Phase 2 Study of M6620 (VX-970) in Combination With Gemcitabine Versus Gemcitabine Alone in Subjects With Platinum-Resistant Recurrent Ovarian or Primary Peritoneal Fallopian Tube Cancer
Phase: PHASE2
Conditions: Ovarian Serous Tumor, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 9944 
Version Date: June 4, 2019 
 
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SUMMARY OF CHANGES  
 
NCI Protocol #: 9944 
Protocol Version Date: June 4, 2019  
Protocol Title: Phase 2 Study of M6620 (VX-970) in Combination with gemcitabine versus 
gemcitabine alone in Subjects with Platinum-Resistant Recurrent Ovarian or Primary Peritoneal 
Fallopian Tube Cancer 
 
Amendment, protocol version date 06/04/2019: 
# 
Section 
Comments 
1. 
 
Header 
 
 
Protocol version date in header updated from February 22, 2019 to June 4, 2019 
 
2. 
Title Page 2 
 
Protocol version date updated from February 22, 2019 to June 4, 2019 
 
3. 
TOC, 3.2.7, 
5.2 
Updated references of “Patient Drug Information Handout and Wallet Card” to 
“Patient Drug Interactions Handout and Wallet Card” 
4. 
7.1.1 
Revision of the Protocol CAEPR: 
 
Protocol Section(s) for Insertion of Revised CAEPR (Version 1.4, April 30, 
2019): 7.1.1   
Page Number(s): 38-40 
 
• The SPEER grades have been updated. 
 
• Added New Risk: 
• Also Reported on M6620 Trials But With Insufficient Evidence 
for Attribution: Ascites; Atelectasis; Colonic obstruction; 
Confusion; Dehydration; Dyspnea; Edema limbs; Generalized 
muscle weakness; Hypertension; Hypophosphatemia; Infections 
and infestations - Other (lower respiratory tract infection); Otitis 
externa; Palpitations; Sepsis; Soft tissue infection; Spinal cord 
compression; Thromboembolic event 
 
• Decrease in Risk Attribution: 
• Changed to Also Reported on M6620 Trials But With Insufficient 
Evidence for Attribution from Possible: Lethargy 
 
• Deleted Risk:  
• Also Reported on M6620 Trials But With Insufficient Evidence 
for Attribution from Possible: Hypohidrosis; Lung infection  
 

NCI Protocol #: 9944 
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# 
Section 
Comments 
5. 
ICF 
Protocol version date in header changed from 02/22/2019 to 06/04/2019 

NCI Protocol #: 9944 
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1 
 
NCI Protocol #: 
9944 
Local Protocol #: 
16-724 
 
ClinicalTrials.gov Identifier:  NCT02595892 
 
TITLE:  Phase 2 Study of M6620 (VX-970) in Combination with gemcitabine versus 
gemcitabine alone in Subjects with Platinum-Resistant Recurrent Ovarian or Primary Peritoneal 
Fallopian Tube Cancer 
 
Corresponding Organization: LAO-MA036 / Dana-Farber/Harvard Cancer Center LAO 
 
Principal Investigator: 
Panagiotis A. Konstantinopoulos MD, PhD 
Dana Farber Cancer Institute 
YC-1424, 450 Brookline Ave 
Boston, MA 02215 
617-632-5269 
617-632-3479 
Panagiotis_Konstantinopoulos@dfci.harvard.edu 
 
Participating Organizations:  
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-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey 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 
 
Statistician: 
 
 
Research Project Manager:  
 
William T Barry, PhD 
Roxanne Quinn 
Center for Life Sciences Bldg, Room 11005 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
450 Brookline Ave.  
Boston, MA 02215 
Boston, MA 02215 
Phone: 617-632-5134 
Phone:  617-632-5735 
Fax: 617-632-2444 
Fax:  617-394-2662 
bbarry@jimmy.harvard.edu 
Roxanne_Quinn@dfci.harvard.edu 

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NCI-Supplied Agent(s):  M6620 (VX-970), NSC# 780162 
 
Other Agent(s):  gemcitabine, NSC# 613327, Commercial 
 
IND #: 129798 
 
IND Sponsor: DCTD, NCI 
 
Version Date: June 4, 2019 

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SCHEMA 
 
PROTOCOL SYNOPSIS 
 
A Phase 2 Study of M6620 (VX-970) in Combination with Gemcitabine (NSC# 613327) 
versus Gemcitabine alone in Subjects with Platinum-Resistant Ovarian or Primary 
Peritoneal Fallopian Tube Cancer 
 
 
STUDY DRUG: 
M6620 (VX-970) 
 
PHASE:  
2 
 
INDICATION: 
Platinum-Resistant Ovarian or Primary Peritoneal or Fallopian Tube 
Cancer 
 
RESEARCH HYPOTHESIS: 
Based on in vitro and in vivo data, we hypothesize that M6620 (VX-970) may enhance activity 
of  gemcitabine and show acceptable toxicity and superior efficacy to gemcitabine alone in  
platinum resistant ovarian or primary peritoneal or fallopian tube cancer. 
 
OBJECTIVES: 
Primary Objective(s) 
• To assess and compare progression free survival (PFS) between gemcitabine/ M6620 
(VX-970) and gemcitabine alone arms 
 
Secondary Objective(s) 
• To determine and compare overall response rate (ORR) by RECIST between 
gemcitabine/ M6620 (VX-970) and gemcitabine alone arms 
• To determine and compare the safety profile of gemcitabine/ M6620 (VX-970) and 
gemcitabine alone regimens 
• To assess and compare PFS at 6 months between gemcitabine/M6620 (VX-970) and 
gemcitabine alone arms 
• To determine and compare the clinical benefit rate (CBR) between gemcitabine/M6620 
(VX-970) and gemcitabine alone arms 
• To determine and compare the duration of response (DOR) between gemcitabine/M6620 
(VX-970) and gemcitabine alone arms 
• To determine and compare CA125 reduction by > 50% between gemcitabine/M6620 
(VX-970) and gemcitabine alone arms 
• To determine and compare OS between gemcitabine/M6620 (VX-970) and gemcitabine 
alone arms 
• To determine the ORR for subjects in the gemcitabine alone arm who cross over to the 
gemcitabine/M6620 (VX-970) arm 

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Exploratory Objective(s) 
• To explore whether the presence of genetic alterations in HR pathway and NER pathway 
genes are predictive of clinical outcome after gemcitabine/M6620 (VX-970) in archival 
FFPE specimens  
• To explore whether TP53, ATM and ATR mutations are predictive of clinical outcome 
after gemcitabine/M6620 (VX-970) in archival FFPE specimens  
• To explore whether amplification of Cyclin E1 (CCNE1) or ATR or MYC are predictive 
of clinical outcome after gemcitabine/M6620 (VX-970) in archival FFPE specimens  
• To explore whether homozygous deletion of PTEN is predictive of clinical outcome after 
gemcitabine/M6620 (VX-970) in archival FFPE specimens  
 
STUDY DESIGN: 
This is a Phase 2, multicenter, open-label, randomized study of M6620 (VX-970) combined with 
gemcitabine compared with gemcitabine alone in subjects with platinum resistant recurrent high-
grade serous epithelial ovarian cancer (HGS EOC). The randomized design is selected to 
evaluate the efficacy and safety of the combination of gemcitabine/M6620 (VX-970) against 
single agent gemcitabine in platinum-resistant ovarian cancer. Furthermore, the proposed study 
design allows crossover from standard arm to gemcitabine/M6620 (VX-970) after disease 
progression to enable the investigation of the efficacy of the gemcitabine/M6620 (VX-970) 
following failure of single agent gemcitabine. Specifically, patients with recurrent platinum 
resistant high grade serous ovarian or primary peritoneal or fallopian tube cancers will be 
randomized 1:1 to either gemcitabine alone or gemcitabine/M6620 (VX-970). There is no limit 
in the number of previous platinum therapies for platinum sensitive recurrence, but patients 
cannot have received more than 1 prior regimen in the platinum resistant setting. Treatment will 
continue until disease progression as measured by RECIST 1.1; patients who progress by 
RECIST 1.1 on weekly gemcitabine alone will be allowed to crossover to the experimental 
gemcitabine/M6620 (VX-970) arm.  Patients with CA125 elevation alone may continue on study 
as long as they have not developed progressive disease by RECIST.  Furthermore, patients on 
weekly gemcitabine alone arm are not allowed to cross over to the combined 
gemcitabine/M6620 (VX-970) arm based on CA125 elevation alone; Progressive disease by 
RECIST must be documented before they are allowed to cross over to the combined 
gemcitabine/M6620 (VX-970) arm.  Only patients with available archival FFPE tissue (either 
one paraffin embedded tissue block OR 10 5-micron unstained slides from the block on regular 
(non-plus) slides and 1 H&E slide) will be eligible to participate in this study.  
 
The primary endpoint of the study is to compare the PFS between gemcitabine/M6620 (VX-970) 
and gemcitabine alone arms. 
 
Subjects may begin protocol treatment at least 4 weeks after their last dose of prior 
chemotherapy or hormonal therapy, assuming they are otherwise eligible.  Patients on the 
gemcitabine alone arm will receive IV gemcitabine 1000mg/m2 IV on Days 1 and 8 of a 21 day 

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cycle which is the most widely studied and most commonly used regimen of single agent 
gemcitabine in platinum resistant ovarian cancer. Patients on the gemcitabine/M6620 (VX-970) 
arm will receive IV gemcitabine 1000mg/m2 on Days 1 and 8 and IV M6620 (VX-970) 
210mg/m2 on Days 2 and 9 of a 21-day cycle. 
 
Treatment will continue until disease progression or intolerable toxicity and patients who 
progress on weekly gemcitabine alone will be allowed to crossover to the experimental 
gemcitabine/M6620 (VX-970) arm. Subjects can voluntarily withdraw at any time during the 
study. Participants will be followed for 3 years after removal from study treatment or until death, 
whichever occurs first. 
 
 
 
 
 
 
TUMOR ASSESSMENTS: 
RECIST v1.1 criteria will be used to assess patient response to treatment by PFS, ORR and 
DCR. The RECIST v1.1 guidelines for measurable, non-measurable, target and non-target 
lesions and the objective TUMOR response criteria (CR, PR, SD or progression of disease) are 
presented in Section 11. 
 
STATISTICAL METHODS: 
In this exploratory trial, in order to have 80% power to detect improvement of median PFS 
(primary endpoint) from 15 weeks with gemcitabine alone to 27.3 weeks with 
gemcitabine/M6620 (VX-970) (HR=0.55) using a stratified log-rank test (with the platinum free 
interval as the stratification factor)with a one-sided alpha level of 0.1, 64 patients would be 
randomized (32 patients on each arm). Final analysis would occur when 50 PFS events are to be 
observed. This assumes a constant accrual over 1 year with 6 months of additional follow-up, 
and a constant hazard of PFS and dropout such that 5% of patients are lost-to-follow-up at 1 
year. Although the target number of evaluable patients is 64, it is anticipated that 10% of subjects 

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will not be evaluable and thus the maximum total number of patients to be enrolled will be 70. 
An interim analysis will be planned at 25 PFS events to stop for futility only. 
 

