: 
• For Phase 2 of the study: Internal site initiation visit (SIV) conducted by the site 
study PI with the site research team  
-SIV checklist and sign-in sheet must be completed and signed by site study PI 
and sent back to the Protocol Liaison of the lead LAO. 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal, log on to the CTSU members’ 
website  Regulatory  Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in 
order to receive further instruction and support. 
 
 


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4.2.4 Checking Site Registration Status 
 
You can verify your site’s registration status on the members’ side of the CTSU 
website.  
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration  
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status shown only reflects institutional compliance with site 
registration requirements as outlined above.  It does not reflect compliance 
with protocol requirements for individuals participating on the protocol or 
the enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
 
4.3.2 OPEN/IWRS User Requirements 
 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, 
ETCTN Corresponding roster, or Participating Organization roster with the role 
of Registrar.  Registrars must hold a minimum of an AP registration type. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.   
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  Please print this confirmation for your records.  


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Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website.  Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry 
with the patient, all site staff must use the CTSU OPEN Slot Reservation System to 
ensure that a slot on the protocol is available to the patient.  Once a slot reservation 
confirmation is obtained, site staff may then proceed to enroll the patient to this study.  
 
4.3.3 Patient Enrollment Instructions 
 
In order to verify eligibility, the following documents should be submitted to the Study 
Coordinator of the Lead Organization at least 48 hours prior to treatment initiation: 
 
• Complete Request for Registration Form  
• Signed consent form and eligibility checklist 
• Recent physical exam note, including performance status 
• Screening labs/urinalysis/pathology report 
• Screening imaging report/EKG/ ECHO 
 
After approval by the Lead Organization, the patient may be enrolled in OPEN. 
 
4.3.4 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/
?National-Cancer-Institute-NCI-11. This link to the Theradex website is also on the 
CTSU website OPEN tab. For questions about the use of IWRS for slot reservations, 
contact the Theradex Helpdesk at 609-619-7802 or Theradex main number 609-799-
7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  If 
a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Study Coordinator should be notified of 
cancellations as soon as possible. 
 
 


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5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
5.1.1 Phase 1: Dose Escalation 
 
Treatment will be administered on an outpatient basis. Reported adverse events and 
potential risks are described in Section 7. Appropriate dose modifications are described in 
Section 6. No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient's malignancy. 
The patient will be requested to maintain a medication diary of each dose of medication 
(see Appendices C and D). The medication diary will be returned to clinic staff at the end 
of each 28-day treatment cycle. 
 
Eligible subjects will be treated with daily oral navitoclax and daily oral vistusertib given 
in a 28-day cycle following the dose- escalation scheme in the table below.  
 
Dose Escalation Schedule 
Dose Level 
Dose 
Navitoclax*  
by mouth,  
once a day 
Vistusertib 
by mouth,  
twice a day 
Level -1 
150 mg 
25 mg 
Level 1      
150 mg 
35 mg 
Level 2 
250 mg 
35 mg 
Level 3 
325 mg 
35 mg 
Level 4 
325 mg 
50 mg 
* To reduce the incidence of significant thrombocytopenia, all patients will receive lead-in 
dosing of navitoclax 150mg po once a day prior to C1D1. At any time after 7 days of  
navitoclax, if the platelet count is >50,000 and stable or increasing, subjects can dose 
escalate to the navitoclax dose defined in the cohort level and start vistusertib. Cycle 1 
day 1 is defined as the first day both study drugs are taken. 
 
The RP2D will be defined as the highest dose level at which < 33% of the dose cohort (0 
of 3 or 1 of 6) experiences DLT during 1 cycle. During the phase 1 portion of this study, 
the RP2D was determined to be navitoclax 150 mg by mouth daily plus vistusertib 35 mg 
by mouth twice a day. 
 
5.1.2 Phase 2  
 
Eligible subjects will be treated with navitoclax and vistusertib at Dose Level 1: 
navitoclax 150 mg by mouth once a day plus vistusertib 35 mg by mouth twice a day. 
 


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Per the drug manufacturer AstraZeneca, clinical supply of Vistusertib (AZD2014) will 
expire on August 31, 2021 (based on the planned expiration date extension), and there 
will be no additional drug available for clinical use after that date.  All patients must 
complete their last treatment on or before August 31, 2021, and the study will be closed 
to accrual and treatment to coincide with this expiration date. 
 
5.1.3 Dosing Instructions 
 
Navitoclax should be taken once a day by mouth on a 28-day cycle. Navitoclax should be 
taken with food. Navitoclax should be swallowed whole; patients should be instructed not 
to split, crush or chew the tablets. If vomiting occurs after taking Navitoclax, the dose 
should not be retaken. 
 
To reduce the incidence of significant thrombocytopenia, all patients will receive 7 days 
of lead-in dosing of navitoclax 150mg po once a day prior to C1D1. At any time after 7 
days of navitoclax, if the platelet count is >50,000 and stable or increasing, subjects can 
dose escalate to the navitoclax dose defined in the cohort level and start vistusertib. C1D1 
dosing should be held for clinically significant bleeding. Cycle 1 day 1 is defined as the 
first day both study drugs are taken. 
 
Vistusertib: where possible all doses of vistusertib should be taken at approximately the 
same times each day. Twice daily doses should be taken approximately 12 hours apart.   
If vomiting occurs within 30 minutes after vistusertib dosing, or later if the tablet(s) can 
be identified in the vomit content, the patient can re-take a new tablet(s).  
 
Should a patient miss a scheduled dose of either agent, the patient will be allowed to take 
the dose up to a maximum of 2 hours after the scheduled dose time. If greater than 2 
hours after the scheduled dose time, the missed dose should not be taken and the patient 
should take their allotted dose at the next scheduled time. If a patient needs to take the 
dose earlier for whatever reason, the patient can take the dose up to 2 hours earlier than 
the scheduled dose time. The patient should make every reasonable effort to take the 
tablets on time. 
 
5.1.3.1 
Food restrictions 
 
• Navitoclax should be given with food 
• Vistusertib can be given with or without food.  
• Sugary and fatty foods should be kept to a minimum in the meals prior to taking a dose of 
vistusertib  
• Large amounts of grapefruit and Seville oranges (and other products 
containing these fruits e.g. grapefruit juice or marmalade) should be avoided 
whilst taking vistusertib. No more than a small glass of grapefruit juice (120 
mL) or half a grapefruit or 1 to 2 teaspoons (15 g) of Seville orange 
marmalade daily is allowed 
 
 


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5.1.3.2 
Sunlight-protection measures 
 
Patients should be advised of the need for sunlight protection measures such as use of 
sunscreen and sunglasses, as well as avoidance of sunbeds/tanning booths, during 
administration of vistusertib, and should be advised to adopt such measures for a 
period of three months after receiving their final dose of vistusertib. 
 
5.2 
Dose Escalation and Definition of Dose-Limiting Toxicity 
 
5.2.1 Definition of Dose Limiting Toxicity 
 
Toxicities will be graded according to the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0).  
 
The occurrence of any of the following toxicities during cycle 1 will be considered a 
dose-limiting toxicity (DLT), if judged by the Investigator to be possibly, probably or 
definitely related to study drug administration:  
• ≥ Grade 3 non-hematologic toxicity  
o Except nausea, vomiting or diarrhea that can be controlled by appropriate 
medical intervention or prophylaxis and that resolves to grade 0-1 within 48 
hours with medical intervention  
o Except electrolyte toxicities that can be corrected to grade 0-1 or baseline 
within 48 hours after holding treatment  
• ≥ Grade 3 rash attributed to the combination will be considered a DLT if grade 3 
despite maximal medical management (including oral antibiotic, topical or oral 
steroids) for > 72 hours  
• Febrile neutropenia; grade 4 neutropenia; grade 4 anemia; grade 4 
thrombocytopenia; or thrombocytopenic bleeding  
• Pneumonitis > grade 2  
• Delay in starting cycle 2 of ≥ 14 days due to toxicity of any grade related to one 
or more protocol drugs  
• Dose intensity in cycles beyond cycle 1 will be considered in the assessment of 
the recommended phase II dose  
• To be evaluable for a DLT, 75% of dose must have been administered in cycle 1 
unless a DLT has occurred.  
 
Management and dose modifications associated with the above adverse events are 
outlined in Section 6. 
 
5.2.2 Dose Escalation Schema 
 
Dose escalation will proceed within each cohort according to the following scheme.  
Dose-limiting toxicity (DLT) is defined above.   
 


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Number of Patients with 
DLT at a Given Dose 
Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be entered 
at the next lowest dose level if only 3 patients were treated 
previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is generally the recommended phase 2 dose. At least 6 
patients must be entered at the recommended phase 2 dose. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of navitoclax and/or vistusertib with other 
concomitantly administered drugs, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.  The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential for drug interactions. The study team should check a frequently-updated 
medical reference for a list of drugs to avoid or minimize use of.  Appendix B (Patient 
Drug Information Handout and Wallet Card) should be provided to patients if available. 
 
5.3.1 Navitoclax 
 
Because there is a potential for interaction of navitoclax with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other 
drugs, over-the-counter medications, or alternative therapies.  The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential 
for drug interactions. The study team should check a frequently-updated medical 
reference for a list of drugs to avoid or minimize use of.  Appendix B (Patient Drug 
Information Handout and Wallet Card) should be provided to patients if available. 
 
Potential issues with navitoclax include drug-drug interactions and thrombocytopenia.  
See the navitoclax supportive care guidelines (Section 6) currently included in all 


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44 
 
company-sponsored protocols for managing thrombocytopenia (with platelet transfusion 
recommendations), lymphopenia, and tumor lysis syndrome. 
 
5.3.1.1 
Cytochrome P450 
 
Navitoclax is a moderate inhibitor of the activity of cytochrome P450 (CYP) 
isoenzyme CYP2C8 (IC50 = 3.4 μM or 3.3 μg/mL) and is a potent inhibitor of 
CYP2C9 activity (IC50 = 1.0 μM or 0.97 μg/mL).  At the expected biologically 
effective plasma concentration of about 3 to 5 μM (3–5 μg/mL), Navitoclax is likely 
to inhibit the metabolism of drugs that are substrates for CYP2C8 and CYP2C9.  
Clinically relevant CYP2C8 substrates include paclitaxel, statins, and glitazones, 
whereas phenytoin and warfarin are substrates of CYP2C9.  Co-dosing with CYP2C8 
and CYP2C9 substrates should be undertaken with caution. When possible, 
investigators should switch to alternative medications or monitor the patients closely 
(particularly in the case of medications that have a narrow therapeutic window such 
as warfarin).   
 
Navitoclax is metabolized in the liver by CYP3A4.  CYP3A4 inhibitors such as 
ketoconazole and clarithromycin are not allowed 7 days prior to the first dose of 
navitoclax or during navitoclax administration. 
 
5.3.1.2 
Thrombocytopenia 
 
In adult monotherapy clinical studies, reductions in circulating platelet counts were 
observed in an expected, dose-dependent predictable manner, with the nadir occurring 
3-5 days after the first dose of navitoclax followed by a subsequent recovery during 
ongoing dosing.  This effect is reversible with interruption of study drug.  Platelets 
recover towards baseline with continued dosing, but may not necessarily reach 
baseline levels.  Therefore, adequate platelet monitoring should be obtained, 
including after initiation of navitoclax therapy and when platelet counts are noted to 
be <50,000/mm3.  Attenuated lead-in dosing appears to ameliorate the risk of early 
grade 4 thrombocytopenia, and continuous dosing mitigates major swings in 
circulating platelet counts. 
 
Colony stimulating factors (G-CSF, GM-CSF) or human erythropoietin will be 
considered during administration of navitoclax if deemed necessary by the 
investigator.   
 
The following concomitant medications are not allowed during navitoclax 
administration due to mechanistic-based platelet toxicities from navitoclax:  
Clopidogrel (Plavix), ibuprofen, tirofiban (Aggrastat), and other anticoagulants, 
drugs, or herbal supplements that affect platelet function.  Administration of heparin 
to keep subject's infusion lines patent is allowed.  Low-dose anticoagulation 
medications that are used to maintain the patency of a central intravenous catheter are 
allowed. 
 


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45 
 
Aspirin will not be allowed within 7 days prior to the first dose of navitoclax or 
during navitoclax administration.  However, subjects who have previously received 
aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 
100 mg QD) of aspirin if platelet counts are stable (≥50,000/mm3) through 6 weeks of 
navitoclax administration.  All decisions regarding treatment with aspirin therapy will 
be determined by the investigator in conjunction with the medical monitor. 
 
5.3.1.3 
Disulfiram  
 
Disulfiram is not allowed due to potential drug interactions  
 
5.3.1.4 
Protein binding  
 
Narrow therapeutic index drugs with high protein binding (>99.8%) should be 
avoided. 
 
5.3.2 Vistusertib (AZD 2014) 
 
Because there is a potential for interaction of vistusertib with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other 
drugs, over-the-counter medications, or alternative therapies.  The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential 
for drug interactions. The study team should check a frequently-updated medical 
reference for a list of drugs to avoid or minimize use of.  Appendix B (Patient Drug 
Information Handout and Wallet Card) should be provided to patients if available. 
 
5.3.2.1 
Cytochrome P450 
 
Vistusertib is a substrate of P450 CYPs 3A4 and 3A5 and drug transporters Pgp 
(MDR1) and BCRP, in vitro.  Concomitant treatment with strong or moderate 
inhibitors of these enzymes/transporters may increase exposure to vistusertib. 
Conversely, strong or moderate inducers of CYP3A may decrease the exposure to 
vistusertib.  Strong or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) 
and BCRP are excluded. 
• If a patient requires short-term administration of a restricted CYP3A4/5, Pgp or 
BCRP inhibitor vistusertib treatment must be withheld for three days prior to 
administration and not restarted until the concomitant therapy has been 
discontinued for the appropriate time period (at least 1 week for competitive 
inhibitors and 2 weeks for time-dependent inhibitors). 
• If a patient requires short-term administration of a restricted CYP3A4/5, Pgp 
(MDR1) or BCRP isoenzyme inducer this should be clearly documented in the 
Case Report Form (CRF) and may then be permitted, but the Investigator will be 
informed that this could lead to lower levels of study drug and a potential 
reduction in clinical efficacy. 
 
 


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46 
 
5.3.2.2 
Substrates of Drug Transporters: OATP1B1, OATP1B3, MATE1 or MATE2K 
 
If a patient requires short term administration of restricted substrates of OATP1B1, 
OATP1B3, MATE1 or MATE2K vistusertib treatment must be withheld for 3 days 
prior to the first administration and not restarted until the concomitant therapy has 
been discontinued for at least 3 half-lives.   
 
5.3.2.3 
QTc prolongation 
 
Drugs which have an increased risk for QTc prolongation should be avoided; for a list 
of these drugs, please refer to http://crediblemeds.org/ 
 
5.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and 
the corresponding dates must be documented in the Case Report Form (CRF). 
 
5.5 
Duration of Follow Up 
 
Phase 1: Patients will be followed for 30 days to document related toxicities after 
removal from study or until death, whichever occurs first.   
 
Phase 2: Patients removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event. Patients who are taken off study for 
any reason other than disease progression or death will continue to reimaging studies 
approximately every 8 weeks until disease progression, start of new therapy or death. 
Patients will be followed in clinic or by telephone approximately every 12 weeks until 
death or 2 years from registration whichever comes first, for purposes of survival follow-
up. 
 
 
 
 


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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Best supportive care and treatment will be allowed for each subject (antiemetics, antibiotics, 
transfusions, nutritional support, pain control, etc.) with the exceptions noted in Section 5.4 
(General Concomitant Medication and Supportive Care Guidelines) and in the subsections 
below.  Colony stimulating factors (G-CSF, GM-CSF) or human erythropoietin will be 
considered during administration of navitoclax if deemed necessary by the investigator. If a 
patient must discontinue one agent due to toxicities, they are permitted to continue on the other 
agent on study. If one agent is discontinued, management of adverse events due to the remaining 
agent continue as outlined below. 
 
6.1 
Phase 1 
 
6.1.1 Dose de-escalation of Navitoclax 
 
Dose Level 
Starting Dose (once a day) 
Dose Reduction 1 
-1 
150 mg 
None* 
1 
150 mg  
None* 
2 
250 mg 
150mg 
3 
325 mg 
250mg 
4 
325 mg 
250mg 
 
6.1.2 Dose de-escalation of Vistusertib 
 
Dose Level 
Starting Dose (twice daily) 
Dose Reduction 1 
-1 
25 mg 
None* 
1 
35 mg  
25 mg 
2 
35 mg 
25 mg 
3 
35 mg 
25 mg 
4 
50 mg 
35 mg 
*Alternate dose de-escalation schemes will be discussed with the CTEP sponsors and 
industry collaborators. 
 
6.1.3 Management of Thrombocytopenia 
 
6.1.3.1 
Dose Reduction and Interruption 
 
Navitoclax accelerates apoptosis of circulating platelets, which differs from typical 
chemotherapy-induced thrombocytopenia related to myelosuppression. 
 
C1D1 dosing should be delayed for clinically significant bleeding.  
 
All decisions regarding continued navitoclax dosing for individual subjects will be 
determined by the investigator, as appropriate.  These decisions should be guided by the 
following: 


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48 
 
 
Additional platelet counts should be performed every other day or at the discretion of the 
investigator for a platelet count on any given day that is less than 50,000/mm3. 
Administration of navitoclax will be interrupted or discontinued for any pre-dose platelet 
count <25,000/mm3.  A platelet count <25,000/mm3 should be confirmed the same day 
by manual reading and a separate peripheral draw. 
 
Thrombocytopenia 
Management for navitoclax 
Management for vistusertib 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. Resume 
at same dose level. 
No change in dose 
Grade 3 
Hold until < Grade 2.  Resume 
at one dose level lower, if 
indicated.* 
No change in dose 
Grade 4 
Off protocol therapy 
Hold until < Grade 2.  Resume 
at one dose level lower, if 
indicated. 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
For any clinically significant bleeding event, defined as grade 2 or 3 hemorrhage 
regardless of platelet count, navitoclax should be withheld, and: 
• Once the toxicity recovers to an acceptable grade level (i.e., ≤grade 1 bleeding 
and/or platelet count is ≥50,000/mm3 and stable or increasing), navitoclax may be 
restarted at a reduced dose of DL –1. 
• If the toxicity recurs at the dose levels above, navitoclax should once again be 
interrupted.  Once the toxicity recovers to an acceptable grade level, navitoclax 
may be restarted at reduced dose of DL –2. 
• If the toxicity recurs at the dose levels above, navitoclax should once again be 
interrupted.  Once the toxicity recovers to an acceptable grade level, navitoclax 
may be restarted at DL –3 or stopped altogether. 
 
Patients with grade 4 bleeding events should be discontinued from the study.  
 
After any grade 4 platelet count <25,000/mm3 is observed for the first time per month in 
a subject, serial PK samples will be collected.  PK samples will be collected as soon as 
possible after the grade 4 platelet count is determined and then 24 and 48 hours after the 
event. 
 
Limited human clinical data are available to understand the response to infusion of 
exogenous platelets in the presence of circulating drug levels.  Data from a single dose 
and a 28-day multiple dose, nonclinical studies in dogs demonstrate that under conditions 
of navitoclax plasma concentrations exceeding concentrations in the clinic (>10 μg/mL) 
and rapid platelet apoptosis, platelet infusions do not have a measurable effect on 
circulating platelet counts.  However, under conditions of lower navitoclax plasma 
concentrations (<10 μg/mL), platelet infusions do result in an increase in circulating 
platelet counts.  This response appears to be more consistent and of greater duration as 


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49 
 
navitoclax plasma concentrations decline.  Although the administration of multiple 
platelet transfusions may produce a sustained increase in circulating platelets, post-
transfusion platelet kinetics should be monitored when clinically indicated. 
If platelet transfusions are required in response to active bleeding, dosing of navitoclax 
should be suspended.  It should be noted that platelet response with transfusions may not 
follow typical platelet kinetics of thrombocytopenia as with typical chemotherapy-
induced myelosuppression.  Procedures consistent with local institutional blood banking 
guidelines regarding platelet transfusions should be followed. 
 
6.1.3.2 
Platelet Transfusion Recommendations 
 
If a platelet transfusion is deemed necessary, the investigator should be aware of the 
following: 
• Due to the rapid apoptotic effect of navitoclax on mature platelets, the initial 
increase in platelet counts post-transfusion(s) may be smaller and the duration of 
response may be shorter.  For this reason, the most recently collected donor 
platelets should be transfused. 
• A post-transfusion platelet count should be obtained within 10 to 60 minutes. 
• Additional transfusions may be necessary to achieve the desired platelet response. 
 
6.1.4 Management of Neutropenia 
 
Standard management practices for neutropenia should be followed.  Preliminary data 
analysis from the ongoing phase 1 studies in subjects with CLL demonstrates an apparent 
trend in decreasing baseline-normalized absolute neutrophil count (ANC) nadir with 
increasing doses, Cmax, or AUC. 
 
Neutropenia 
Management for navitoclax 
Management for vistusertib 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until < Grade 2.  Resume at 
one dose level lower, if indicated.* 
No change in dose 
Grade 4 
Hold until < Grade 3.  Resume at 
one dose level lower.* 
Hold until < Grade 2.  Resume at 
one dose level lower, if indicated.* 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
6.1.5 Management of Febrile Neutropenia 
 
Standard management practices for febrile neutropenia should be followed.   
 