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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Primary Objectives ...................................................................................................9 
1.2 
Secondary Objectives ...............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Ovarian Cancer ........................................................................................................9 
2.2 
CTEP IND Agent(s) ...............................................................................................12 
2.3 
Other Agent ............................................................................................................16 
2.4 
Rationale ................................................................................................................17 
2.5 
Correlative Studies Background ............................................................................21 
3. 
PATIENT SELECTION ....................................................................................................23 
3.1 
Eligibility Criteria ..................................................................................................23 
3.2 
Exclusion Criteria ..................................................................................................24 
3.3 
Inclusion of Women and Minorities ......................................................................25 
4. 
REGISTRATION PROCEDURES ...................................................................................25 
4.1 
Investigator and Research Associate Registration with CTEP ..............................26 
4.2 
Site Registration .....................................................................................................27 
4.3 
Patient Registration ................................................................................................28 
4.4 
General Guidelines .................................................................................................30 
5. 
TREATMENT PLAN ........................................................................................................30 
5.1 
Agent Administration .............................................................................................30 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................33 
5.3 
Duration of Therapy ...............................................................................................33 
5.4 
Duration of Follow Up ...........................................................................................34 
5.5 
Criteria for Removal from Study ...........................................................................34 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................34 
6.1 
Dose Modifications due to Non-Hematologic Toxicity .........................................35 
6.2 
Dose Modifications due to Hematologic Toxicity .................................................36 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................38 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................38 
7.2 
Adverse Event Characteristics ...............................................................................42 
7.3 
Expedited Adverse Event Reporting ......................................................................42 
7.4 
Routine Adverse Event Reporting .........................................................................44 
7.5 
Secondary Malignancy ...........................................................................................45 

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7.6 
Second Malignancy ................................................................................................45 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................45 
8.1 
M6620 (VX-970) (NSC # 780162) ........................................................................45 
8.2 
Gemcitabine (NSC 613327) ...................................................................................49 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................50 
9.1 
Exploratory/Ancillary Correlative Studies ............................................................50 
10. 
STUDY CALENDAR .......................................................................................................53 
11. 
MEASUREMENT OF EFFECT........................................................................................54 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................54 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................61 
12.1 
Data Reporting .......................................................................................................62 
12.2 
Data Safety Monitoring ..........................................................................................63 
12.3 
Collaborative Agreements Language .....................................................................64 
13. 
STATISTICAL CONSIDERATIONS...............................................................................65 
13.1 
Study Design/Endpoints.........................................................................................65 
13.2 
Sample Size/Accrual Rate ......................................................................................67 
13.3 
Stratification Factors ..............................................................................................68 
13.4 
Analysis of Secondary Endpoints ..........................................................................68 
13.5 
Reporting and Exclusions ......................................................................................69 
14. 
PUBLICATION PLAN .....................................................................................................70 
REFERENCES ..............................................................................................................................71 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................73 
APPENDIX B: PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD .......74 
 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
The primary objective of the study is to: 
  
• Assess and compare progression free survival (PFS) between gemcitabine/M6620 (VX-
970) and gemcitabine alone arms 
 
1.2 
Secondary Objectives 
The secondary objective of the study is to: 
 
• Determine and compare overall response rate (ORR) by RECIST between 
gemcitabine/M6620 (VX-970) and gemcitabine alone arms 
• Determine and compare the safety profile of gemcitabine/M6620 (VX-970) and 
gemcitabine alone regimens 
• Assess and compare PFS at 6 months between gemcitabine/M6620 (VX-970) and 
gemcitabine alone arms 
• Determine and compare the clinical benefit rate (CBR) between gemcitabine/M6620 
(VX-970) and gemcitabine alone arms 
• Determine and compare the duration of response (DOR) between gemcitabine/M6620 
(VX-970) and gemcitabine alone arms 
• Determine and compare CA125 reduction by > 50% between gemcitabine/M6620 (VX-
970) and gemcitabine alone arms 
• Determine and compare OS between gemcitabine/M6620 (VX-970) and gemcitabine 
alone arms 
• Determine the ORR for subjects in the gemcitabine alone arm who cross over to the 
gemcitabine/M6620 (VX-970) arm 
 
2. BACKGROUND 
 
2.1 
Ovarian Cancer 
 
Ovarian Cancer and high grade serous histology  
 
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and the fifth most 
common cause of female cancer death in the United States1, 2. Fallopian tube and primary 
peritoneal cancers are less frequently diagnosed, but exhibit histological and prognostic features 
that are identical to those of ovarian cancer and are treated similarly to EOC3, 4.  
 
High-grade serous carcinomas (HGSCs) represent the most common histologic subtype and 
account for approximately 70% of all EOCs. HGSCs are characterized by high degree of 
genomic instability with high frequency of DNA copy number changes and almost universal 

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presence of TP53 mutations5. A number of molecular studies and most recently The Cancer 
Genome Atlas (TCGA) project have shown that HGSCs are characterized by frequent genetic 
and epigenetic alterations in gene members of the homologous recombination (HR) DNA repair 
pathway6-8. Specifically, in the TCGA dataset, approximately 20% of HGSCs harbored germline 
BRCA1 or BRCA2 mutations while approximately 30% harbored alternative molecular HR 
alterations including somatic BRCA1/2 mutations, hypermethylation of BRCA1 or RAD51C, 
amplification or mutation of EMSY, focal deletion or mutation of PTEN, mutation of ATM or 
ATR, and mutation of Fanconi anemia genes (Figure 1). Of note, another 20% of HGSCs harbor 
cyclin E1 amplification while approximately 8% harbor deficient nucleotide excision repair 
(NER) (Figure 1)8, 9. Finally, another 4% of HGSCs harbor ATR amplification which may be a 
marker of replication stress and dependence on ATR signaling. 
 
 
Figure 1. Molecular alterations in DNA repair pathways in high grade serous ovarian cancers (Adapted from Ovarian TCGA 
dataset, Nature, 2011).  
 
Platinum resistant ovarian cancer  
 
Although first line platinum based chemotherapy results in clinically complete remissions in 
>70% of EOC patients, relapse occurs in >90% of those responders, at which point the disease is 
much less responsive to subsequent treatment and is essentially non-curable 1, 10. Platinum-free 
interval is a powerful predictor of treatment success in recurrent ovarian cancer and disease that 
relapses within 6 months after platinum-containing therapy is categorized as platinum resistant1, 
10.  
 
Platinum resistant EOC is routinely managed using single agents such as anthracyclines 
(formulated as pegylated liposomal doxorubicin [PLD]), taxanes, topotecan, and gemcitabine10. 
Physician decision as to which agent to administer is usually based upon toxicity, patient 
preference on specific side effects, tumor response and quality of life. Recently, the AURELIA 
study demonstrated that addition of bevacizumab to chemotherapy (weekly paclitaxel, or 
topotecan or PLD) statistically significantly improved PFS, response rate and patient reported 
outcomes11, 12, and led to the FDA approval of bevacizumab in combination with weekly 

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paclitaxel, or topotecan or PLD in patients with platinum resistant EOC. However, even with the 
addition of bevacizumab, the outlook for patients with platinum resistant disease is poor; median 
overall survival (OS) is approximately 17 months so novel strategies are needed11.  
 
Role of ATR in Cancer DNA damage and response  
 
The DNA damage response (DDR) requires the integration of cell cycle control via checkpoint 
signaling to allow time for repair to prevent permanent DNA damage produced by replication 
and mitosis17. The PI3K-related protein kinases (PIKKs) Ataxia-telangiectasia mutated (ATM) 
and Ataxia-telangiectasia and Rad3-related (ATR) have crucial roles by signaling DNA damage 
to cell cycle checkpoints and DNA repair pathways (Figure 2). The ATM–CHK2 pathway 
primarily responds to double strand breaks (DSBs) to induce G1 arrest, while the ATR–CHK1 
pathway triggers S and G2 phase arrest17. ATM promotes HR by recruiting BRCA1 to DSBs but 
can also antagonize BRCA1 and promote NHEJ by recruiting TP53 binding protein 1 (53BP1), 
and these antagonistic functions are cell cycle regulated. ATR is activated by DNA single-
strand–double-strand junctions that arise as intermediates in nucleotide excision repair (NER), by 
replication stress and at resected DSBs, and it phosphorylates CHK1 to activate S and G2 
arrest18. Replication stress is defined as the slowing or stalling of replication fork progression 
during DNA synthesis18, 19. Sources of replication stress include single strand DNA 
accumulation, loss of G1/S checkpoint (as in TP53 loss), DNA damage during S phase, 
oncogene-driven state (i.e. by HRAS, MYC, cyclin E1 overexpression, EGFR-vIII) and DNA 
repair deficiency (tumor cells deficient in FA, BLM, or ATM pathways)19, 20. The cellular 
response to replication stress includes activation of ATR/CHK1 which mediates activation of 
DNA repair pathways and stabilization of replication fork18. Activation of ATR triggers the 
intra-S phase and the G2 checkpoints via phosphorylation of CHK1, which in turn 
phosphorylates WEE1 (which activates this kinase) and cell division cycle 25 (CDC25) 
phosphatases (which inhibits it) to inhibit cell cycle progression through the coordinate 
suppression of cyclin-dependent kinase (CDK) activity. ATR and CHK1 also phosphorylate a 
number of proteins involved in HRR and ICL repair, including BRCA2, RAD51, FANCD2 and 
FANCE21. 
 

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Figure 2. Signaling DNA damage to cell cycle checkpoints via the ATM/CHK2 and ATR/CHK1 
pathways (Figure from Curtin N.J. Nat Rev Cancer, 2012). 
 
 
 
2.2 
CTEP IND Agent(s) 
 
M6620 (VX-970) 
 
M6620 (VX-970) is a potent highly selective ATR inhibitor (ATR inhibition constant [Ki] <300 
pM, ATR IC50 19nM), with more than 500-fold selectivity over 278/291 kinases tested and 
more than 25 fold selectivity over the remaining 13 kinases (M6620 (VX-970) Investigator 
Brochure). Furthermore, M6620 (VX-970) demonstrates a low potential for drug-drug 
interactions based on minimal inhibition or induction of cytochrome (CYP) 450 isozymes. In 
vitro, M6620 (VX-970) has demonstrated potent sensitization of multiple cancer cell lines and 
primary human tumor cells but not of normal cell lines, to ionizing radiation (IR) and to a wide 
range of DNA-damaging agents including cisplatin, gemcitabine, irinotecan, and etoposide. The 
selective activity of M6620 (VX-970) in cancer cells is attributed to disruption of alternative 
DNA damage repair pathways in these cells; in contrast, normal cell tolerance to ATR inhibition 
is attributed to the presence of alternative, compensatory DDR pathways. Normal cell tolerance 
to inhibition of ATR by M6620 (VX-970) is attributed to compensatory DDR signaling that is 
mediated by ATM. Accordingly, cells with defects in ATM signaling, for example cells with loss 

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(VX-970) single-agent therapy. One subject with colorectal cancer exhibited a partial response 
(80% reduction of tumor lesion diameter).  
 