Febrile 
Neutropenia 
Management for navitoclax 
Management for vistusertib 
Grade 3 
Hold until infection is resolved, 
antibiotics are no longer required 
and ANC < Grade 2.  Resume at 
Hold until infection is resolved, 
antibiotics are no longer required 
and ANC < Grade 2.  Resume at 


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Febrile 
Neutropenia 
Management for navitoclax 
Management for vistusertib 
one dose level lower, if indicated.* one dose level lower, if 
indicated.* 
Grade 4 
Hold until infection is resolved, 
antibiotics are no longer required 
and ANC < Grade 2.  Resume at 
one dose level lower, if indicated.* 
Hold until infection is resolved, 
antibiotics are no longer required 
and ANC < Grade 2.  Resume at 
one dose level lower, if 
indicated.* 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
6.1.6 Management of EKG Changes 
 
Patients who develop persistent, confirmed T wave repolarization abnormalities 
(inversion or flattening) on regularly scheduled ECGs may be referred for a cardiology 
opinion and should have the following assessments performed:  
• ECHO/MUGA as clinically indicated and end of study and/or safety follow-up 
visit if any abnormal LV function was diagnosed. 
• ECG at safety follow-up visit  
• Troponin measurement as clinically indicated and at end of study 
 
6.1.7 Management of Liver Function Test Abnormalities 
 
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 Section 13.2. 
 
Adverse Event 
Management for navitoclax 
Management for vistusertib 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until G ≤ 2 and reduce 1 
dose level if related to navitoclax. 
If there is a treatment delay >2 
weeks, discontinue navitoclax.  
Hold until G ≤ 2, then rechallenge 
at the same dose. If subject 
develops G3 liver function 
abnormalities again, hold until  ≤ 
2, reduce 1 dose level.  
Grade 4 
Hold until grade ≤ 2, reduce 1 
dose level. 
Hold until grade ≤ 2, reduce 1 
dose level.  
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
 
 
 
 


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6.1.8 Management of other adverse events 
 
Adverse Event 
Management for navitoclax 
Management for vistusertib 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Reduce 1 dose level if related to 
navitoclax. If there is a treatment 
delay >2 weeks, discontinue 
navitoclax.  
Reduce 1 dose level if related to 
vistusertib. If there is a treatment 
delay >2 weeks, discontinue 
vistusertib.  
Grade 4 
Hold until grade ≤ 2, reduce 1 
dose level. 
Hold until grade ≤ 2, reduce 1 
dose level.  
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
6.2 
Phase 2 
 
6.2.1 Dose de-escalation of Navitoclax 
 
There are no dose reductions of navitoclax in Phase 2. If navitoclax is 
discontinued, vistusertib may be continued. 
 
6.2.2 Dose de-escalation of Vistusertib 
 
Vistusertib may be dose reduced once. If further dose reduction is indicated, the 
subject will discontinue vistusertib. If vistusertib is discontinued, navitoclax may 
be continued. 
 
Dose Level 
Dose (twice daily) 
1 
35 mg  
-1 
25 mg 
 
6.2.3 Management of Thrombocytopenia 
 
6.2.3.1 
Dose Reduction and Interruption 
 
Navitoclax accelerates apoptosis of circulating platelets, which differs from typical 
chemotherapy-induced thrombocytopenia related to myelosuppression. 
 
C1D1 dosing should be delayed for clinically significant bleeding.  
 
All decisions regarding continued navitoclax dosing for individual subjects will be 
determined by the investigator, as appropriate.  These decisions should be guided by the 
following: 
 
Additional platelet counts should be performed every other day or at the discretion of the 
investigator for a platelet count on any given day that is less than 50,000/mm3. 


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Administration of navitoclax will be interrupted or discontinued for any pre-dose platelet 
count <25,000/mm3.  A platelet count <25,000/mm3 should be confirmed the same day 
by manual reading and a separate peripheral draw. 
 
Thrombocytopenia 
Management for navitoclax 
Management for vistusertib 
≤ Grade 1 
No change in dose. 
No change in dose. 
Grade 2 
Hold until ≤ Grade 1. Resume 
at same dose level. 
No change in dose. 
Grade 3 
Discontinue navitoclax. 
No change in dose 
Grade 4 
Discontinue navitoclax. 
Hold until ≤ Grade 1.  Resume 
at one dose level lower. 
 
For any clinically significant bleeding event, defined as grade 2 or higher hemorrhage 
regardless of platelet count, navitoclax should be discontinued 
 
After any grade 4 platelet count <25,000/mm3 is observed for the first time per month in 
a subject, serial PK samples will be collected.  PK samples will be collected as soon as 
possible after the grade 4 platelet count is determined and then 24 and 48 hours after the 
event. 
 
Limited human clinical data are available to understand the response to infusion of 
exogenous platelets in the presence of circulating drug levels.  Data from a single dose 
and a 28-day multiple dose, nonclinical studies in dogs demonstrate that under conditions 
of navitoclax plasma concentrations exceeding concentrations in the clinic (>10 μg/mL) 
and rapid platelet apoptosis, platelet infusions do not have a measurable effect on 
circulating platelet counts.  However, under conditions of lower navitoclax plasma 
concentrations (<10 μg/mL), platelet infusions do result in an increase in circulating 
platelet counts.  This response appears to be more consistent and of greater duration as 
navitoclax plasma concentrations decline.  Although the administration of multiple 
platelet transfusions may produce a sustained increase in circulating platelets, post-
transfusion platelet kinetics should be monitored when clinically indicated. 
If platelet transfusions are required in response to active bleeding, dosing of navitoclax 
should be suspended.  It should be noted that platelet response with transfusions may not 
follow typical platelet kinetics of thrombocytopenia as with typical chemotherapy-
induced myelosuppression.  Procedures consistent with local institutional blood banking 
guidelines regarding platelet transfusions should be followed. 
 
6.2.3.2 
Platelet Transfusion Recommendations 
 
If a platelet transfusion is deemed necessary, the investigator should be aware of the 
following: 
• Due to the rapid apoptotic effect of navitoclax on mature platelets, the initial 
increase in platelet counts post-transfusion(s) may be smaller and the duration of 
response may be shorter.  For this reason, the most recently collected donor 
platelets should be transfused. 


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• A post-transfusion platelet count should be obtained within 10 to 60 minutes. 
• Additional transfusions may be necessary to achieve the desired platelet response. 
 
6.2.4 Management of Neutropenia 
 
Standard management practices for neutropenia should be followed.  Preliminary data 
analysis from the ongoing phase 1 studies in subjects with CLL demonstrates an apparent 
trend in decreasing baseline-normalized absolute neutrophil count (ANC) nadir with 
increasing doses, Cmax, or AUC. 
 
Neutropenia 
Management for navitoclax 
Management for vistusertib 
≤ Grade 1 
No change in dose. 
No change in dose. 
Grade 2 
No change in dose. 
No change in dose. 
Grade 3 
Discontinue navitoclax. 
No change in dose. 
Grade 4 
Discontinue navitoclax. 
Hold until < Grade 2.  Resume at 
one dose level lower. 
 
6.2.5 Management of Febrile Neutropenia 
 
Standard management practices for febrile neutropenia should be followed.   
 
Febrile 
Neutropenia 
Management for navitoclax 
Management for vistusertib 
Grade 3 
Discontinue navitoclax. 
Hold until infection is resolved, 
antibiotics are no longer required 
and ANC < Grade 2.  Resume at 
one dose level lower. 
Grade 4 
Discontinue navitoclax. 
Hold until infection is resolved, 
antibiotics are no longer required 
and ANC < Grade 2.  Resume at 
one dose level lower. 
 
6.2.6 Management of EKG Changes 
 
Patients who develop persistent, confirmed T wave repolarization abnormalities 
(inversion or flattening) on regularly scheduled ECGs may be referred for a cardiology 
opinion and should have the following assessments performed:  
• ECHO/MUGA as clinically indicated and end of study and/or safety follow-up 
visit if any abnormal LV function was diagnosed. 
• ECG at safety follow-up visit  
• Troponin measurement as clinically indicated and at end of study 
 
 
 
6.2.7 Management of Liver Function Test Abnormalities 


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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 Section 13.2. 
 
Adverse Event 
Management for navitoclax 
Management for vistusertib 
≤ Grade 1 
No change in dose. 
No change in dose. 
Grade 2 
No change in dose. 
No change in dose. 
Grade 3 
Discontinue navitoclax. 
Hold until G ≤ 2, then rechallenge 
at the same dose. If subject 
develops G3 liver function 
abnormalities again, hold until  ≤ 
2, reduce 1 dose level.  
Grade 4 
Discontinue navitoclax. 
Hold until grade ≤ 2, reduce 1 
dose level.  
 
6.2.8 Management of other adverse events 
 
Adverse Event 
Management for navitoclax 
Management for vistusertib 
≤ Grade 1 
No change in dose. 
No change in dose 
Grade 2 
No change in dose. 
No change in dose 
Grade 3 
Discontinue navitoclax. 
Reduce 1 dose level if related to 
vistusertib. If there is a treatment 
delay >2 weeks, discontinue 
vistusertib.  
Grade 4 
Discontinue navitoclax. 
Hold until grade ≤ 2, reduce 1 
dose level.  
 
 
 
 










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NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Lethargy; Seizure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Photosensitivity 
VASCULAR DISORDERS - Thromboembolic event 
 
Note: Vistusertib (AZD2014) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for SAE reporting only. This study will 
continue to utilize CTCAE version 4.0 for routine toxicity reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0 and 5.0.  A 
copy of the CTCAE version 4.0 and 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in 
the SPEER column, Section 7.1.1) should be reported through CTEP-AERS only 
if the grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
Event Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented 
in the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements 
for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse even
ts.htm).  These requirements are briefly outlined in the tables below (Section 
7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 


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original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” 
in the system organ class (SOC) “General disorders and administration site conditions.  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any pregnancy loss should be 
reported expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium 
and perinatal conditions SOC. A pregnancy loss should NOT be reported as a Grade 5 
event under the Pregnancy, puerperium and perinatal conditions SOC, as currently 
CTEP-AERS recognizes this event as a patient death.  
 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under 
the General disorders and administration SOC. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 
CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious 
Adverse Events, whether or not they are considered related to the investigational 
agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of 




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expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents.  AEs are reported in a routine manner at 
scheduled times during the trial using Medidata Rave.  For this trial the Adverse Event 
CRF is used for routine AE reporting in Rave. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are 
available to describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine AE reporting unless otherwise specified. 
 
 
 


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8. PHARMACEUTICAL INFORMATION 
 
8.1 
CTEP IND Agents 
 
8.1.1 Navitoclax (ABT-263; NSC 750238) 
 
Chemical Name: Benzamide, 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-
yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-
[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl] 
 
Other Names: ABT-263  
 
Classification: Bcl-2 family protein inhibitor 
 
Molecular Formula:C47H55ClF3N5O6S3 
              M.W.: 974.61 g/mol 
 
Approximate Solubility: Navitoclax free base is practically insoluble in water. 
 
Mode of Action: Navitoclax is an orally bioavailable BCL-2 family protein inhibitor that 
binds with high affinity to multiple antiapoptotic proteins including BCL-XL, BCL-2, and 
BCL-W.  Antiapoptotic BCL-2 family members are associated with tumor initiation, disease 
progression, and drug resistance, and compelling targets for oncology drug development. 
 
Description:  White to light pink powder. 
 
How Supplied:  AbbVie supplies and the DCTD/NCI distributes navitoclax as 25 mg and 
100 mg film coated tablets packaged in 28-Count and 30-Count high-density polyethylene 
(HDPE) bottles, respectively. 
 
Note:  Navitoclax must be dispensed in its original bottle.  If need to dispense the exact 
count to patient, removing extra tablet(s) from the original bottle is allowed. Document 
the extra tablet(s) as wasted in Oral DARF. 
 