Clinical Safety 
Preliminary safety data are available for 38 subjects from Study 001 and 11 subjects from Study 
002.  During the 7- to 14-day Lead-in Phase in Part A of Study 001, 2 subjects had serious AEs 
(SAEs) of palpitations, pyrexia, and dyspnea. No subjects had Grade ≥3 AEs, AEs leading to 
study drug discontinuation, dose-limiting toxicities (DLTs), or AEs leading to death. During the 
21-day Lead-in Phase in Part B of Study 001, 1 subject had an SAE of metastases to central 
nervous system that led to study drug discontinuation. No subjects had DLTs or AEs leading to 
death.  
In Study 001 Part A (M6620 (VX-970) + gemcitabine combination therapy), 31 subjects 
included in the Combination Safety Set received intravenous doses of M6620 (VX-970) ranging 
from 18 to 140 mg/m2 in combination with intravenous doses of gemcitabine ranging from 500 
to 875 mg/m2. Four of 27 subjects (14.8%) included in the dose-limiting toxicity (DLT) 
evaluable set receiving M6620 (VX-970) in combination with gemcitabine had a total of 7 
DLTs: alanine aminotransferase increased (2 subjects [7.4%]); aspartate aminotransferase 
increased (2 subjects [7.4%]); blood alkaline phosphatase increased (1 subject [3.7%]); 
thrombocytopenia (1 subject [3.7%]); and fatigue (1 subject [3.7%]). A total of 16 subjects (2 
subjects receiving single-agent M6620 (VX-970) during the Lead-Phase and 14 subjects 
receiving M6620 (VX-970) + gemcitabine combination therapy) had serious adverse events 
(SAEs). In Study 001 Part A (M6620 (VX-970) + gemcitabine combination therapy) 9 subjects 
(29.0%) had SAEs classified as related to study drug, 3 subjects (9.7%) had SAEs of Grade 1 
pyrexia classified as possibly related or related to study drug, and 2 subjects (6.5%) had SAEs of 
Grade 4 thrombocytopenia classified as related to study drugs. No other SAEs were reported in 
more than 1 subject. The most common adverse events (AEs), regardless of causality, were 
nausea (20 subjects [64.5%]), vomiting (17 subjects [54.8%]), and fatigue (15 subjects [48.4%]). 
Overall the AST/ALT elevations occurred at the same frequency as with gemcitabine 
monotherapy and although there was a possible potentiation of gemcitabine-associated 
myelosuppression, this did not prevent dose escalation.   
In Study 001 Part B (M6620 (VX-970) + cisplatin combination therapy), 6 subjects in the 
Combination Safety Set received intravenous doses of M6620 (VX-970) ranging from 90 to 140 
mg/m2 in combination with intravenous doses of cisplatin 40 mg/m2. There were no DLTs. Two 
subjects had SAEs of metastases to central nervous system (1 subject receiving single-agent 
M6620 (VX-970) during the Lead-Phase) and dyspnea (1 subject receiving M6620 (VX-970) + 
cisplatin combination therapy), which were not related to study drugs. The most common AEs, 
regardless of causality, were nausea (4 subjects [66.7%]) and fatigue (4 subjects [66.7%]).  
In Study 002 Part A (single-agent M6620 (VX-970) therapy), 11 subjects included in the Safety 
Set received intravenous doses of M6620 (VX-970) ranging from 60 to 480 mg/m2. There were 
no DLTs. Two subjects had SAEs of Grade 3 ascites, which were classified as not related to 
study drug, and Grade 3 fatigue, which was classified as possibly related to study drug. Five 
subjects (45.5%) had an AE of fatigue. AEs of nausea, urinary tract infections, headache, and 
flushing were each reported in 3 subjects (27.3%).  
Serious acute hypersensitivity reactions have occurred in a few subjects receiving M6620 (VX-
970). These reactions occured within minutes of re-exposure to M6620 (VX-970), and in cases 

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gemcitabine/M6620 (VX-970) may be particularly attractive for the platinum resistant tumors 
because ATR inhibition is particularly relevant in situations of high replicative stress such as in 
tumors with CCNE1 amplification. CCNE1 amplification is observed in 20% of ovarian cancers 
and is mutually exclusive with BRCA1 mutations.  Ovarian cancers with CCNE1 amplification 
are HR proficient and are enriched for platinum resistance and poorer outcome, suggesting that 
the gemcitabine/ATR inhibition combination may be particularly relevant for the platinum 
resistant setting. 
 
 
 
In summary, we hypothesize that M6620 (VX-970) may enhance activity of gemcitabine and 
show acceptable toxicity and superior efficacy to gemcitabine alone in platinum resistant ovarian 
or primary peritoneal or fallopian tube cancer. We expect that high grade serous ovarian or 
primary peritoneal or fallopian tube cancers which are known to be TP53 mutated, and 
commonly harbor molecular HR and NER alterations and cyclin E1 (CCNE1) amplification may 
be particularly sensitive to the gemcitabine/M6620 (VX-970) combination. Therefore we 
propose a randomized open label, Phase 2 trial of M6620 (VX-970) and gemcitabine versus 
gemcitabine alone in patients with recurrent platinum resistant high grade serous ovarian or 
primary peritoneal or fallopian tube cancers. The primary objective of the study would be to 
compare the PFS between gemcitabine/M6620 (VX-970) and gemcitabine alone arms while the 
secondary objective of the study would be to compare safety and other measurements of clinical 
outcome (i.e. overall response rate (ORR) by RECIST, duration of response, clinical benefit 
response, CA125 response, PFS at 6 months and overall survival) between gemcitabine/M6620 
(VX-970) and gemcitabine alone arms. Finally, another secondary objective of our study is to 
enable the investigation of the efficacy (ORR) of the gemcitabine/M6620 (VX-970) after 

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crossover following failure of single agent gemcitabine. In this regard, he hypothesize that 
addition of M6620 (VX-970) to gemcitabine will be clinically effective for patients who develop 
disease progression on gemcitabine alone.  
 
Rationale for dosing of gemcitabine/M6620 (VX-970) and gemcitabine alone in this study 
In gemcitabine alone arm, gemcitabine IV 1000mg/m2 Days 1 and 8 of a 21 day cycle will be 
used. This is based on a phase III trial comparing gemcitabine with PLD (which is a standard, 
FDA approved regimen for platinum resistant EOC) in platinum resistant ovarian cancer. In that 
trial15 which included 195 patients with platinum resistant EOC, gemcitabine (1,000 mg/m2 days 
1 and 8; every 21 days) exhibited similar PFS, ORR and OS compared to PLD (50mg/m2 day 1; 
every 28 days). 
The doses of gemcitabine and M6620 (VX-970) that will be used in the combination arm of this 
Phase II study were established in Study 001 Part A which was a Phase 1 dose escalation study 
of M6620 (VX-970) in combination with gemcitabine.  In that study, gemcitabine was 
administered on Days 1 and 8 and M6620 (VX-970) on Days 2 and 9 of a 21 day cycle. M6620 
(VX-970) was escalated up to 210mg/m2 on Days 2 and 9 of a 21 day cycle (the predicted 
human dose of M6620 (VX-970) to achieve exposure with maximum activity in mouse = 120 
mg/m2). Therefore, 210 mg/m2 given on Days 2 and 9 of a 21 day cycle will be the dose that we 
will use in this Phase 2 study. In study 001 Part A, Gemcitabine was escalated to 1000mg/m2 on 
Days 1 and 8 of a 21 day cycle (Table below) and this will be the dose (in combination with 
210mg/m2 on Days 2 and 9 of a 21 day cycle) which will be used in the combination arm of this 
Phase 2 study. 

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2.5 
Correlative Studies Background 
 
In the exploratory endpoints of our study, we hypothesize that tumors with high replicative stress 
may be associated with enhanced sensitivity to M6620 (VX-970)/gemcitabine. Therefore, we 
propose to explore whether baseline alterations associated with high replicative stress are 
predictive of clinical outcome after gemcitabine/M6620 (VX-970) including: 
i) mutations in HR and NER pathway genes,  
ii) mutations in TP53, ATM and ATR,  
iii) Amplification of CCNE1, ATR or MYC, 
iv) homozygous deletion of PTEN  
v) Immunohistochemistry for ATM 
 
Although TP53 mutations are found almost universally in high grade serous ovarian cancers, not 
all TP53 mutations abrogate TP53 function; a small fraction of TP53 mutations (approximately 
10%) are not deleterious.  Furthermore, in high grade serous ovarian cancer, approximately one 
third of TP53 mutations are truncating mutations leading to no expression of TP53 by 
immunohistochemistry. The remaining two thirds of TP53 mutations are missense mutations or 
in-frame deletions leading to increased expression of TP53 by immunohistochemistry.  Given 
that the functional consequence of the heterogeneous TP53 mutations in terms of ATR inhibition 
is not known, we will explore their association with response to gemcitabine/M6620 (VX-970). 
For these reasons, we propose to sequence TP53 and to perform TP53 immunohistochemistry 
(IHC). Of note, TP53 IHC is a standard test that is routinely performed and should be available 
for most patients prior to enrollment in our trial.  
Finally, given that Alternative Lengthening of Telomeres (ALT) has been shown to be associated 
with response to ATR inhibition23, we propose to evaluate whether ALT at baseline is predictive 
of clinical outcome after gemcitabine/M6620 (VX-970).  
 
The following assays will be performed (all on archival FFPE samples) to evaluate the 
aforementioned proposed exploratory biomarkers: 
 
1. Multigene next generation sequencing assay (Oncopanel Assay) 
At Dana Farber Cancer Institute, in the Department of Pathology Center for Advanced Molecular 
Diagnostic at Brigham and Women’s Hospital, we have developed a cancer genomic assay to 
detect somatic mutations, copy number variations and structural variants in tumor DNA 
extracted from fresh, frozen or formalin-fixed paraffin-embedded samples “(Wagle et al. High-
throughput detection of actionable genomic alterations in clinical tumor samples by targeted, 
massively parallel sequencing. Cancer Discovery 2012.)” The Oncopanel assay surveys exonic 
DNA sequences of 447 cancer genes and 191 regions across 60 genes for rearrangement 

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detection. DNA is isolated from tissue containing at least 20% tumor nuclei and analyzed by 
massively parallel sequencing using a solution-phase Agilent SureSelect hybrid capture kit and 
an Illumina HiSeq 2500 sequencer. The Oncopanel assay assesses genes including mutations and 
copy number variations in TP53, CCNE1, MYC, ATR, ATM, PTEN and HR pathway and NER 
pathway genes. This assay will be performed in archival FFPE specimens if it has not already 
been performed (it is now standard for patients at Dana Farber Cancer Institute). In cases where 
Oncopanel sequencing has already been performed on patient samples through DF/HCC protocol 
11-104, we will plan to access these results to conserve primary patient samples for additional 
analyses 
 
 
2. TP53 and ATM Immunohistochemistry (IHC) 
This will be performed in archival FFPE specimens using standard IHC protocols for TP53 and 
ATM IHC. TP53 IHC is a standard diagnostic test that is performed in most ovarian cancers to 
establish the diagnosis; the test will be performed only if it was not previously performed. TP53 
IHC will be performed in the Department of Pathology at Brigham and Women’s Hospital. 
 
3. Detection of Alternative Lengthening of Telomeres (ALT) 
Fluorescent in-situ hybridization (FISH) in archival FFPE samples with telomere specific probes 
will be performed in our institution in the Center of DNA Damage and Repair (CDDR). 
 