Navitoclax inactive ingredients: Copovidone, Vitamin E polyethylene glycol succinate, 
colloidal silicon dioxide, croscarmellose sodium, sodium stearyl fumarate (coating, 25 
mg:  iron oxide red or iron oxide yellow, polyvinyl alcohol, polyethylene glycol 3350, 
talc, titanium dioxide; and 100 mg:  iron oxide yellow or oxide red, polyvinyl alcohol, 
polyethylene glycol 3350, talc, titanium dioxide). 
 
Storage:  Store intact bottles of navitoclax at room temperature 150 – 250C (590- 770F), 
protect from light. If a storage temperature excursion is identified, promptly return 
navitoclax to between 15-25°C and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability 
 
Stability:  Shelf life stability studies for the intact bottles of navitoclax are on-going. 


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Route of Administration: Oral. 
 
Method of Administration:  Take navitoclax tablets with food. 
 
Potential Drug Interactions: Navitoclax metabolizes via CYP3A4.  It is a moderate 
inhibitor of CYP2C8 and a strong inhibitor of CYP2C9. Use caution when navitoclax is 
administered with drugs of CYP3A4 inhibitors/inducers, CYP2C8 and CYP2C9 
substrates.  Concomitant use of strong CYP3A4, CYP2C8, CYP2C9 
substrates/inhibitors/inducers or drugs with narrow therapeutic window (e.g., warfarin) 
should be avoided.  Use alternative medications if possible.   
 
Patient Care Implications:   For trials using single agent navitoclax, female patients of 
childbearing potential must agree to use highly effective methods of contraception 
throughout the study and for 30 days after the last dose of study treatment. For clinical 
studies with navitoclax in combination, use of contraception may be longer and male 
subjects may need to use contraceptive methods. 
 
It is unknown whether navitoclax is excreted in human milk; thus, breastfeeding is not 
allowed. 
 
Availability: Navitoclax is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. Navitoclax is provided to the 
NCI under a Collaborative Agreement between the Pharmaceutical Collaborator and the 
DCTD, NCI (see Section 12.3). 
 
8.1.2 Vistusertib (NSC 787289) 
 
Other Names: AZD2014  
 
Classification: mTOR kinase inhibitor 
 
Approximate Solubility: Vistusertib has solubility of >14.8 mg/mL in Simulated Gastric 
Fluid (pH 1.7) and 0.018 mg/mL in Sorensen’s phosphate buffer (pH 6.8). The pKa of 
vistusertib is 6. The melting point of vistusertib is approximately 239°C. 
 
Mode of Action: Vistusertib is an inhibitor of the kinase activity of mammalian Target of 
Rapamycin (mTOR) serine threonine kinase, which plays a critical role in regulating 
cellular energy sensing, growth and metabolism. 
 
Description:  Crystalline powder. 
 
How Supplied:  Vistusertib is supplied by AstraZeneca and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as film-coated tablets available in 
10 mg (plain, round, biconvex, yellow), 25 mg (plain, round, biconvex, yellow), and 50 
mg (plain, round biconvex, or oval, yellow) strengths.  Tablets contain vistusertib, 


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mannitol, microcrystalline cellulose, croscarmellose sodium, povidone and magnesium 
stearate.  The tablet film coat comprises polyvinyl alcohol, titanium dioxide, polyethylene 
glycol 3350, talc and yellow iron oxide.  Each high density polypropylene (HDPE) bottle 
contains 40 tablets. 
 
Storage:  Store at room temperature below 30°C (86°F). If a storage temperature 
excursion is identified, promptly return vistusertib to room temperature below 30°C and 
quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability 
 
Stability:   Based on the planned expiration extension, clinical supply of Vistusertib 
(AZD2014) will expire on August 31, 2021.  Supplies can be used until the terminal lot 
shelf life dating of August 31, 2021 is reached or the NCI inventory is exhausted. 
 
Route of Administration: Oral administration.  Vistusertib can be given with or without 
food. 
 
Potential Drug Interactions: Vistusertib is metabolized by CYP3A/5 and is substrate for 
Pgp (MDR1) and BCRP transporters.  Vistusertib is a weak inhibitor of CYPs 2C8, 2C9, 
2C19, 2D6, and transporters OATP1B1, OATP1B3, MATE1, and MATE2K in vitro.  “Co-
medications which are moderate or strong inhibitors or inducers of CYP3A4/5, Pgp 
(MDR1) and BCRP, or sensitive substrates of CYPs 2C8, 2C9, 2C19, 2D6, or the drug 
transporters OATP1B1, OATP1B3, MATE1 and MATE2K, should be avoided.” 
 
8.2 
Agent Ordering, Accountability and Investigator Brochure Availability 
 
8.2.1 NCI-supplied agents may be requested by the responsible investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution 
where the patient is to be treated.  PMB does not permit the transfer of agents 
between institutions (unless prior approval from PMB is obtained).  The CTEP-
assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each participating 
institution must be registered with CTEP, DCTD through an annual submission of 
FDA Form 1572 (Statement of Investigator), Biosketch, Agent Shipment Form, 
and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application.  Access to OAOP requires the establishment of a CTEP 


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Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call or email PMB any time.  Refer to the PMB’s website for 
specific policies and guidelines related to agent management.   
 
8.2.2 Agent Inventory Records - The investigator, or a responsible party designated by 
the investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the 
CTEP forms page.  Store and maintain separate NCI Investigational Agent 
Accountability Records for each agent, strength, formulation and ordering 
investigator on this protocol. 
 
8.2.3 Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status and a “current” 
password.  Questions about IB access may be directed to the PMB IB coordinator via 
email. 
 
8.2.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• Registration and Credential Repository (RCR):  https://ctepcore.nci.nih.gov/rcr/ 
• RCR Help Desk: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• IB Coordinator: IBCoordinator@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 
 
 
 
 
 
 
 
 


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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Overview 
 
Mandatory research bloods will be obtained in the phase 1 and phase 2 portions of this 
study for integrated correlative studies including navitoclax and vistusertib 
pharmacokinetic profiles. Mandatory tumor biopsies will be obtained in the Phase 2 
portion of this study for integrated correlative biomarker studies. 
 
9.1.1 Blood Samples  
 
During both Phase 1 and Phase 2, mandatory PK blood samples will be obtained at the 
time points as outlined above and on the Study Calendar. In the event that a subject 
cannot have all blood samples or volume needed at a single visit, the samples and/or 
remaining samples should be collected at the next possible visit.  
 
Optional blood samples will be obtained pretreatment, on treatment and at progression 
for exploratory studies. 
 
9.1.2 Tissue Samples  
 
In Phase 2, mandatory tumor biopsies will be obtained pretreatment and on treatment as 
outlined in the study calendar. Optional biopsies will be requested at progression and for 
patients on the Phase 1 portion of the study. In the event that a subject cannot undergo a 
second biopsy for any reason, including refusal, or the baseline biopsy was unsuccessful 
or inevaluable, the subject can continue to be treated per study protocol.  
 
Subjects will undergo a direct or image-guided research biopsy procedure. FNA and on-
site cytopathologic evaluation, where appropriate, will be done for sample/site adequacy 
followed by core biopsies for collection of tissue for the research correlates outlined. The 
biopsy site will be clearly documented in the records; baseline and each follow-up biopsy 
will preferentially be done in the same organ site. Approximately 4-6 core biopsy 
specimens will be obtained with each biopsy as outlined; the cytopathology slide will 
also be retained and submitted, if performed. If a subject discontinues the study prior to a 
planned follow-up biopsy, an attempt should be made to collect the next scheduled 
biopsy when the decision is made to discontinue and prior to initiation of additional 
treatment, if possible.  
 
The study staff will be notified when a biopsy is taking place. If core biopsy is not 
possible, other methods may be approved in advance by the Protocol Chair/designee.  
 
9.1.3 Handling and Shipping of Tissue Specimens  
 
A unique subject identifier will be assigned to each subject by the coordinating center and 
will be used to label the samples. The protocol scientific investigator(s) analyzing the 
samples will be blinded as to the direct subject identifiers.  


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A PK Sheet will be provided for specific handling and processing instructions; this 
document is available on the CTSU website under the Case Report Forms tab.  
 
Sites should contact the laboratory before shipping specimens to ensure the laboratory is 
open and receiving specimens. 
 
Research bloods and biopsies will be sent to Johns Hopkins to the laboratories of Drs. 
 and 
 as described in the PK Sheet. After shipping, samples, and 
associated data, will be stored at Johns Hopkins unless the subject withdraws consent. 
 
9.2 
Integrated Correlative Studies 
 
9.2.1 Navitoclax Pharmacokinetic Profile 
 
Background: This assay will be utilized to determine navitoclax concentrations and 
ultimately the drug exposure.  There is a potential for a drug-drug interaction between 
CYP2C8 with navitoclax as a moderate inhibitor and vistusertib as a substrate. Since 
navitoclax will need to be given for 1 week prior to the combination to attenuate 
thrombocytopenia, a formal drug-drug interaction trial design will not be performed.  
Navitoclax concentrations will be used to correlate with any thrombocytopenia.  We will 
incorporate the expansion to a full pharmacokinetic profile for navitoclax if toxicities are 
frequent and severe with the combination. 
 
Method: Navitoclax blood levels will be measured by LC-MS/MS. The bioanalytical 
method for determining navitoclax in human plasma has been developed and validated 
utilizing liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) 
techniques.  The analytical method was be validated as recommended by the FDA 
Guidance for Industry: Bioanalytical Method Validation, May 2001 (58). Navitoclax was 
extracted from plasma using acetonitrile precipitation. Chromatographic separation was 
achieved with a ACQUITY UPLC® BEH C18 column (1.7 μm 2.1 x 50 mm) and 
isocratic elution with an acetonitrile-water-formic acid mobile phase over a 3 min total 
analytical run time. An AB Sciex 4500 triple quadrupole mass spectrometer operated in 
positive electrospray ionization mode was used for the detection of navitoclax. The assay 
range was 5-5,000 ng/mL and proved to be accurate (89.5-104.9%) and precise (CV ≤ 
11.0%). Long-term frozen plasma stability for navitoclax at -70°C has been determined 
for at least 211 d and is on-going. 
 
Analysis: For navitoclax, individual PK parameters will be estimated for Cmax, AUC, T1/2, 
apparent Cl/F and apparent V/F using non-compartmental or compartmental PK methods 
with the software WinNonlin. Advanced population PK methods may be employed to 
assess the link between drug exposure and biological effects and efficacy. Steady-state 
trough concentrations will also be calculated. The PK parameters will be tabulated and 
descriptive statistics (e.g., geometric means and coefficients of variation) calculated for 
each dose level. The PK parameters (i.e., T1/2, C) will be compared across dose level 
using nonparametic statistical testing techniques. Exploratory correlative studies with 


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pharmacodynamic (biological endpoints, toxicity and efficacy) will be analyzed using 
nonparametric statistics. Significance for comparisons will be at the p<0.05 level. All p 
values for secondary endpoints will be two-sided. 
 
9.2.1.1 
Collection of Specimens 
Blood samples (~6 mL) will be taken into heparin tubes at designated time points, 
and immediately placed on ice.  
• Phase 1 portion: Blood samples will be taken at the following time points: Day -7 
pretreatment, C1D1 pretreatment, C1D1 6 hours post-dose, C1D8 pretreatment, 
C1D15 pretreatment and 1, 2, 3, 4, 6 and 8 hours post-dose, C1D16 pre-treatment 
and C2D1 pretreatment. 
• Phase 1 portion (expanded): If there are multiple DLTs (tolerability issues) an 
additional 7 samples will be collected at the following time points: on D-7 at 1, 2, 
3, 4, 6 and 8 hours after administration, and D-6 pre-treatment (~24 hr after D-7 
administration).  This is in addition to the 12 samples listed above for the standard 
Phase 1 portion. 
• Phase 2 portion: Blood samples will be taken at the following time points: Day -7 
pretreatment, C1D1 pretreatment, C1D8 pretreatment, C1D15 pretreatment and 
C2D1 pretreatment. 
 
If a participant misses a dose of navitoclax or vistusertib during Cycle 1 prior to Cycle 1 
Days 15/16 and will continue on treatment, Dr. 
 should be contacted to 
determine the optimal timing of the PK collection, which may no longer occur on Cycle 1 
Days 15/16. Since navitoclax and vistusertib are to be administered continuously, the 
adjustment may occur in the date of the collection but not the 8 samples to be obtained. 
The exact timing will depend on the duration of interruption and proximity to Cycle 1 
Days 15/16. In some circumstances, the PK collection may be waived due to difficulties 
in re-scheduling the PK. 
 
9.2.1.2 
Handling of Specimens 
 
At each time point, ~6 mL of peripheral blood will be collected in a green-top heparin 
vacutainer (Becton Dickinson Catalog # 367878, Franklin Lakes, NJ).  
1. Obtain venous blood by standard phlebotomy technique from a peripheral access 
point.  NOTE:  Suggest using a minimum 18G needle to avoid sample hemolysis.   
2. Fill-up the tubes as much as possible until blood flow stops. 
3. GENTLY invert each tube several times (8-10 times) immediately after collection 
to avoid sample hemolysis. 
4. Place samples immediately on ice after collection; samples must be processed 
within 30 minutes. 
 
Processing instructions: 
1. Invert sample 8-10 times immediately before processing.   
2. Centrifuge at 2500-3000 rpm for 10 minutes in swinging bucket (SW) or 15 
minutes in a fixed angel (FA) rotor at 4ºC in a refrigerated centrifuge. Make sure 
that the centrifuge reaches speed and is maintained throughout the entire spin. 
-
-


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3. Carefully remove tube from centrifuge.  
4. Using a pipette, transfer equal aliquots of plasma into 2-3 labeled 2 mL cryovials, 
not exceeding ~1 mL per cryovial.   
5. Label samples as navitoclax PK, including study number (NCI10070), unique 
patient ID (assigned by the consortium), initials, date of collection, draw time, and 
time point. 
6. Store plasma samples at -70oC or below until shipment or transfer to Johns 
Hopkins. 
 
9.2.1.3 
Shipping of Specimens 
 
Specimens should be stored through the duration of navitoclax correlative studies 
(through C2D1) and shipped as a batch by participant (more than one 
participant/shipment is acceptable if the site has >1 participant on-study). A 
participant's samples should be shipped to the APC lab within 6 months of the first 
sample's collection date. (i.e., if D-7 sample is collected on 1/1/2017, all of that 
participant's samples should be at the APC lab by 7/1/2017). The APC lab may 
contact the study team to request shipment off-schedule.  The navitoclax and 
vistusertib pharmacokinetic specimens can be shipped in the same shipment. 
 
Please ship 1-2 aliquots to the APC laboratory. Once receipt is confirmed, the 
back-up aliquot may be shipped.  The back-up can be shipped later 
 
Preparing the shipment  
− Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH).  
− Please organize the samples by Patient and Time point in the box.  
− Do not store in plastic bags (they break on dry-ice and labels will detach).  
− A copy of each of the pharmacokinetic sample collection forms for the respective 
patients or a sample list should be included with each shipment. To prevent 
problems with illegible writing on tubes, consider numbering them (in addition to 
sample label) and numbering samples on the sample sheet.  
− Note the study number, PI, and the drugs used/to be measured.  
− A name, phone number and email address should be included with samples so that 
receipt can be acknowledged.  
− Please notify the lab by telephone (410-502-7192 or 410-955-1129) or fax (410-
502-0895) at least 24 hours prior to shipment.  
 
Shipping  
− All samples should be shipped via overnight express courier in insulated 
containers with enough dry ice to maintain the samples in a frozen state.  
− Overnight shipments should occur on Monday through Wednesday (Tuesday is 
the preferred day) except when the following day is a holiday. 
 
Analytical Pharmacology Core Laboratory* 
Attn: NCI10070 Navitoclax/Vistusertib Study Samples 
1650 Orleans St. CRB1 Rm 184 


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Baltimore, MD 21231-1000 
Phone: 410-502-7192 or 410-955-1129 
Fax: 410-502-0895 
 
9.2.1.4 
Sites Performing Correlative Study 
 
ETCTN Central Laboratory: Dr. 
, The Analytical Pharmacology Core 
Laboratory at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
(SKCCC) 
 
9.2.2 Vistusertib Pharmacokinetic Profile 
 
Background: This assay will be utilized to determine vistusertib concentrations and 
ultimately the drug exposure.  Since navitoclax will need to be given for 1 week prior to 
the combination to attenuate thrombocytopenia, a formal drug-drug interaction trial 
design will not be performed. Vistusertib trough concentrations will be assessed over the 
course of the first cycle to compare to historical controls and correlate with toxicity, 
efficacy and pharmacodynamics correlatives. 
 
Method: Vistusertib blood levels will be measured by LC-MS/MS. The bioanalytical 
method for determining vistusertib in human plasma has been developed and validated 
utilizing liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) 
techniques.  The analytical method was validated as recommended by the FDA Guidance 
for Industry: Bioanalytical Method Validation, May 2001 (58). Vistusertib was extracted 
from plasma using acetonitrile precipitation. Chromatographic separation was achieved 
with an ACQUITY UPLC® BEH C18 column (1.7 μm 2.1 x 50 mm) and isocratic elution 
with an acetonitrile-water-formic acid mobile phase over a 3 min total analytical run 
time. An AB Sciex 4500 triple quadrupole mass spectrometer operated in positive 
electrospray ionization mode was used for the detection of vistusertib. The assay range 
was 5-5,000 ng/mL and proved to be accurate (98.7-105.7%) and precise (CV ≤ 10.5%). 
Long-term frozen plasma stability for vistusertib at -70°C is on-going. 
 
Analysis: Trough concentrations for vistusertib will be obtained to correlate with 
pharmacodynamics outcomes; a full profile will be employed if there are multiple DLTs 
(tolerability issues). Steady-state trough concentrations will be calculated. Steady-state 
trough concentrations will be tabulated and descriptive statistics (e.g., geometric means 
and coefficients of variation) calculated for each dose level. Steady-state trough 
concentrations will be compared across dose level using nonparametric statistical testing 
techniques. Exploratory correlative studies with pharmacodynamic (biological endpoints, 
toxicity and efficacy) will be analyzed using nonparametric statistics. Significance for 
comparisons will be at the p<0.05 level. 
 
9.2.2.1 
Collection of Specimen(s) 
 
Blood samples (~6 mL) will be taken into heparin tubes at designated time points, 
and immediately placed on ice.  


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• Phase 1 portion: Blood samples will be taken at the following time points: C1D1 
pretreatment, C1D1 2 hours post-treatment, C1D8 pre-treatment, C1D15 
pretreatment, C1D15 2 hours post-treatment and C2D1 pretreatment. 
• Phase 1 portion (expanded): If there are multiple DLTs (tolerability issues) an 
additional 8 samples will be collected at the following time points: on C1D15 at 
0.5, 1, 1.5, 2, 4, 6 and 8 hours after administration, and C1D16 pre-treatment 
(~24hr after C1D15 administration). This is in addition to the 4 samples listed 
above for the standard Phase 1 portion. 
• Phase 2 portion: Blood samples will be taken at the following time points: C1D1 
pretreatment, C1D8 pretreatment, C1D15 pretreatment and C2D1 pretreatment. 
 
9.2.2.2 
Handling of Specimens(s)  
 
At each time point, ~6 mL of peripheral blood will be collected in a green-top heparin 
vacutainer (Becton Dickinson Catalog # 367878, Franklin Lakes, NJ).  
 
1. Obtain venous blood by standard phlebotomy technique from a peripheral access 
point.  NOTE:  Suggest using a minimum 18G needle to avoid sample hemolysis.   
2. Fill-up the tubes as much as possible until blood flow stops. 
3. GENTLY invert each tube several times (8-10 times) immediately after collection 
to avoid sample hemolysis. 
4. Place samples immediately on ice after collection; samples must be processed 
within 30 minutes. 
 
Processing instructions: 
1. Invert sample 8-10 times immediately before processing.   
2. Centrifuge at 2500-3000 rpm for 10 minutes in swinging bucket (SW) or 15 
minutes in a fixed angel (FA) rotor at 4ºC in a refrigerated centrifuge.  Make sure 
that the centrifuge reaches speed and is maintained throughout the entire spin. 
3. Carefully remove tube from centrifuge.  
4. Using a pipette, transfer equal aliquots of plasma into 2-3 labeled 2 mL cryovials, 
not exceeding ~1 mL per cryovial.   
5. Label samples as vistusertib PK, including study number (NCI10070), unique 
patient ID (assigned by the consortium), initials, date of collection, draw time, and 
time point. 
6. Store plasma samples at -70oC or below until shipment or transfer to Johns 
Hopkins. 
 
9.2.2.3 
Shipping of Specimens 
 
Specimens should be stored through the duration of navitoclax correlative studies 
(through C2D1) and shipped as a batch by participant (more than one 
participant/shipment is acceptable if the site has >1 participant on-study).  Details on 
shipments to the Analytical Pharmacology Core Laboratory at the Sidney Kimmel 
Comprehensive Cancer Center at Johns Hopkins (SKCCC) can be found in Section 
9.3.1.3. 


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9.2.2.4 
Site Performing Correlative Study 
 
ETCTN Central Laboratory: Dr. 
, The Analytical Pharmacology Core 
Laboratory at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
(SKCCC) 
 
9.2.3 Pharmacodynamic Studies: Reverse Phase Protein Array (RPPA) 
 
Background: RPPA is a quantitative assay that analyzes nanoliter amounts of sample for 
potentially hundreds of proteins.  This antibody-based assay determines levels of protein 
expression, as well as protein modifications such as phosphorylation, cleavage, and fatty 
acid modification and allows concordant interrogation of multiple signaling molecules 
and their functional status. Major strengths include identification and validation of 
cellular targets, characterization of signaling pathways and networks, as well as 
determination of on and off target activity of novel drugs. Samples are analyzed for 
proteins involved in cell cycle progression, apoptosis, functional proteomics, and 
signaling networks.  The integrated information will display the potential biomarkers to 
predict intracellular signaling networks and functional outcomes affected by therapeutics. 
RPPA has been used to profile and validate signaling networks in human cancer cell lines 
and tumor tissue. 
 