4. Whole Exome Sequencing (WES) 
In addition to the Oncopanel assay, archival FFPE samples will be submitted to Dr Levi 
Garraway’s Lab in collaboration with the Broad Institute Genomics Platform for WES. WES 
allows evaluation of additional potential exploratory biomarkers of replicative stress that are not 
captured by Oncopanel. The Broad Genomics Platform has made a series of technological 
innovations that maximize the quality and speed of WES data generation, even when limiting or 
degraded FFPE starting material is used. As a result the platform is capable of generating WES 
data using as little as 20ng of genomic DNA. This assay will be performed on an individual 
basis, i.e. depending on findings from the Oncopanel assay and availability of FFPE tissue.  
 
5.  Pharmacokinetic Drug Level Monitoring 
Blood samples will be collected from all patients enrolled in the gemcitabine and M6620 (VX-
970) combination arm of the clinical trial to monitor the concentration of M6620 (VX-970) in 
plasma achieved at the end of the 60 min i.v. infusion of the drug for the doses given on days 2 
and 9 of cycles 1 and 2. The pre-dose PK blood draw should be done 5 to 1 minute before 
infusion start. There is no time window for the post-infusion PK collection. Blood should be 
drawn at the same time that the infusion ends. PKs should be collected in a later cycle if they are 
missed or if drug is held during cycle 1 or 2. 
 
The concentrations of M6620 (VX-970) will be determined by validated analytical method based 
upon reversed-phase high-performance liquid chromatography with electrospray ionization 
tandem mass spectrometry.  The data will be used to estimate the variability in the peak 
concentration of M6620 (VX-970) in plasma within and between patients and to assess 
correlations with measures of toxicity, response, and pharmacodynamic effects.   
 

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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically confirmed high grade serous ovarian or primary 
peritoneal or fallopian tube cancer. Platinum Resistant disease is defined as progression 
within 6 months after last platinum regimen. 
 
3.1.2 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) with conventional 
techniques or as ≥10 mm (≥1 cm) with spiral CT scan, MRI, or calipers by clinical exam.  
See Section 11 for the evaluation of measurable disease. Measurable disease by RECIST 
v1.1 with at least one measurable target lesion. 
 
3.1.3 Prior therapy:  No line limit but no more than 1 prior regimens in the platinum resistant 
setting. No prior treatment targeting the ATR/CHK1 pathway and no prior gemcitabine 
as single agent. Hormonal therapies, immunotherapy and antiangiogenic therapies (as 
single agents) do not count as lines; PARP-inhibitors count as a line of therapy unless 
given in the maintenance setting. PARP-inhibitors given as maintenance after platinum 
therapy do not count as a line of therapy. Prior carboplatin/gemcitabine is allowed 
provided that there was no disease progression within 12 months after completion of the 
carboplatin/gemcitabine regimen. Subjects may begin protocol treatment at least 4 weeks 
or 5 half lives, whichever is shorter, after their last dose of chemotherapy or hormonal 
therapy, assuming they are otherwise eligible.  
 
3.1.4 Age ≥18 years.  Because no dosing or adverse event data are currently available on the 
use of M6620 (VX-970) in combination with gemcitabine in patients <18 years of age, 
children are excluded from this study, but will be eligible for future pediatric trials. 
 
3.1.5 ECOG performance status 0 or 1 (Karnofsky ≥70%, see Appendix A). 
 
3.1.6 Life expectancy of greater than 6 months. 
 
3.1.7 Adequate hematologic and end-organ function determined within 2 weeks prior to 
initiation of study treatment. Patients must have normal organ and marrow function as 
defined below: 
 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
within normal institutional limits 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
creatinine 
≤ upper limit of institutional normal  
OR 

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− 
creatinine clearance 
≥60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
 
3.1.8 Confirmation of availability of a formalin-fixed, paraffin-embedded (FFPE) tumor 
specimen with adequate tumor tissue (either one paraffin embedded tissue block OR 10 
5-micron unstained slides from the block on regular (non-plus) slides and 1 H&E slide).  
 
3.1.9 All acute, clinically significant treatment-related toxicity from prior therapy, except for 
alopecia, must have resolved to Grade ≤ 1 prior to study entry. 
 
 
3.1.10 At least 4 weeks since major surgery or radiation therapy. 
 
3.1.11 The effects of M6620 (VX-970) on the developing human fetus are unknown. For this 
reason and because DNA damage inhibitors as well as other therapeutic agents used in 
this trial are known to be teratogenic, women of child-bearing potential must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and 6 months after completion of 
study. 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.  
 
3.1.12 No known hypersensitivity or contraindication to the components of study treatment 
(M6620 (VX-970), gemcitabine). 
 
3.1.13 Ability to understand and the willingness to sign a written informed consent document 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients with primary platinum refractory disease, defined as progression while first line 
platinum based chemotherapy 
 
3.2.2 Patients who have had chemotherapy within 4 weeks or five half lives, whichever is 
shorter, (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those 
who have not recovered from adverse events due to agents administered more than 4 
weeks earlier 
 
3.2.3 Patients who have had radiotherapy within 4 weeks 
 
3.2.4 Patients who are receiving any other investigational agents. 
 

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25 
 
3.2.5 Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
A scan to confirm the absence of brain metastasis is not required.  
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to M6620 (VX-970) or gemcitabine. 
 
3.2.7 M6620 (VX-970) is primarily metabolized by CYP3A4; therefore concomitant 
administration with strong inhibitors or inducers of CYP3A4 should be avoided. Because 
the lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated medical reference for a list of drugs to avoid or minimize use of. 
Appendix B (Patient Drug Interactions Handout and Wallet Card) should be provided to 
patients. Patients receiving any medications or substances that are inhibitors or inducers 
of cytochrome P450 3A (CYP3A4 enzyme) are ineligible. As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product.   
 
3.2.8 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. 
 
3.2.9 Pregnant women are excluded from this study because M6620 (VX-970) and/or 
gemcitabine are agents with the potential for teratogenic or abortifacient effects.  Because 
there is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with M6620 (VX-970) and/or gemcitabine, breastfeeding should 
be discontinued if the mother is treated with M6620 (VX-970) and/or gemcitabine. 
 
3.2.10 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with M6620 (VX-970) and/or gemcitabine.  In 
addition, these patients are at increased risk of lethal infections when treated with 
marrow-suppressive therapy.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Members of all races and ethnic groups are eligible for this trial. This study is design for female 
patient only. 
 
 
4. REGISTRATION PROCEDURES 
 

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4.1 
Investigator and Research Associate Registration with CTEP 
 
4.1.1 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. 
 
For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk by email at pmbregpend@ctep.nci.nih.gov. 
 
4.1.2 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only.  (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
 
An active CTEP-IAM user account is required to access all CTEP applications and, if 
applicable (e.g., all Network trials), all Cancer Trials Support Unit (CTSU) applications 
and websites. 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm. 
 
For questions about Associate Registration or CTEP-IAM Account Creation, please 

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contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to: an active Federal Wide 
Assurance (FWA) number, an active roster affiliation with the Lead Network or a participating 
organization, a valid IRB approval, and compliance with all protocol specific requirements. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB's approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 9944 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-MA036, 
and protocol 9944. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Submitting Regulatory Documents 
 
Requirements For 9944 Site Registration: 

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• CTSU Transmittal Sheet (optional)  
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, 
or combination is accepted) 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.3 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU website.   
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements as outlined by the Lead 
Network. 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 
 

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4.3.1 
OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
Once a slot reservation request has been made, the following source documentation 
should be faxed to the Lead Institution or designee for confirmation of eligibility. 
• Copy of required laboratory tests: 
o CBC with differential 
o Serum chemistries (sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, albumin, calcium, AST (SGOT), ALT (SGPT), 
alkaline phosphatase, total bilirubin, total protein) 
o PT or INR with PTT  
o CA125 
o B-HCG pregnancy test, if applicable 
• Signed informed consent form 
• HIPAA authorization form (if separate from the informed consent document) 
• EKG 
• CT scan 
• Pathology report 
• Screening or most recent clinic visit note (including documentation of oncologic 
history, past medical history, concomitant medications) 
 
The Lead Institution or designee may then approve the slot reservation to allow 
completion of enrollment.  
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 
OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. 

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• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  
•  If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 
OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk 609-619-7862: or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days. Other 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. 
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
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. 
 
Premedication with anti-emetics (excluding aprepitant [Emend]) is allowed according to standard 
practice guidelines. Hematopoietic growth factors may be used to treat neutropenia as indicated 
by the current American Society of Clinical Oncology (ASCO) or Institutional guidelines. 
 
Gemcitabine Administration 

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Gemcitabine should be administered by IV infusion at a dose of 1000 mg/m2 alone or at a dose 
of 1000 mg/m2 in combination with M6620 (VX-970) over 30 minutes (study sites may follow 
standard of care dosing windows) on days 1 and 8 of a 21 day cycle (or until toxicity necessitates 
reducing or holding a dose). The gemcitabine dose will be individually calculated for all infusion 
visits according to the subject’s current weight. In calculating the dose, there will be no 
downward adjustment to “ideal” body weight unless institution policy requires it. Treatment 
regimen is described in the tables below  
 
M6620 (VX-970) Administration 
M6620 (VX-970) should be administered 24 hours (+/- 4 hour) after Gemcitabine by IV infusion 
at a dose of 210 mg/m2 over 1 hour on days 2 and 9 of a 21 day cycle. The M6620 (VX-970) 
dose on Day 2 will be calculated using the weight on Day 1 or Day 2 (i.e. weight assessment on 
day 2 is optional, and M6620 (VX-970) dose may be calculated based on weight taken on Day 
1). Similarly, the M6620 (VX-970) dose on Day 9 will be calculated using the weight on Day 8 
or Day 9 (i.e. weight assessment on day 9 is optional, and M6620 (VX-970) dose may be 
calculated based on weight taken on Day 8).   In calculating the dose, there will be no downward 
adjustment to “ideal” body weight unless institution policy requires it. M6620 (VX-970) should 
not come in contact with 0.9% Sodium Chloride due to incompatibility.  5% dextrose in water 
solution must be used for IV line priming and flushing. Infuse using an infusion set containing 
low-sorption or non-PVC, DEHP-free tubing and an in-line 0.2 micron filter. Treatment regimen 
is described in the tables below:  
 
Regimen Description: gemcitabine alone arm 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Gemcitabine Per institutional 
guidelines  
1000 mg/m2 in 
NS per 
institutional 
guidelines 
IV over 30 minutes 
or according to 
institutional 
standards 
Days 1 
and 8 
21 days  
(3 weeks) 
 
 
Regimen Description: M6620 (VX-970) plus gemcitabine arm 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
M6620 (VX-
970) 
Steroid and 
antihistamine 
combination 
(Section 5.1.1) 
 
210 mg/m2 in 
D5W to a final 
concentration 
between 0.075 
mg/ml and 1 
mg/ml 
 
IV over 1 hour 
 
Days 2 
and 9 
21 days  
(3 weeks) 
 
 
 
Gemcitabine 
 
Per institutional 
guidelines 
1000 mg/m2 in 
NS per 
institutional 
IV over 30 minutes 
or according to 
institutional 
Days 1 
and 8 

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guidelines 
 
standards 
 
 
Patients on the gemcitabine/M6620 (VX-970) arm will receive: Based on Study 001 Part A, 
which was a dose escalation study of M6620 (VX-970) in combination with gemcitabine, 
gemcitabine is administered on Days 1 and 8 and M6620 (VX-970) on Days 2 and 9 of a 21 day 
cycle. M6620 (VX-970) has been escalated up to 210mg/m2 on Days 2 and 9 of a 21 day cycle 
(the predicted human dose of M6620 (VX-970) to achieve exposure with maximum activity in 
mouse = 120 mg/m2). Gemcitabine was escalated to 1000mg/m2 on Days 1, 8 of a 21 day cycle 
with M6620 (VX-970) given at 210mg/m2 on days 2 and 9 of a 21 day cycle and was  tolerated 
well. Therefore in the combination arm we will treat according to the table above with 
1000mg/m2 of gemcitabine on days 1 and 8, and 210mg/m2 of M6620 (VX-970) on days 2 and 
9 of a 21 day cycle. 
 