Methods: Paired pre-treatment and on treatment core biopsies will be obtained from 
patients on the phase 2 portion of the trial in order to provide the opportunity to correlate 
pharmacodynamic effects with tumor response and pharmacokinetic parameters at the 
RP2D. Pre-treatment biopsies will be obtained during screening and on-treatment 
biopsies will be obtained on Cycle 1 Day 15 (+/-7days).   
 
Protein extracted from snap frozen tissue will be adjusted to a concentration of 1ug/ul, 
denatured by SDS. The lysates will be serial diluted to define the linear range of each 
antigen-antibody reaction and will be printed on nitrocellulose-coated slides and probed 
with validated antibodies (antibody list attached).  A Tecan robotic liquid handling 
system is utilized for serial dilution of cell lysates and sample transfer; a G3 GeneTac 
arrayer and an Aushon 2470 arrayer for printing of up to 24 (G3) or 100 slides (2470) per 
run. A Biogenix i600TM and two DAKO Universal Staining systems are used to probe 
each slide with a different antibody. Each autostainer is capable of staining 
approximately 60 slides per day under conditions that are specific for each individual 
antibody. Signals are captured by tyramide dye deposition (CSA System, DAKO). 
 
9.2.3.1 
Collection and Handling of Specimens 
 
The time points of collection are provided in the study calendar (Section 10).   
 
Below is a guideline for a recommended procedure. 
 
1. Obtain 3 biopsy cores preferably 16g or 14g needle, 18g minimum – the larger the bore 


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the better within reason. 
2. Samples should be labeled with the NCI protocol number (NCI10070), unique patient ID 
(assigned by the consortium), “RPPA”, initials, date of collection, draw time, and time 
point. 
3. Snap freeze in liquid nitrogen and store at -80 degrees Celsius until shipping. 
 
9.2.3.2 
Shipping of Specimen(s) 
 
Biopsy specimens for RPPA should be sent on dry ice to:  
 
Johns Hopkins SKCCC 
1550 Orleans Street, CRB2, 
 
Baltimore, MD 21287 
Tel:
Fax:
 
Samples will be sent to Dr. 
 lab in batches every 3-6 months 
 
9.2.3.3 
Sites Performing Correlative Study 
 
The 
 Lab at MD Anderson Cancer Center, Houston, TX 
 
9.3 
Exploratory/Ancillary Correlative Studies 
 
When available, archival tissue and fresh biopsies (pretreatment, on-treatment and on 
progression) and plasma will be studied to identify biomarkers associated with drug 
activity.  
 
9.3.1 Optional blood and tissue collection for correlative genomic studies 
 
The following samples will be optional for subjects on study:  
• Archival tumor tissue: FFPE block (preferred) or 25 x 5 micron slides, cut under 
DNA/RNA precautions mounted on plus slides. Please do not prebake the slides. 
• Fresh tissue biopsy: FFPE or flash frozen samples collected at the time points 
listed in the Study Calendar (Section 10). Please collect snap frozen samples as 
described in the laboratory manual 
• Peripheral blood: 2 x 10ml collected in Streck tubes at time points listed in the 
Study Calendar (Section 10). Streck tubes can be provided by JHH.  
 
9.3.1.1 
Collection and Handling of Optional Blood and Tissue Specimens 
 
A Laboratory Manual will be provided for specific handling and processing 
instructions; this document will be disseminated with the clinical protocol. 
 
Optional peripheral blood handling: 
1. At each time point, 2 x 10 mL of peripheral blood will be collected in Streck tube  


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2. Obtain venous blood by standard phlebotomy technique from a peripheral access 
point. Suggest using a minimum 21G needle.   
3. Fill-up the tubes as much as possible until blood flow stops. 
4. GENTLY invert each tube 8-10 times immediately after collection  
5. Samples should be labeled with the NCI protocol number (NCI10070), unique 
patient ID (assigned by the consortium), “Peripheral Blood”, initials, date of 
collection, draw time, and time point. 
6. STORE tubes at ambient temperature 
7. SHIP at ambient temperature within 3 days of blood collection 
 
9.3.1.2 
Shipping of Specimen(s) 
 
Optional Tissue and Blood Specimens should be sent to:  
 
Johns Hopkins SKCCC 
1550 Orleans Street, CRB2, 
 
Baltimore, MD 21287 
Tel: 
Fax:
 
 
 






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Base-
line 
Run-In 
D(-7) C1D1 C1D8 
C1 
D15 
C1 
D16 
C2D1 
C2 
D15 
C3D1, 
etc 
C3 
D15, 
etc 
Off 
Study 
l: Adverse event evaluation as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
m: During the run-in period additional platelet counts may be performed at the discretion of the treating investigator 
or as clinically indicated. 
n: Plasma for Biomarkers will be collected whenever Disease Assessment imaging is performed. 
o: EKG to be done prior to dosing and at 2 hours and 6 hours after dosing of navitoclax and vistusertib 
p: 3 EKGs must be obtained if abnormal QT interval is present during baseline/screening.  
 
 
 




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Base-
line 
Run-In 
D(-7) C1D1 C1D8 
C1 
D15 
C1 
D16 
C2D1 C3D1, 
etc 
Off 
Treatmentq 
Follow 
Upr 
b: As described in section 6.6, additional echocardiograms may be performed in the event of abnormal ECGs or if 
otherwise indicated. 
c: For WOCBP (women of childbearing potential) only: A urine pregnancy test is required ≤7 days prior to the 
first dose of navitoclax. 
d: CT scan of the chest and other relevant sites will be performed ≤ 4 weeks prior to the start of therapy. For 
SCLC or other tumor types where brain metastases are common, MRI brain with gadolinium (or CT scan brain 
with contrast if MRI is contraindicated) should also be performed at Baseline. MRI window is between 2 
weeks and start of D-7 Navitoclax lead-in dose. 
e: Subjects will receive lead-in dosing of navitoclax at 150mg daily for 7 days prior to C1D1. At any time after 
7 days of navitoclax, if the platelet count is >50,000 and stable or increasing, the subject can start Phase 2 
dosing of navitoclax and vistusertib. 
f: Dose as assigned; daily by mouth. 
g: Dose as assigned, BID by mouth, unless alternative dosing schedule has been used. 
h: On all PK days specimens will be collected prior to dosing. In addition on C1D1 PK specimens will be drawn at 
2 hours after dosing for vistusertib and at 6 hours after dosing for navitoclax. On C1D15, PK specimens will be 
drawn at 1, 2, 3, 4, 6, and 8 hours after dosing. If there are multiple DLTs (tolerability issues), additional samples 
will be collected on Day -7 at 1, 2, 3, 4, 6 and 8 hours after dosing, Day -6 pre-dose, C1D15 at 0.5 and 1.5 hours 
post-dose as described in sections 9.2.1.1 and 9.2.2.1. 
i: On all PK days specimens will be collected prior to dosing. If dose is missed during C1D1, Dr. 
 should 
be contacted to determine optimal timing collection. 
j: After any grade 4 platelet count <25,000/mm3 is observed for the first time per month in a subject, serial PK 
samples will be collected. PK samples will be collected as soon as possible after the grade 4 platelet count 
is determined and then 24 and 48 hours after the event. 
k: Mandatory fresh tissue will be collected during Phase 2 for integrated biomarker studies at baseline and 
C1D15. A biopsy at time of progression is optional. Phase 1 participants may opt to provide fresh tissue at any 
of these time points. We recommend that participating sites follow their institutional guidelines regarding 
threshold platelet counts required for biopsy and minimal duration between last platelet count and on-study 
biopsy. General guidelines followed at Hopkins include: a threshold platelet count of 50,000 -70,000 for core 
biopsy and a maximum of 2 days between last platelet check and biopsy. 
l: Adverse event evaluation as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
m: During the run-in period additional platelet counts may be performed at the discretion of the treating 
investigator or as clinically indicated. 
n: Plasma for Biomarkers will be collected whenever Disease Assessment imaging is performed. 
o: EKG to be done prior to dosing and at 2 hours and 6 hours after dosing of navitoclax and vistusertib  
p: Triplicate EKG must be obtained for eligibility. 
q: Off treatment assessments will be conducted 30 days (+ 14 days) after the last dose of either study drug. 
r: For patients taken off study for reasons other than disease progression, will continue imaging studies every 8 
weeks until disease progression, start of a new therapy, or 2 years from registration. Survival status will be 
collected every 12 weeks by clinic or by telephone until 2 years from registration. 
 
 


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11. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of these drugs has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be 
carefully monitored for tumor response and symptom relief in addition to safety and 
tolerability.  Patients with measurable disease will be assessed by standard criteria.   
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated every 8 weeks.  In addition 
to a baseline scan, confirmatory scans will also be obtained 8 (not less than 4) weeks 
following initial documentation of an objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) (59).  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant 
lymph nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with navitoclax and/or vistusertib. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Tumor lesions that are situated in a previously irradiated area may only be considered 
measurable if they are growing on pre-treatment imaging. 


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Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic 
metastases can be considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 


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83 
 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 


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cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published (60-
62).  In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression 
criteria which are to be integrated with objective tumor assessment for use in first-line 
trials in ovarian cancer (63) 
 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 


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Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
 


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11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/ Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/ Non-
PD/  
not evaluated 
No 
PR 
SD 
Non-CR/ Non-
PD/ 
not evaluated 
No 
SD 
Documented at least once 
≥4 wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.”  Every effort should be 
made to document the objective progression even after discontinuation of 
treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 


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Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival (PFS) 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
11.1.7 Response Review 
 
There is no independent or central review of the radiology assessments planned for this 
trial. It is the responsibility of each Principal Investigator to ensure that tumor 
assessments are reported per the RECIST 1.1 criteria outlined above. The Protocol Chair 
(or her designee) may choose to review select cases. 
 
 
 
 
 
 
 
 


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12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol 
Principal Investigator is responsible for monitoring the conduct and progress of the 
clinical trial, including the ongoing review of accrual, patient-specific clinical and 
laboratory data, and routine and serious adverse events; reporting of expedited adverse 
events; and accumulation of reported adverse events from other trials testing the same 
drug(s).  The Protocol Principal Investigator and statistician have access to the data at all 
times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose 
escalation/expansion/de-escalation require sign-off by the Protocol Principal Investigator 
through the CTMS/IWRS.  In addition, for the Phase 1 portion, the Protocol Principal 
Investigator will have at least monthly, or more frequently, conference calls with the 
Study Investigators and the CTEP Medical Officer(s) to review accrual, progress, and 
adverse events and unanticipated problems.   
 
For a Phase 1/2 trial, enrollment to the Phase 2 portion of the trial will not begin until a 
protocol amendment has been submitted which summarizes the Phase 1 results, the 
recommended Phase 2 dose, and the rationale for selecting it.  The amendment must be 
reviewed and approved by CTEP before enrollment to the Phase 2 portion can begin. 
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to 
the second stage of a Phase 2 trial will require sign-off by the Protocol Principal 
Investigator and the Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given 
protocol are responsible for timely submission of data via Medidata Rave and timely 
reporting of adverse events for that particular study.  This includes timely review of data 
collected on the electronic CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety 
monitoring plan. 
 