Treatment will continue until disease progression or intolerable toxicity and patients who 
progress on weekly gemcitabine alone will be allowed to crossover to the experimental 
gemcitabine/M6620 (VX-970) arm. 
 
 
5.1.1 M6620 (VX-970) (preparation and recommendations)  
 
M6620 (VX-970) absorbs in the UV-visible radiation spectrum and is widely distributed including to 
the skin, so subjects should be cautioned to minimize exposure to the sun and other sources of visible 
and UV radiation and to take protective measures when necessary. Furthermore: 
 
(1) M6620 (VX-970) will be supplied as 20 mg/mL M6620 (VX-970) (in betadex sulfobutyl 
ether and acetate buffer) to be diluted in D5W before intravenous infusion. M6620 (VX-970) 
solution will be constituted into the individual dosing containers by a qualified pharmacist.  
(2) To minimize the possibility of phlebitis, M6620 (VX-970) should be administered through a 
large bore catheter into a large caliber peripheral vein or via a standard intravenous catheter or 
port/port-a-cath. The intravenous infusion site should be monitored closely for the development 
of erythema, induration, purulence, tenderness, or warmth. 
If any subject develops phlebitis, or signs or symptoms of inflammation that may progress to 
phlebitis or that the patient cannot tolerate, standard measures should be employed to ameliorate 
these symptoms (including removal of the infusion catheter and resumption of infusion through a 
different vein). 
Based on the observation of acute hypersensitivity in 3 subjects at various doses of M6620 (VX-
970) and of pruritus in 2 subjects at 480 mg/m2 of M6620 (VX-970), pre-medication with a 
corticosteroid and an antihistamine will be performed for all subjects receiving M6620 (VX-970)  
and gemcitabine to prophylax against possible acute hypersensitivity. 
Corticosteroid and antihistamine combinations that may be used include: 100 mg to 200 mg 
hydrocortisone intravenously approximately 60 minutes (± 15 minutes) before M6620 (VX-970) 
infusion, and either 10 mg of chlorphenamine or 25 mg of diphenhydramine intravenously 

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approximately 30 minutes (± 10 minutes) before M6620 (VX-970) infusion. Alternative 
antihistamine and steroid doses, timing, routes of administration and agents may be considered, 
as long as not prohibited by protocol. In addition, treatment with an H2-blocker (e.g., ranitidine) 
may be considered for subjects not responsive to a regimen with an H1-blocker.  
If standard procedures to limit symptoms of injection site reaction, or pruritus or acute 
hypersensitivity are insufficient, then the infusion time may be extended beyond 60 minutes, but 
no more than 90 minutes. 
 
5.1.2 Gemcitabine 
 
Please refer to gemcitabine package insert for additional information. 
 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of M6620 (VX-970) and/or gemcitabine 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. Appendix B (Patient Drug Interactions Handout and Wallet Card) should be 
provided to patients. Because M6620 (VX-970) is primarily metabolized by CYP3A4, 
concomitant administration with strong inhibitors or inducers of CYP3A4 should be avoided. 
Because the lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated medical reference for a list of drugs to avoid or minimize use of. Appendix B 
(Patient Drug Interactions Handout and Wallet Card) should be provided to patients. Patients 
receiving any medications or substances that are inhibitors or inducers of cytochrome P450 3A 
(CYP3A4 enzyme) are ineligible. As part of the enrollment/informed consent procedures, the 
patient will be counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the-counter 
medicine or herbal product.   
 
M6620 (VX-970) is a moderate inhibitor of P-gp and BCRP. Use caution when administered with 
substrates of P-gp and BCRP. 
 
 
5.3 
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 as per RECIST 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s), 

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• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
Patients with CA125 elevation alone may continue on study as long as they have not developed 
progressive disease by RECIST.   
Patients who develop disease progression by RECIST 1.1 on weekly gemcitabine alone will be 
allowed to crossover to the experimental gemcitabine/M6620 (VX-970) arm; in that case, 
treatment will continue until one of the above criteria stated in this section applies.  Importantly, 
patients on weekly gemcitabine alone arm are not allowed to cross over to the combined 
gemcitabine/M6620 (VX-970) arm based on CA125 elevation alone; Progressive disease by 
RECIST must be documented before cross over is allowed to the combined gemcitabine/M6620 
(VX-970) arm. 
 
 
5.4 
Duration of Follow Up 
 
Participants will be followed for 3 years after removal from study treatment or until death, 
whichever occurs first. They will be followed up for survival status every 3 months (+/- 2 
weeks) for one year after stopping study treatment; and every 6 months (+/- 2 weeks) thereafter 
until death. Subjects may withdraw from study treatment but still continue study follow-up 
procedures. Date and cause of death should be provided for participants who become deceased 
within the 3 year interval following removal from the study treatment. 
 
Participants removed from study treatment for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  
 
5.5 
Criteria for Removal from Study Treatment 
 
Patients will be removed from study treatment when any of the criteria listed in Section 5.3 
applies.  The reason for study removal and the date the patient was removed from study 
treatment must be documented in the Case Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Toxicity will be assessed utilizing the NCI CTCAE v4.0 until March 31, 2018 for AE reporting. 
CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 2018. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.   
 
Brief treatment or visit delays as defined in Section 10 do not constitute a protocol violation, but 
should be recorded. 

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Any patient requiring a toxicity-related dose delay of more than 28 days from the intended day 
of the next scheduled dose must be discontinued from the study unless there is approval from 
the Principal Investigator for the patient to continue. 
 
The M6620 (VX-970) and gemcitabine dose level reductions for both treatment Arms are 
presented in the tables below. 
 
 
M6620 (VX-970) Dose Level Reductions for Toxicity 
Arm 
M6620 (VX-970) 
Starting dose 
M6620 (VX-970) 
-1 level 
M6620 (VX-970) 
-2 level 
 
 
 
 
gemcitabine/M6620 (VX-970)a 
210 mg/m2 
165 mg/m2 
120 mg/m2 
a M6620 (VX-970) once daily for 2 days on Days 2 and 9 of a 21 day cycle 
 
 
 
gemcitabine Dose Level Reductions for Toxicity 
Arm 
gemcitabine 
Starting dose 
gemcitabine 
-1 level 
gemcitabine 
-2 level 
 
 
 
 
gemcitabine alone 
1000 mg/m2 
750 mg/m2 
500 mg/m2 
gemcitabine a /M6620 (VX-970) 
1000 mg/m2 
750 mg/m2 
500 mg/m2 
a gemcitabine once daily for 2 days on Days 1 and 8 of a 21 day cycle 
 
Cross Over 
For patients on the gemcitabine alone arm who cross over to the gemcitabine/M6620 (VX-970) 
arm and their gemcitabine dose was already reduced, then the dose of gemcitabine in the 
combined arm will be the same as the reduced dose they were receiving on the gemcitabine alone 
arm (i.e. if it was dose reduced to 750mg/m2, they will get 750mg/m2 in the combined 
gemcitabine/M6620 (VX-970) arm).   
 
 
6.1 
Dose Modifications due to Non-Hematologic Toxicity 
 
• 
In case of Grade 3 nausea/vomiting/diarrhea despite adequate supportive and 
prophylactic antiemetic and/or antidiarrheal coverage, both M6620 (VX-970) and gemcitabine 
will be dose reduced by 1 dose level. Furthermore, treatment will be interrupted and may be 
resumed when all toxicities (nausea/vomiting/diarrhea) have returned to Grade 2 or less at the 
discretion of the investigator. If adequate supportive and prophylactic antiemetic and/or 

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antidiarrheal coverage had not been provided, then the investigators may continue with the same 
dosing as long as maximum antiemetic and/or antidiarrheal coverage is provided. 
 
• 
In case of Grade 3 or higher non-hematologic toxicity (excluding 
nausea/vomiting/diarrhea), treatment will be interrupted and may be resumed when all toxicities 
have returned to Grade 2 or less, at the discretion of the investigator.  
o For the following non-hematologic toxicities, once the toxicity has returned to 
Grade 2 or less, dosing can be resumed at a lower dose level of gemcitabine 
(gemcitabine and not M6620 (VX-970) is dose reduced).  If any of the below 
drug-related toxicity is subsequently observed with the reduced dose of 
gemcitabine, VX 970 dose will then be reduced by one dose level: 
a) Grade 3 non-hematologic toxicity  
b) Any Grade 2 or lower non-hematologic toxicity requiring dose delay of more 
than 2 weeks 
 
o For Grade 4 non-hematologic toxicities, treatment will be interrupted and may be 
resumed at a lower dose when toxicity has returned to Grade 2 at less. Both 
gemcitabine and M6620 (VX-970) will be reduced by one dose level. 
 
• 
For infusion reactions, hypersensitivity or allergic reactions related or possibly related 
to M6620 (VX-970) then please refer to section 5.1.1 for management with prophylactic steroids 
and H1-blockers. If an infusion reaction/hypersensitivity or allergic reaction related or possibly 
related to M6620 (VX-970) occurs despite prophylactic steroids and H1-blockers then protocol 
treatment with be discontinued. 
 
• 
If any toxicity not described above results in delay in dosing in any Part of the Study 
and the subject may be benefitting from therapy, then at the discretion of the investigator, the 
dose of VX 970 or chemotherapy may be reduced by one dose level. 
 
• 
For toxicities that lead to a dose reduction, the dose will not be re-escalated during 
subsequent cycles.  
 
• 
If both drugs have been dose reduced by 2 dose levels and another dose reduction is 
required then M6620 (VX-970) can be continued alone (i.e. -2 dose level). 
 
If gemcitabine is held on day 1 of a cycle, then the cycle will be delayed. If gemcitabine is held 
on day 8 of a cycle, then day 8 will be omitted and treatment will be resumed 14 days later (day 
1 of the next cycle). Note that if gemcitabine is held on either day 1 or day 8, M6620 (VX-970) 
will also be held on either day 2 or 9, respectively. 
 
 
6.2 
Dose Modifications due to Hematologic Toxicity 
 
• 
Complete blood counts (CBC) will be obtained for all patients at Days 1 and 8 of 
each cycle.  In case of Grade 3 or higher hematologic toxicity on day 1 only, treatment will be 

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interrupted and ANC and platelets should be monitored weekly until recovery. If hematologic 
parameters do not recover within 28 days, the patient should be removed from the study 
treatment.  Treatment may be resumed when all toxicities have returned to Grade 2 or less, at the 
discretion of the investigator. 
 
• 
The following hematologic dose modifications and management guidelines will be 
followed: 
 
Day 1 of any cycle 
ANC 
PLT 
Action 
                
                   ≥1000                   AND              ≥75,000                     
 
 
No dose modification. Proceed 
with treatment with 
gemcitabine on Day 1 and 
M6620 (VX-970) on Day 2 
                   <1000                    OR                <75,000                     
 
Delay by 1 week intervals 
until recovery  
 
Day 8 of any cycle 
ANC 
PLT 
Action 
                
                   >750                   AND              >75,000                       
 
 
No dose modification. Proceed 
with treatment with 
gemcitabine on Day 8 and 
M6620 (VX-970) on Day 9 
                 500-750                  OR            50,000-75,000                
 
Hold gemcitabine on Day 8 
and M6620 (VX-970) on Day 
9; Consider G-CSF 
                   <500                     OR              <50,000                        
 
Hold gemcitabine on Day 8 
and M6620 (VX-970) on Day 
9; Dose reduce gemcitabine by 
one level; Consider G-CSF 
 
• 
For the following hematologic toxicities, once the toxicity has returned to Grade 2 or 
less, dosing can be resumed with one dose level reduction in gemcitabine dose (except if 
gemcitabine has already been dose reduced in the same cycle). If, after reduction of gemcitabine 
dose, any of the below drug-related hematologic toxicities is subsequently observed, then the 
dose of M6620 (VX-970) will be reduced by one level. 
a) Grade 4 thrombocytopenia 
b) Febrile neutropenia (growth factor support, per site protocol, may be used in lieu of dose 
reduction) 
c) Grade 4 neutropenia lasting more than 7 days (growth factor support, per site protocol, 
may be used in lieu of dose reduction) 
 
If gemcitabine is held on day 1 of a cycle, then the cycle will be delayed. If gemcitabine is held 
on day 8 of a cycle, then day 8 will be omitted and treatment will be resumed 14 days later (day 
1 of the next cycle). Note that if gemcitabine is held on either day 1 or day 8, M6620 (VX-970) 

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will also be held on either day 2 or 9, respectively. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm for further clarification.  
 
The CAEPR may not provide frequency data; if not, refer to the Investigator’s Brochure for this 
information. 
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
 
7.1.1 CAEPR for M6620 (VX-970) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
M6620 (VX-970, NSC 780162) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. The CAEPR does not provide frequency data; refer to the Investigator's 
Brochure for this information. Below is the CAEPR for M6620 (VX-970). 

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Note: M6620 (VX-970) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
 
7.1.2 Adverse Event List(s) for gemcitabine 
 
The following adverse events have been associated with gemcitabine: 
 
i) Schedule-dependent Toxicity 
In clinical trials evaluating the maximum tolerated dose of Gemcitabine, prolongation of the 
infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased 
incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and 
asthenia. The half-life of Gemcitabine is influenced by the length of the infusion). 
 
ii) Myelosuppression 
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with 
Gemcitabine as a single agent and the risks are increased when Gemcitabine is combined with 
other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia 
occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent Gemcitabine. The 
frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 
to 28%, and 5 to 55%, respectively, in patients receiving Gemcitabine in combination with 
another drug. 
 
iii) Pulmonary Toxicity and Respiratory Failure 
Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, 
and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these 
pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The 
onset of pulmonary symptoms may occur up to 2 weeks after the last dose of Gemcitabine.  
 
iv) Hemolytic Uremic Syndrome 
Hemolytic uremic syndrome, including fatalities from renal failure or the requirement for 
dialysis, can occur in patients treated with Gemcitabine. In clinical trials, HUS was reported in 6 
of 2429 patients (0.25%).  
 
v) Hepatic Toxicity 
Drug-induced liver injury, including liver failure and death, has been reported in patients 
receiving Gemcitabine alone or in combination with other potentially hepatotoxic drugs. 
Administration of Gemcitabine in patients with concurrent liver metastases or a pre-existing 
medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the 
underlying hepatic insufficiency. 
 
vi) Embryofetal Toxicity 
Gemcitabine can cause fetal harm when administered to a pregnant woman, based on its 
mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and 
rabbits.  

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vii)  Exacerbation of Radiation Therapy Toxicity 
Gemcitabine is not indicated for use in combination with radiation therapy. 
 
viii) Capillary Leak Syndrome 
Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving 
Gemcitabine as a single agent or in combination with other chemotherapeutic agents.  
 
ix) Posterior Reversible Encephalopathy Syndrome 
Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving 
Gemcitabine as a single agent or in combination with other chemotherapeutic agents. PRES can 
present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and 
neurologic disturbances.  
 
Please refer to the package insert for the comprehensive list of adverse events. 
 
 
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 
4.0 will be utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
The investigator must determine and record the severity of all serious and non-serious 
AEs.  
 
• 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 
 

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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 events.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 
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.  
 
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 

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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. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 
M6620 (VX-970) (NSC # 780162)  
 
8.1.1 Pharmaceutical Information for M6620 (VX-970) (NSC # 780162) 
 
Other Names: VRT-0768079, MSC2527093A, VX-970 

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Method of Administration: Prior to administration the solution should be given one hour at 
ambient temperature to warm up if stored refrigerated following preparation. Infuse over 60 minutes 
using an infusion set containing low-sorption or non-PVC, DEHP-free tubing and an in-line 0.2 
micron filter.  5% dextrose in water solution must be used for IV line priming and flushing.  M6620 
(VX-970) should not come in contact with 0.9% Sodium Chloride due to incompatibility. The 
infusion time may be extended beyond 60 minutes (as tolerated) but no more than 90 minutes if 
standard procedures to limit symptoms of an infusion reaction are insufficient or if the total 
volume of the infusion exceeds 600 mL.  To minimize the possibility of phlebitis, M6620 (VX-
970) should be administered through a large bore catheter into a large caliber peripheral vein or 
central venous access. 
 
Patient Care Implications: Monitor for infusion site reactions, irritation, and phlebitis. M6620 
(VX 970) absorbs in the UV-visible radiation spectrum and is widely distributed including skin, 
so patients receiving M6620 (VX-970) should take protective measures to minimize sun 
exposure. 
 
Women of childbearing potential and men should use appropriate contraception while on study 
drug and for 6 months after discontinuation of M6620 (VX-970). 
 
Potential Drug Interactions: M6620 (VX-970) is primarily metabolized by CYP3A4.  M6620 
(VX-970) has a low potential to inhibit CYP1A2, 2C9, 2C19, 2D6, and 3A4, and a moderate 
potential to reversibly inhibit CYP2E1.  The potential for M6620 (VX-970) to induce CYP450 
enzymes is low.  Concomitant administration with strong inhibitors or inducers of CYP3A4 
should be avoided. 
 
M6620 (VX-970) is a weak/moderate inhibitor of UGT1A1, UGT1A14, UGT1A9, UGT2B15, 
and UGT2B17.  UGT2B7, UGT1A3, and UGT1A6 were weakly or not inhibited.  M6620 (VX-
970) is predicted to not inhibit significantly the metabolic clearance of SN-38 (active metabolite 
of irinotecan) at therapeutic exposures.   
 
M6620 (VX-970) is a moderate inhibitor of P-gp and BCRP.  Use caution when administered 
with substrates of P-gp and BCRP transporters. 
 
 
Availability 
 
M6620 (VX-970) (NSC # 780162) is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
M6620 (VX-970) is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
 
 
 
 

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8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by the eligible participating Investigators (or 
their authorized designee) at each participating institution.  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 Identity and Access Management (IAM) account and the maintenance of 
an “active” account status, “current” password, and active person registration status.  
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.   
 
8.1.2.2 
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. 
 
8.1.2.3 
The current version of the Investigator Brochure 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, status, a “current” password, and active person registration status. Questions 
about IB access may be directed to the PMB IB coordinator via email.    
 
8.1.2.4 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 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: 

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https://ctepcore.nci.nih.gov/OAOP 
• 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 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
• PMB IB Coordinator: IBcoordinator@mail.nih.gov 
 
8.2 
Gemcitabine (NSC 613327) 
 
8.2.1 Pharmaceutical Information for Gemcitabine (NSC 613327) 
 
8.2.1.1 Description/How Supplied/Storage 
Gemcitabine (gemcitabine for injection, USP) is a nucleoside metabolic inhibitor that exhibits 
antitumor activity. Gemcitabine HCl is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride ( -
isomer). The empirical formula for gemcitabine HCl is C9H11F2N3O4 • HCl. It has a molecular 
weight of 299.66.  
Gemcitabine HCl is soluble in water, slightly soluble in methanol, and practically insoluble in 
ethanol and polar organic solvents. 
Gemcitabine is supplied in a sterile form for intravenous use only. Vials of gemcitabine contain 
either 200 mg or 1 g of gemcitabine HCl (expressed as free base) formulated with mannitol (200 
mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile 
lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added for pH 
adjustment. 
Unopened vials of Gemcitabine are stable until the expiration date indicated on the package 
when stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for 
excursions between 15° and 30°C (59° and 86°F).  
Exercise caution and wear gloves when preparing Gemcitabine solutions. Immediately wash the 
skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine contacts the 
skin or mucus membranes. Death has occurred in animal studies due to dermal absorption.  
 
8.2.1.2 Preparation for Intravenous Infusion Administration and Stability 
Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives. 
Add 5 mL to the 200-mg vial or 25 mL to the 1-g vial. These dilutions each yield a Gemcitabine 
concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg or 1 g 
of Gemcitabine. Prior to administration the appropriate amount of drug must be diluted with 
0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL. 
Reconstituted Gemcitabine is a clear, colorless to light straw-colored solution. Inspect visually 
prior to administration and discard for particulate matter or discoloration. Gemcitabine solutions 
are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not 
refrigerate as crystallization can occur. No incompatibilities have been observed with infusion 
bottles or polyvinyl chloride bags and administration sets. 
 

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8.2.1.3 Agent Source 
Commercially available from various manufacturers. See package insert for further information. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
In the exploratory endpoints of our study, we hypothesize that tumors with high replicative stress 
may be associated with enhanced sensitivity to M6620 (VX-970)/gemcitabine. Therefore, we 
propose to explore whether baseline alterations associated with high replicative stress such as: 
i) mutations in HR and NER pathway genes,  
ii) mutations in TP53, ATM and ATR,  
iii) Amplification of CCNE1, ATR or MYC, 
iv) homozygous deletion of PTEN  
v) loss of ATM expression by immunohistochemistry 
are predictive of clinical outcome after gemcitabine/M6620 (VX-970).  
 