12.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system 


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and role assignments.  To access Rave via iMedidata: 
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account, and  
• 
Assigned one of the following Rave roles on the relevant Lead Protocol 
Organization (LPO) or Participating Organization roster at the enrolling site:  
Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator.  Refer to https://ctep.cancer.gov/investigatorResources/default.htm 
for registration types and documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type, 
o To hold Rave Investigator role, the individual must be registered as an 
NPIVR or IVR, and 
o To hold Rave Read Only role, site staff must hold an Associates (A) 
registration type. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata.  To accept the invitation, site staff must log in to the 
Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM username 
and password, and click on the accept link in the upper right-corner of the iMedidata 
page.  Site staff will not be able to access the study in Rave until all required Medidata 
and study specific trainings are completed.  Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right 
pane of the iMedidata screen.  If an eLearning is required and has not yet been taken, the 
link to the eLearning will appear under the study name in iMedidata instead of the Rave 
EDC link; once the successful completion of the eLearning has been recorded, access to 
the study in Rave will be granted, and a Rave EDC link will display under the study 
name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will also receive a separate invitation 
from iMedidata to activate their account.  Account activation instructions are located on 
the CTSU website in the Rave section under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance).  Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > 
Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com.   
 
12.2.1 Method 
 
For studies assigned for CTMS Comprehensive Monitoring: 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  


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For CTMS monitored studies, after users have activated their accounts, please contact the 
Theradex Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for 
additional support with Rave and completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.
htm)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS 
will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/
interoperability-and-semantics/metadata-and-models).  Customized eCRFs will be 
included when appropriate to meet unique study requirements.  The PI is encouraged to 
review the eCRFs, working closely with CTMS to ensure prospectively that all required 
items are appropriately captured in the eCRFs prior to study activation.  CTMS will 
prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 


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Guidelines (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/
adverse events.htm). 
 
12.2.3 Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports.  Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website.  Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note:  Some Rave protocols may not have delinquent form details or reports specified on 
the DQP.  A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP.  Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality 
 
12.3 
CTEP Multicenter Guidelines 
N/A  
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI 
Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained within the terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators.  The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 


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distributed without the permission of the NCI.  If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement.  A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator (http://ctep.cancer.gov/
industryCollaborations2/intellectual_property.htm). Additionally, all Clinical Data 
and Results and Raw Data will be collected, used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 
30 days from the date of receipt for review.  Collaborator shall have the right to 
request that publication be delayed for up to an additional 30 days in order to ensure 
that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 


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preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings.  Press releases and other 
media presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
Email:  ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
 
 


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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a phase 1/2 study of the combination of navitoclax plus vistusertib for patients 
with recurrent SCLC and other solid tumors. The primary endpoint of the phase 1 portion 
is to study the safety and tolerability of the combination in patients with advanced solid 
tumors. The primary endpoint of the phase 2 portion is to assess the response rate of the 
combination in patients with recurrent SCLC. 
 
13.1.1 Phase 1: Dose Escalation 
 
The primary endpoint for the dose escalation portion of this trial will be toxicity as 
graded by CTCAE v.4.0. All patients who start treatment will be included in the 
summaries of toxicity. 
 
The Phase 1 portion will follow a dose-escalation schema with standard 3+3 design.   At 
least 3 patients must be treated for 4 weeks without the development of a DLT prior to 
treating a new cohort at a higher dose level. The occurrence of 1 dose-limiting toxicity 
(DLT) will prompt expansion of a given dose level to 6 subjects. The occurrence of 2 
DLTs will mean that the maximal tolerated dose has been exceeded, and expansion of the 
prior dose level to 6 subjects will occur, if not already performed.  Dose escalation will 
proceed until the MTD is determined, or until the recommended phase 2 dose (RP2D) of 
each compound individually is reached.  
 
The dose of drugs used for the Phase 2 portion of the trial will be the highest dose level at 
which no more than 1 subject out of 6 experiences a DLT. 
 
During the Phase 1 portion of the study, 14 subjects were enrolled. Five subjects were 
deemed not evaluable – 4 did not complete the DLT period and 1 did not comply with the 
expected study dosing. No  DLTs were observed in the first 3 subjects enrolled to Dose 
Level 1. Two of the three subjects experienced grade 3 elevated ALT/AST at Dose Level 
2. Three additional subjects were enrolled to Dose Level 1. No DLTs were observed in 
these subjects. Based on this information, we determined the RP2D dose to be Dose 
Level 1: navitoclax 150 mg by mouth once a day plus vistusertib 35 mg by mouth twice a 
day. 
 
13.1.2 Phase 2 
 
The primary endpoint for the phase 2 portion of this trial will be objective response rate 
(ORR), defined as the proportion of eligible subjects who have a complete response (CR) 
or partial response (PR) using RECIST 1.1 criteria.  A Simon's optimal two-stage design 
(57) will be used. The null hypothesis that the true response rate is 5% will be tested 
against a one-sided alternative. The alternative hypothesis in this Simon two-stage design 
is 20%. In the first stage, 12 patients will be accrued. If there are 0 responses in these 12 
patients, the study will be stopped. Otherwise, 25 additional patients will be accrued for a 






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13.4 
Analysis of Primary Endpoints  
 
13.4.1 Phase 1  
 
Safety and tolerability will be analyzed through the incidence of adverse events, serious 
adverse events, and specific laboratory abnormalities (worst grade). Toxicities will be 
tabulated by type and grade for all doses and presented using frequencies and percentages 
based on the NCI CTCAE v4.0. The proportion of DLTs at each dose level will be 
reported with exact binomial 95% confidence intervals.  
 
13.4.2 Phase 2  
 
All patients who meet eligibility criteria and receive at least one dose of the study drug 
will be included in the interim and final analysis of the primary objective.  Each patient 
will be assigned one of the following categories:  1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 
6) early death from toxicity, 7) early death because of other cause, or 8) unknown (not 
assessable, insufficient data).   
 
Patients in response categories 3-8 will be included in the denominator for the interim 
and final analyses. The ORR (response categories 1 and 2) will be reported with its 
corresponding 95% confidence interval. 
 
13.5 
Analysis of Secondary Endpoints 
 
13.5.1 Phase 1 
 
The secondary endpoint for the dose escalation portion of this trial is to preliminarily 
assess whether a bi-directional pharmacokinetic interaction occurs when navitoclax and 
vistusertib are co-administered.  
 
Descriptive statistics will be provided for selected PK, and PD data by dose and time as 
appropriate. Descriptive statistics on continuous data will include means, medians, 
standard deviations, and ranges, while categorical data will be summarized using 
frequency counts and percentages. Graphical summaries of the data may be presented.  
 
For navitoclax and vistusertib, steady-state trough concentrations will be calculated. For 
vistusertib, individual PK parameters will be estimated for Cmax, AUC, T1/2, apparent 
Cl/F, and apparent V/F using non-compartmental or compartmental PK methods with the 
software WinNonlin. Advanced population PK methods may be employed to assess the 
link between drug exposure and biological effects and efficacy. The PK variables will be 
tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) 
calculated for each dose level. PK parameters (i.e., T½, Cl, and AUC) will be compared 
across dose level using nonparametic statistical testing techniques. Exploratory 
correlative studies with pharmacodynamic (biological endpoints, toxicity and efficacy) 


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will be analyzed using nonparametric statistics. Significance for comparisons will be at 
the p<0.05 level. All p values for secondary endpoints will be two-sided. 
 
Operating characteristics of the 3+3 study design 
   
A summary of the results of a series of simulations for standard 3+3 dose escalation are 
given below to demonstrate the operating characteristics of this design when the true 
probabilities of toxicity are varied by scenario.  The target probability of DLT with 
standard 3+3 designs is <30% for all simulations and results are from 1,000 repetitions of 
the trial.   
 
For each scenario and dose level, the table reports the simulated true toxicity (true tox), 
the mean number of patients across simulations at a dose level (N pat), the mean number 
of DLTs across simulations at that dose level (N DLT), the percentage of DLTs at that 
dose level (sum of DLTs/ sum of patients; % DLT), the percent of time a dose level was 
the recommended dose (% Recommend), and the overall percentage of time patients were 
treated at a dose (% Experimentation). 
 
Scenario 1:  Highest dose less than 30% is dose level 3: 
   
true 
tox 
N 
pat 
N 
DLT 
% 
DLT 
% 
Recommend 
% 
Experimentation 
dose 1   0.10 
3.81 
0.42 
0.11 
31 
33.96 
dose 2   0.20 
3.66 
0.82 
0.22 
28 
32.62 
dose 3   0.25 
2.46 
0.68 
0.28 
19 
21.93 
dose 4   0.35 
1.29 
0.47 
0.36 
9 
11.50 
Overall:  No Recommendation 13% 
 
Mean patients 11.22 
 
Mean DLTs 2.39 
 
Mean last dose 2.5 
 
 
Scenario 2:  Highest dose less than 30% is dose level 2: 
 
true 
tox 
N 
pat 
N 
DLT 
% 
DLT 
% 
Recommend 
% 
Experimentation 
dose 1   0.20 
4.08 
0.80 
0.11 
29.1 
42.28 
dose 2   0.25 
3.02 
0.77 
0.22 
25.3 
31.33 
dose 3   0.35 
1.83 
0.64 
0.28 
12.2 
18.96 
dose 4   0.40 
0.72 
0.30 
0.36 
5.0 
7.43 
Overall:  No Recommendation 28.4% 
 
Mean patients 9.65 
 
Mean DLTs 2.51 
 
Mean last dose 2.03 
 
 
Scenario 3:  Highest dose less than 30% is dose level 1: 
 
true 
tox 
N 
pat 
N 
DLT 
% 
DLT 
% 
Recommend 
% 
Experimentation 
dose 1   0.25 
4.28 
1.09 
0.26 
35.9 
53.35 


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99 
 
dose 2   0.35 
2.51 
0.89 
0.36 
16.2 
31.35 
dose 3   0.40 
0.96 
0.40 
0.42 
4.7 
12.01 
dose 4   0.45 
0.26 
0.11 
0.41 
1.9 
3.29 
Overall:  No Recommendation 41.3% 
 
Mean patients 8.01 
 
Mean DLTs 2.49 
 
Mean last dose 2.47 
 
 
Scenario 4:  Highest dose less than 30% is below dose level 1: 
 
true 
tox 
N 
pat 
N 
DLT 
% 
DLT 
% 
Recommend 
% 
Experimentation 
dose 1   0.30 
4.37 
1.31 
0.30 
29.9 
57.90 
dose 2   0.35 
2.15 
0.74 
0.34 
13.9 
28.53 
dose 3   0.40 
0.82 
0.33 
0.41 
3.8 
10.82 
dose 4   0.50 
0.21 
0.10 
0.48 
1.3 
2.75 
Overall:  No Recommendation 51.1% 
 
Mean patients 7.5 
 
Mean DLTs 2.48 
 
Mean last dose 1.22 
 
Scenario 5:  Highest dose less than 30% is above dose level 4: 
 
true 
tox 
N 
pat 
N 
DLT 
% 
DLT 
% 
Recommend 
% 
Experimentation 
dose 1   0.05 
3.27 
0.09 
0.03 
8 
23.85 
dose 2   0.10 
3.63 
0.34 
0.09 
18 
26.48 
dose 3   0.15 
3.69 
0.58 
0.16 
22 
26.91 
dose 4   0.20 
3.12 
0.62 
0.20 
52 
22.76 
Overall:  No Recommendation 0.0% 
 
Mean patients 13.71 
 
Mean DLTs 1.63 
 
Mean last dose 3.66 
 
13.5.2 Phase 2  
 
The secondary endpoints of the phase 2 portion of this study are to assess safety and 
tolerability, progression free survival (PFS), overall survival (OS) and disease control 
rate based on RECIST 1.1. The proportion of toxicities by type and grade in the phase 2 
study will be reported with exact binomial 95% confidence intervals. Standard life table 
methods will be used to analyze PFS and OS.  We will report the one-year and median 
PFS and OS with 95% confidence intervals.  The DCR is defined as the sum of CR, PR, 
and SD divided by the total number of patients in the phase 2 part of the study. The 
proportion of patients achieving disease control will be reported with exact 95% binomial 
confidence intervals.  If a patient is allowed to stay on study for clinical benefit past 
progression, for the purposes of the analysis of PFS, the event will be dated at the first 
documentation of progression by RECIST 1.1 criteria. 
 