Regarding TP53 mutations, although TP53 mutations are found almost universally in high grade 
serous ovarian cancers, not all TP53 mutations abrogate TP53 function; a small fraction of TP53 
mutations (approximately 10%) are not deleterious.  Furthermore, in high grade serous ovarian 
cancer, approximately one third of TP53 mutations are truncating mutations leading to no 
expression of TP53 by immunohistochemistry. The remaining two thirds of TP53 mutations are 
missense mutations or in-frame deletions leading to increased expression of TP53 by 
immunohistochemistry.  Given that the functional consequence of the heterogeneous TP53 
mutations in terms of ATR inhibition is not known, we will explore their association with 
response to gemcitabine/M6620 (VX-970). For these reasons, we propose to sequence TP53 and 
to perform TP53 immunohistochemistry. Of note, TP53 IHC is a standard test that is routinely 
performed and should be available for most patients prior to enrollment in our trial. 
Finally, given that Alternative Lengthening of Telomeres (ALT) has been shown to be associated 
with response to ATR inhibition, we propose to evaluate whether ALT at baseline is predictive 
of clinical outcome after gemcitabine/M6620 (VX-970).  
 
9.1 
 Exploratory/Ancillary Correlative Studies 
 
The following assays will be performed to evaluate the aforementioned proposed exploratory 
biomarkers: 
 
1. Multigene next generation sequencing assay (Oncopanel Assay) 
At Dana Farber Cancer Institute, in the Department of Pathology Center for Advanced Molecular 
Diagnostic at Brigham and Women’s Hospital, we have developed a cancer genomic assay to 
detect somatic mutations, copy number variations and structural variants in tumor DNA 
extracted from fresh, frozen or formalin-fixed paraffin-embedded samples (Wagle et al. High-
throughput detection of actionable genomic alterations in clinical tumor samples by targeted, 
massively parallel sequencing. Cancer Discovery 2012). The Oncopanel assay surveys exonic 
DNA sequences of 447 cancer genes and 191 regions across 60 genes for rearrangement 
detection. DNA is isolated from tissue containing at least 20% tumor nuclei and analyzed by 
massively parallel sequencing using a solution-phase Agilent SureSelect hybrid capture kit and 
an Illumina HiSeq 2500 sequencer. The Oncopanel assay assesses genes including mutations and 

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label with protective cryogenic freezer tape (Fisher Scientific, product no. 1186750).  Be sure not 
to allow the label or tape to cover any part of the vial cap.  Place the tube on crushed dry-ice until 
stored in a freezer maintained at  -70°C until packaged for shipment 
 
The samples in the vials labeled "Aliquot A" must be shipped separately from the "Aliquot B" 
vials.  Place the sample tubes in a fiberboard freezer box sealed in a zip lock plastic bag.  Put at 
least three inches of crushed dry ice in a seamless styrofoam container.  Place the plastic bag 
containing the samples in the box, on top of the crushed dry ice, and cover with an additional 
three inches or more of dry ice.  Seal the styrofoam container within a tight-fitting cardboard 
shipping box.  Send the samples on a Monday, Tuesday, or Wednesday by overnight courier for 
next day delivery by 10:00 a.m. to:   
 
 
Dr. Jeffrey G. Supko 
 
Massachusetts General Hospital 
 
55 Fruit St., GRJ 1025 
 
Boston, MA 02114 
 
Tel: 617-724-1970 
 
Notification of the shipment, the name of the courier service, and the courier tracking no. must 
be made by sending an e-mail to alitman@partners.org and jsupko@partners.org.  Attach files 
for the Shipping Manifest and the Pharmacokinetic Sample Time Form for each set of samples to 
the email.   
 
 
9.1.1 
 Collection, Shipping and Sites performing exploratory assays. 
 
As a part of the eligibility criteria, only patients with available archival FFPE tissue (either 
one paraffin embedded tissue block OR 10 5-micron unstained slides from the block on 
regular (non-plus) slides and 1 H&E slide) will be accrued onto this study. This archival 
FFPE tissue specimen will be analyzed with the aforementioned assays (section 9.1). 
FFPE block or unstained slides will be batch shipped upon trial completion to Dana-
Farber Cancer Institute. 
 
Sarah Farooq, MPH 
Dana-Farber Cancer Institute  
450 Brookline Ave, Boston, MA 02215  
 
All studies will be performed at the DFCI/Brigham and Women’s hospital. Specifically, 
the Oncopanel assay and TP53 IHC will be performed at the Department of Pathology at 
Brigham and Women’s Hospital. ALT assay will be performed at the Center of DNA 
Damage and Repair (CDDR) at DFCI.  WES will be performed at Dr Levi Garraway’s 
Lab at DFCI in collaboration with the Broad Institute of Genomics. 
 
 
 
 

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10. STUDY CALENDAR 
 
The medical history, concomitant medications should be recorded; and physical examination, 
EKG, ECOG PS, complete blood count with differential and platelets, and clinical chemistry 
should be done ≤14 days prior to initiation of treatment. However, if these initial examinations 
are obtained within 3 days prior to the initiation of treatment they do not have to be repeated on 
Cycle 1 day 1. Scans to document evaluable disease (i.e., tumor measurement) should be 
performed ≤ 28 days prior to initiation of treatment and should be performed as close to the start 
of treatment as possible. 
 
Assessments must be performed prior to administration of any study agent.  
 
A +/- 3 day window will be allowed for Day 1 of Cycle 2 and subsequent treatment cycles. 
Please note that Day 8 should occur 7 days +/- 1 day from Day 1. Day 2 and Day 9 should occur 
24 hours (+/- 4 hours) after Day 1 and Day 8, respectively. 
 
 
Pre 
Study Screen 
Day 
1 
Day 
2 
Day 
8 
Day 
9 
Off Study 
treatment8 
M6620 (VX-970)12 
 
 
 
X 
 
X 
 
Gemcitabine 
 
 
X 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
Archival FFPE sample 
X 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Physical exam 
 
X 
X 
 
 
 
X 
Concomitant Medications 
 
X 
X 
 
X 
 
 
Vital signs1 
 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
Weight13 
 
X 
X 
X 
X 
X 
 
ECOG Performance status 
 
X 
X 
 
X 
 
X 
Coagulation (PT, PTT, INR)3 
 
X 
 
 
 
 
 
CBC w/diff, plts 
 
X 
X11 
 
X 
 
X 
Clinical chemistry2 
 
X 
X11 
 
X 
 
X 
CA1259 
 
X 
X 
 
 
 
X 
Adverse event evaluation 
 
 
X 
 
X 
 
X 
CT or MRI scan (chest, 
abdomen, pelvis) and Tumor 
assessments (RECIST 1.1)5, 6, 7 
 
X 
CT scan and tumor assessment should be 
performed every 9 weeks.  Documentation 
(radiologic) must be provided for patients 
removed from study for progressive 
disease. 
 
B-HCG4 
 
X 
 
 
 
 
 
EKG 
 
X 
 
 
 
 
 
PK10 
 
 
 
X 
 
X 
 

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1 Vital signs will include resting heart rate, blood pressure, temperature and weight at the  
screening visit will include height. After Screening, height will not be measured. Vital signs and weight 
will be obtained prior to chemotherapy administration according to institutional practice.  
2 Clinical chemistry will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, 
calcium, CO2, ALP, AST, ALT, total bilirubin, total protein, and albumin. 
3 Coagulation studies will be performed at baseline only (PT or INR with PTT); they will be repeated 
beginning of every cycle if patient on coumadin. 
4 Pregnancy tests will only be performed in women of childbearing potential within 14 days prior to first 
dose of study treatment. 
5 Patients will be restaged after every 3 cycles (every 9 weeks [±7 days]). Patients with unacceptable 
toxicity should be discontinued from the study; patients with SD or response to therapy will continue 
treatment. Patients without evidence of undue toxicity may continue treatment with study drugs until 
disease progression occurs as long as they are achieving clinical benefit and desire to continue therapy. 
If a patient on the gemcitabine alone arm is removed for clinical progression a CT scan may be done to 
prove RECIST progression. Patients with progressive disease per RECIST 1.1 on the gemcitabine alone 
arm are allowed to cross over to the gemcitabine/M6620 (VX-970) arm. Patients with progressive 
disease per RECIST 1.1 on gemcitabineM6620 (VX-970) arm will be discontinued from the study. 
6 CT scans of the chest and abdomen and pelvis are required at baseline and every 3 cycles (9   
weeks). The same method of assessment and the same technique must be used to characterize each 
identified and reported lesion at baseline and during subsequent imaging procedures.  
7 Patients continuing study treatment for a minimum of 1 year may have the tumor imaging assessments 
expanded to every 4 cycles (12 weeks [±7 days]). 
8 The End of Study Treatment Visit will be performed within 30 days from the last treatment dose.  
Reassessments for toxicity, disease progression, and survival will be performed 30 days from last 
treatment dose. Follow up of patients after removal from study treatment will be as described in Section 
5.4.  
9 CA-125 serum sample collected at baseline, Day 1 of each cycle and at the end-of-study treatment visit. 
10 PK: Blood samples will be collected from patients enrolled on the gemcitabine + M6620 (VX-970) arm 
of the clinical trial to monitor the concentration of M6620 (VX-970) in plasma achieved at the end of 
the 60 min i.v. infusion of the drug for the doses given on days 2 and 9 of cycles 1 and 2. The pre-dose 
PK blood draw should be done 5 to 1 minute before infusion start. There is no time window for the 
post-infusion PK collection. Blood should be drawn at the same time that the infusion ends. PKs should 
be collected in a later cycle if they are missed or if drug is held during cycle 1 or 2. Please refer to 
section 9 for more details.  
11Patients do not need to re-meet eligibility criteria on Cycle 1 Day 1 in order to be treated. 
12 Only patients being treated on the gemcitabine + M6620 (VX-970) arm need to come in on Day 2 and 
Day 9. 
13 Weight assessment on day 2 and 9 are optional, and M6620 (VX-970) dose may be calculated based on 
weight taken on day 1 and 8, respectively.  
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 9 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained ≥ 4 weeks following 
initial documentation of objective response. 
 

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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) [Eur J Ca 45:228-247, 2009].  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 M6620 (VX-970). 
 
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). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
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 

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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. 
 
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 

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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 
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 

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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 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  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 [JNCI 92:1534-1535, 2000]. 
 
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. 
 
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. 
 

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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). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 

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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. 
**    Confirmatory scans will be required for response (PR or CR) 
***  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 
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 
 

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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 is defined as the number of days from the date the subject was randomized to the 
date of documented progressive disease (PD) by RECIST version 1.1 or death (regardless 
of cause). 
 
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.   
 
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. 
 

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All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (https://ctepcore.nci.nih.gov/iam/) and the 
appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on either the Corresponding 
Organization or Participating Organization roster at the enrolling site.   
 
Upon initial site registration approval for the study in 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 users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users 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.   
 
Users 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, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  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 

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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 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. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm). 
 
12.3 
Data Safety Monitoring  
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 

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unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. The DSMC will provide the Overall PI an outcome of the review, which 
will be forwarded to all sites, and discussed on regular teleconferences if needed. 
 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a 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. 
 

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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 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. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
We propose a randomized open label, Phase 2 trial of M6620 (VX-970) and gemcitabine versus 
gemcitabine alone in patients with recurrent platinum resistant high grade serous ovarian or 
primary peritoneal or fallopian tube cancers. Specifically, patients with platinum resistant high 
grade serous ovarian or primary peritoneal or fallopian tube cancer will be randomized 1:1 to 
either gemcitabine alone or gemcitabine/M6620 (VX-970). There is no limit in the number of 

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previous chemotherapy regimens, but patients are not eligible if they have received more than 1 
prior regimen in the platinum resistant setting. Treatment will continue until disease progression 
and patients who progress on weekly gemcitabine alone will be allowed to crossover to the 
experimental gemcitabine/M6620 (VX-970) arm. Only patients with available archival FFPE 
tissue (either one paraffin embedded tissue block OR 10 5-micron unstained slides from the 
block on regular (non-plus) slides and 1 H&E slide) will be eligible to participate in this study. 
 
The primary endpoint of the study is to compare the PFS between gemcitabine/M6620 (VX-970) 
and gemcitabine alone arms. PFS is defined as the number of days from the date the subject was 
randomized to the date of documented progressive disease (PD) by RECIST version 1.1 or death 
(regardless of cause). 
 
The secondary endpoints include to determine and compare overall response rate (ORR) by 
RECIST, PFS at 6 months, CBR, DOR, CA125 reduction by 50% and OS between 
gemcitabine/M6620 (VX-970) and gemcitabine alone arms. Furthermore, we will determine and 
compare the safety profile of gemcitabine/M6620 (VX-970) and gemcitabine alone regimens.  
 
We will perform a modified intent-to-treat analysis that includes all patients who are randomized 
and initiate protocol therapy. Patients who go off treatment for reasons unrelated to progression 
will be included in the analysis regardless of non-protocol therapy. Patients who will be included 
in the analysis who start another non-protocol treatment prior to progression will be censored at 
the time they start the non-protocol therapy.  
 
Finally, another secondary objective of our study is to enable the investigation of the efficacy 
(ORR) of the gemcitabine/M6620 (VX-970) after crossover following disease progression after 
single agent gemcitabine. In this regard, we hypothesize that addition of M6620 (VX-970) to 
gemcitabine will be clinically effective for patients who develop disease progression on 
gemcitabine alone. 
Specifically, if there is significant response observed in patients who cross over to 
gemcitabine/M6620 (VX-970) after progression on gemcitabine alone, then this would be a 
clinically important observation.  These patients are platinum resistant (we allow unlimited lines 
in platinum sensitive setting and up to 1 line in the platinum resistant setting) and would have 
progressed on gemcitabine already. Therefore, a significant ORR of the gemcitabine/M6620 
(VX-970) combination in this very resistant and heavily pretreated population would be 
clinically important. In this regard, ORR was the endpoint used for the recent approval of 
olaparib in ovarian cancer and is also consistent with the consensus statement of the SGO white 
paper (Herzog et al. Gyn Onc, 2013) stating that ORR is a valid endpoint for heavily pretreated 
patients.  Furthermore, given that many ovarian cancer patients receive a combination of 
gemcitabine with carboplatin in the platinum sensitive setting (either after first or second 
recurrence), evidence of response to gemcitabine/M6620 (VX-970) after progression on 
gemcitabine alone, would support use of this combination in patients who have already received 
gemcitabine in the past, either alone or in combination with carboplatin. 
 
In this exploratory trial, in order to have 80% power to detect improvement of median PFS 

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(primary endpoint) from 15 weeks with gemcitabine alone to 27.3 weeks with 
gemcitabine/M6620 (VX-970) (HR=0.55) using a stratified log-rank test with the platinum free 
interval as the stratification factor with a one-sided alpha level of 0.1, 64 patients would be 
randomized (32 patients on each arm). Final analysis would occur when 50 PFS events are to be 
observed. This assumes a constant accrual over 1 year with 6 months of additional follow-up, 
and a constant hazard of PFS and dropout such that 5% of patients are lost-to-follow-up at 1 
year. Although the target number of evaluable patients is 64, it is anticipated that 10% of subjects 
will not be evaluable and thus the maximum total number of patients to be enrolled will be 70. 
An interim analysis will be planned at 25 PFS events to stop for futility only. 
 
ORR will be the endpoint for the patients who crossover to gemcitabine/M6620 (VX-970) after 
progression on gemcitabine alone. Based on this design, there will be about 32 evaluable patients 
on single agent gemcitabine arm. Assuming 75% (n=24) of the these 32 patients elect to switch 
to combination agents arm after progression,  the following table provides the effect sizes to 
reject a null hypothesis of 5% ORR with at least 80% power and one-sided alpha of 0.1 or lower. 
For example, if 21 patients on single agent arm elect to switch to combination agents arm after 
progression, and if the true ORR is 20%, 3 or more responses are needed to reject the null 
hypothesis of 5% ORR with 82% power and one-sided alpha of 0.08. 
 
Table: Effect sizes for which there will be 80% power to reject a null of a 5% ORR (one-sided 
alpha = 0.1)  
Actual 
Sample Size 
True ORR 
that yields 
80% power 
Obs ORR to 
reject the 
null (N) 
Obs ORR to 
reject the 
null (%) 
Power 
One-sided 
Alpha 
21 
20% 
≥ 3 
14.3% 
0.82 
0.08 
24 
22% 
≥4 
16.7% 
0.81 
0.03 
27 
20% 
≥4 
14.8% 
0.82 
0.04 
 
 
13.2 
Sample Size/Accrual Rate 
 
In order to have 80% power to detect improvement of median PFS (primary endpoint) from 15 
weeks with gemcitabine alone to 27.3 weeks with gemcitabine/M6620 (VX-970) (HR=0.55) 
using a stratified log-rank test with the platinum free interval as the stratification factor with a 
one-sided alpha level of 0.1, 64 patients would be randomized (32 patients on each arm). Final 
analysis would occur when 50 PFS events are to be observed. This assumes a constant accrual 
over 1 year with 6 months of additional follow-up, and a constant hazard of PFS and dropout 
such that 5% of patients are lost-to-follow-up at 1 year. Although the target number of evaluable 
patients is 64, it is anticipated that 10% of subjects will not be evaluable and thus the maximum 
total number of patients to be enrolled will be 70. An interim analysis will be planned at 25 PFS 
events (50% information) to stop for futility only. The stopping boundary is defined as a Z-
statistic from the logrank test less than 0 (i.e. observed HR of 1.0 or greater under a univariable 
Cox proportional hazard model). No early stopping for efficacy is allowed, and the nominal 
alpha at final analysis will not be increased according to the planned futility analysis (i.e. non-
binding).  

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with measurable disease that were not assessable for objective response due to early 
discontinuation of protocol therapy. 
 
Overall survival is the number of days from the date the subject was randomized  
until date of death (regardless of cause). PFS and OS will be summarized using Kaplan-Meier 
analyses and compared between the two arms using a stratified log-rank test with the platinum 
free interval as the stratification factor. PFS and OS will additionally be analyzed using a Cox 
Proportional Hazards Model, including the stratification factor, and will be used to estimate the 
Hazard Ratio (HR) of the gemcitabine/M6620 (VX-970) arm relative to the gemcitabine alone 
arm and the associated 90% CI.  
 
Objective response rate (ORR) is defined as the percentage of subjects achieving a response 
rating of complete response (CR) or partial response (PR) by RECIST guideline v1.1 during the 
study. Clinical benefit rate (CBR) is defined as the percentage of subjects achieving a response 
rating of stable disease (SD) ≥ 4 months, PR, or CR during the study. These rates and 95% 
confidence intervals will be determined for both gemcitabine/M6620 (VX-970) and gemcitabine 
alone arms. Percent of subjects with at least 50% reduction in CA-125 will be evaluated and 
presented with 95% confidence intervals and compared across the two groups using z-test for 
independent proportions. Treatment group comparisons in ORR, CBR and CA-125 50% 
reduction will be evaluated using logistic regression and expressed as odds ratios with associated 
90% CIs. In the event that rates are low, comparisons will be based on Fisher’s Exact test.  
 
Duration of response (DOR) will be computed with “start” of response being:  
• for subjects whose best response is SD, the day protocol therapy was first administered;  
• for subjects whose best response is CR or PR, the earliest assessment of CR or PR.  
Duration of best response will not be estimated for subjects who leave the study prior to a first 
assessment of response (scheduled at the end of treatment Cycle 2), subjects whose best response 
is progressive disease, and subjects who leave the study prior to an assessment of progressive 
disease.  
“End” of response is the earliest assessment of progressive disease or death or last follow up 
where the subject has not yet progressed from her prior response. For DOR, informational 
summaries and Kaplan Meier plots, without formal statistical comparisons, will be produced.  
The following minimum data summaries will be presented by treatment arm for safety 
assessments:  
• Treatment-emergent adverse events (TEAEs) of any CTCAE grade – summarized by system 
organ class and CTCAE grade  
• SAEs  
• Deaths summarized by primary cause  
• Laboratory parameters (hematology and chemistry), vital signs, ECG data and concomitant 
medications will be summarized appropriately.  
 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 

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All patients will be evaluable for toxicity from the time of their first treatment with 
Gemcitabine and M6620 (VX-970).  
 
13.5.2 Evaluation of Response 
 
 
The analysis population for all secondary efficacy and exploratory endpoints will be the 
modified intention to treat which includes all patients to receive protocol therapy, 
including those with measurable disease that were not assessable for objective response 
due to early discontinuation of protocol therapy. 
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).  [Note:  By arbitrary convention, category 9 
usually designates the “unknown” status of any type of data in a clinical database.] 
Patients in response categories 4-9 should be considered to have a treatment failure 
(disease progression).   
 
 
14. PUBLICATION PLAN 
 
The results should be made public within 12 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  

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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 9944 
Version Date: June 4, 2019   
 
 
74 
 
APPENDIX B: PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis:  
      
Trial #: 
      
Study 
Doctor: 
      
Study Doctor 
Phone #:  
      
Study 
Drug(s)
: 
      
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse 
practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the 
National Cancer Institute.  
 
These are the things that your healthcare providers need to know: 
M6620 (VX-970) interacts with specific enzymes in the liver or other tissues like the gut and 
certain transport proteins that help move drugs in and out of the cell. 
 
 
Explanation 
CYP 
isoenzymes 
The enzyme in question is CYP3A4.  M6620 (VX-970) is metabolized by 
CYP3A4 and may be affected by other drugs that inhibit or induce this 
enzyme.  
Protein 
transporters 
The proteins in questions are P-gp and BCRP.  M6620 (VX-970) is a 
moderate inhibitor of these proteins and may affect drugs that are moved in 
and out of cells/organs by these transport proteins. 
 
These are the things that you need to know: 
The study drug M6620 (VX-970), may interact with other drugs which can cause side effects. 
For this reason, it is very important to tell your doctors about all your medicines, including: (a) 
medicines you are taking before this clinical trial, (b) medicines you start or stop taking during 
this study, (c) medicines you buy without a prescription (over-the-counter remedy), (d) herbals 
or supplements (e.g. St. John’s Wort). It is helpful to bring your medication bottles or an updated 
medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health 
care providers to review any medicines and herbal supplements that are considered strong 
inhibitors or inducers of CYP3A4 and substrates of P-gp and BCRP. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
• Make sure your doctor knows to avoid certain prescription medications.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.   
Version Feb/2019