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13.6 
Safety monitoring and early stopping rules for safety 
 
Safety will be monitored after every patient in the phase 2 portion of the study, using the 
same definition of DLT as in the dose-escalation part of the study.  The stopping rule for 
safety is based on the posterior probability that the adverse event (AE) rate is too high.  
Trial enrollment will be suspended for a safety evaluation if the AE rate convincingly 
exceeds 30%.  This stopping rule will halt enrollment and trigger review of the data by 
the study team if the posterior probability of the AE rate exceeding 0.30 is 70% or higher.  
The prior probability for this toxicity monitoring rule will be a Beta distribution with 
parameters of 1 and 5, based on the assumption that there was one toxicity in the cohort 
of six patients treated at the MTD in the dose escalation.  The stopping rule applies this 
prior distribution to the observed number of patients experiencing an AE and computes 
the resulting posterior probability that the rate is too high.  If the posterior certainty that 
the rate is too high based on these assumptions is 70% or higher, the study should stop.  
The following table shows the resulting rules. 
 
Study paused 
if:  
3 AEs 
4 AEs 
5 AEs 
6 AEs 
7 AEs 
8 AEs 
And patients 
between: 
3-4 
5-7 
8-10 
11-13 
14-16 
17-19 
 
Study paused if:  9 AEs 
10 AEs 
11 AEs 
12 AEs 
13 AEs 
14 AEs 
And patients 
between: 
20-22 
23-25 
26-28 
29-31 
32-35 
36-37 
 
For example, the rule will call for stopping the study if 4 out of the first 5 patients 
experience AEs.  The next table shows the percent of the time that the stopping rule will 
terminate the study under different hypothetical risks of AEs, along with the average 
sample size (based on 5000 simulations).  
 
Risk of AE 
0.10 
0.20 
0.25 
0.30 
0.35 
0.40 
0.45 
0.50 
% of Time 
Study Stops 
0.7% 
8.8% 
20.3% 
41.2% 
62.1% 
80.4% 
93.2% 
97.8% 
Expected 
Sample Size 
36.8 
34.7 
32.2 
27.5 
22.9 
17.9 
13.3 
10.5 
 
 
13.7 
Analysis of Correlative Endpoints 
 
13.7.1 Reverse Phase Protein Array (Integrated Biomarker) 
 
Intensity of protein expression will be analyzed following standard data normalization for 
this type of array.  Vistusertib is an ATP-competitive inhibitor of TORC1 and TORC2 


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complexes. The primary measure for assessing the PD effect of a drug on inhibition of 
TORC1 is decreased phosphorylation of 4EBP1 and S6. We will measure 
phosphorylated-4EBP1 (p4EBP1) and phosphorylated-S6 (primary measurement) as well 
as the ratio of p4EBP1 and pS6 to total (p4EBP1/4EBP1; pS6/S6) (secondary 
measurement) before and on treatment.  Use of the ratio (phosphorylated to total) has 
been previously described in publications from the 
 group as another indicator of 
pathway activation status.  In addition, it is expected that AZD2014 drug exposure 
sufficient to reduce p4EBP1 (and pS6) will result in reduced MCL-1 (due to decreased 
p4EBP1) and correlate with increased BAX, both of which may be associated with 
response. BAX and MCL-1 intensity will be measured pre- and on-treatment. Descriptive 
statistics and box plots with jittered data points will be used to visualize all raw data. The 
overall changes in p4EBP1, the ratio p4EBP1/4EBP1, pS6/S6, BAX, and MCL-1 will be 
assessed with paired t-tests. With at least 17 paired biopsies, we would be able to detect a 
one standard deviation change, assuming a correlation of 0.1, with 82% power and a two-
sided alpha of 0.05. Exploratory correlative studies with pharmacodynamics (biological 
endpoints, toxicity and efficacy) will be analyzed using nonparametric statistics. 
 
The Simon two-stage design for the primary objective requires that there is one response 
for the study to continue to the second stage.  If the study is a success, four or more 
responses will have been observed at the final analysis.  If all of the responders have 
biopsies, the sample size for comparisons between responders and non-responders would 
be 4 responders and 13 non-responders.  In this case, assuming conservatively 4 per 
group, if the coefficient of variation in the pre and post treatment changes is 80% or less, 
there would be 81% power to detect fold changes of 3.2 with one-sided 0.10 alpha level 
t-tests.  First priority will be given to comparisons between responders and non-
responders.  If the number of responders with paired biopsies is lower than expected, 
Cuzick non-parametric tests for trend will be used to assess pre minus post changes 
across categories of progressive disease, stable disease and response (64). 
 
Data from biopsies taken at baseline will be used to provide estimates of the intra-patient 
standard deviations for p4EBP1, pS6, BAX, and MCL-1 as measured with RPPA.  
Because repeated samples of tumor biopsies are not possible, the inter-patient variability 
will be used as a conservative estimate since this will always be greater than the intra-
patient variability. 
 
As suggested for phase 0 testing (65), a statistically significant (at the 0.10 significance 
level) response at the patient level will be defined as post treatment changes that are 1.8 
times this baseline standard deviation. Summaries of the proportions of these responses 
with 90% confidence intervals will be provided. If there are a reasonable number of 
responses, logistic regression models or Fisher’s exact tests may be used to assess if 
patients with protein marker responses also have an increased probability of achieving an 
OR. 
 
13.8 
Reporting and Exclusions 
 
13.8.1 Evaluation of Toxicity 


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102 
 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
navitoclax and vistusertib.  
 
13.8.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).   
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 
 
 


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61. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, et al. Eligibility 
and response guidelines for phase II clinical trials in androgen-independent prostate cancer: 
recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 
1999;17:3461-7. 
62. Sonpavde G, Fleming MT, Hutson TE, Galsky MD. Trial design for metastatic castration-
resistant prostate cancer. J Clin Oncol. 2008;26:3647-8; author reply 8-9. 
63. Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK, et al. 
Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. 
Gynecologic Cancer Intergroup. J Natl Cancer Inst. 2000;92:1534-5. 
64. Cuzick J. A Wilcoxon-type test for trend. Statistics in medicine. 1985;4:87-90. 
65. Rubinstein LV, Steinberg SM, Kummar S, Kinders R, Parchment RE, Murgo AJ, et al. The 
statistics of phase 0 trials. Statistics in medicine. 2010;29:1072-6. 
 
 


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


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APPENDIX B. PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drugs, navitoclax and vistusertib.  This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
 
Navitoclax and vistusertib interact with certain specific enzymes in the liver and certain transport 
proteins that help move drugs in and out of cells.  
 
• The enzymes in question are CYP 3A4 and 3A5. Navitoclax and vistusertib are 
metabolized by these enzymes and may be affected by other drugs that strongly inhibit or 
induce CYP3A4 and 3A5.  
• Navitoclax is also a moderate inhibitor of CYP2C8 and a strong inhibitor of CYP2C9 and 
may prevent other drugs that need these enzymes to be processed further in the liver.  
• Vistusertib is a substrate of the drug transport proteins P-glycoprotein (P-gp) and breast 
cancer resistance protein (BCRP).  
• Vistusertib induces CYP3A4 in test tubes but it is not known if this will happen in 
patients. Concomitant treatment with vistusertib may increase the exposure to specific 
substrates of the drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K. 
Substrates of these drug cannot be given until after the appropriate wash-out period (a 
minimum of 5 x reported elimination half-life) before the first dose of vistusertib.  
 
 
TO THE PATIENT: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Navitoclax and vistusertib may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know:  
 






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APPENDIX D. DRUG ADMINISTRATION DIARY FOR NAVITOCLAX AND 
VISTUSERTIB  
 
Subject ID:  _________ Subject Initials:  _____ Dose Level:  __1___ 
 
Cycle #:  ___ Cycle Start Date: __________ 
 
Instructions: 
• Use this diary to record each dose of navitoclax and vistusertib that you take – write in 
the date, the number of tablets and the time taken as well as any comments 
 
• Your navitoclax dose is:  150 mg once a day   
o Take two (2) 25 mg tablets and one (1) 100 mg tablets. 
o Navitoclax should be taken with food and swallowed whole. Do not split, crush or 
chew the tablets. 
o If you miss a dose of navitoclax (not taken within 8 hours of scheduled time), skip 
the dose and resume taking navitoclax at the next scheduled time; do not “double 
up” doses to make up a missed dose. 
o If you vomit after taking navitoclax, do not retake the dose. Mark the vomited 
dose in the diary. Resume taking navitoclax at the next scheduled time. 
 
• Your vistusertib dose is ______ mg twice a day, approximately 12 hours apart 
o Take _____ 10 mg tablets and one (1) 25 mg tablets at each dose. 
o Vistusertib can be taken with or without food. 
 If you do take with food, do not eat overly sugary or fatty foods. 
 Avoid taking with grapefruit juice. 
o If you miss a scheduled vistusertib dose, you may take it up to 2 hours after the 
regular dose time. If it is more than 2 hours after the scheduled dose time, the 
missed dose should not be taken. Take the next dose at the regularly scheduled 
time; do not “double up” doses to make up a missed dose. 
o If you need to take a vistusertib dose earlier for whatever reason, you can take the 
dose up to 2 hours earlier then the scheduled dose time. You should make every 
effort to take the tablets on time. 
o If vomiting occurs within 30 minutes after taking vistusertib, or later if the 
tablet(s) can be identified in the vomit content, you can re-take a new tablet(s). 
Mark the vomited dose in the diary. 
 
• Whenever possible, all doses should be taken at approximately the same time each day. 
 
• Use the comments section to record any side effects or anything else you would like to 
tell the doctor/research nurse. 
 
• Please bring the empty bottle or any leftover tablets and this diary to your next 
clinic visit.