Phase 1 Dose Escalation and Expansion Cohort of Carboplatin and Gemcitabine With or Without M6620 (VX-970) in First or Second Recurrence Platinum-Sensitive Epithelial Ovarian, Peritoneal, and Fallopian Tube Cancer
Phase: PHASE1
Conditions: Metastatic Fallopian Tube Carcinoma, Metastatic Ovarian Carcinoma, Metastatic Primary Peritoneal Carcinoma, Ovarian Endometrioid Tumor, Ovarian High Grade Serous Adenocarcinoma, Platinum-Sensitive Ovarian Carcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Stage IV Fallopian Tube Cancer AJCC v6 and v7, Stage IV Ovarian Cancer AJCC v6 and v7, Stage IV Primary Peritoneal Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)

1 
Protocol Version 25Feb2021 
 
 
 
MC1563: Phase 1 Dose Escalation and Expansion Cohort Trial of Carboplatin and 
Gemcitabine with or without M6620 (VX-970) in First or Second Recurrence 
Platinum-Sensitive Epithelial Ovarian, Peritoneal, and Fallopian Tube 
Cancer 
 
MCCC Amendment 7 
1 
Title 
page and 
headers 
Updated to reflect the current Protocol Version date submitted in response to an 
Amendment from CTEP 
2 
Section 
2.51 
Change “Pharmacodynamic Assay Development & Implementation Section (PADIS)” to 
“PADIS, Frederick National Laboratory for Cancer Research (FNLCR)”.  
3 
Section 
9.1.1.2 
Replace “Dr. Kinders” with “Dr. Ralph Parchment”.  
 
4 
Section 
9.1.1.3 
Delete entire section and add the below: 
The pATR and Rad51 IFA assays will be performed in the laboratory of Dr. Parchment at 
PADIS, Frederick National Laboratory for Cancer Research (FNLCR) under the guidance 
of Dr. Deborah Wilsker. ɣH2AX, pNBS1 IFA with βCATN segmentation assay will be 
performed in the NCLN PD Assay Laboratory at MD Anderson under the guidance of Dr. 
Kate Ferry-Galow. 
 
5 
Section 
9.1.1.5 
Replace the sentence “Samples will be submitted to Dr. Kinders' laboratory for evaluation 
of DNA damage markers, and H&E pathology evaluation.” with the below: 
 Samples will be first submitted to Dr. Ralph Parchment’s laboratory at PADIS, Frederick 
National Laboratory for Cancer Research (FNLCR), then routed to IFA assay performance 
sites as described in Section 9.1.1.3.  
 
6 
Section 
9.2.1.3 
Replace “Frederick National Laboratory for Cancer Research (FNLCR) Pharmacodynamic 
(PD) Specimen Central Receiving” with “PADIS, Frederick National Laboratory for 
Cancer Research (FNLCR) Specimen Central Receiving”.  
Replace “Email FNCLR PD specimen Control Receiving” with “PADIS, Frederick 
National Laboratory for Cancer Research (FNLCR) Specimen Central Receiving”.  
 
7 
Section 
9.2.1.4 
Delete entire section and add the below: 
The pATR and RAD51 IFA assays will be performed at PADIS, Frederick National 
Laboratory for Cancer Research (FNLCR). The ɣH2AX, pNBS1 IFA with βCATN 
segmentation assay will be performed at the NCLN PD Assay Laboratory at MD 
Anderson. 
 
8 
ICD 
Version date changed to match new protocol 
 
 
 
 

2 
Protocol Version 25Feb2021 
 
 
TITLE: 
Phase 1 Dose Escalation and Expansion Cohort of Carboplatin and 
Gemcitabine with or without M6620 (VX-970) in First or Second 
Recurrence Platinum-Sensitive Epithelial Ovarian, Peritoneal, and Fallopian 
Tube Cancer 
 
Corresponding Organization: MA036 / Dana-Farber - Harvard Cancer Center LAO 
 
 
Principal Investigator: 
Andrea Wahner Hendrickson, M.D. 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Telephone: (507) 284-2511 
Fax: (507) 284-5280 
Email: wahnerhendrickson.andrea@mayo.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-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: 
Nathan R. Foster, M.S. 
Mayo Clinic 
200 First Street SW 
Rochester, Minnesota 
Telephone: (507) 284-5051 
Email: foster.nathan@mayo.edu 
 
 

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Protocol Version 25Feb2021 
 
 
 
NCI-Supplied Agent: M6620 (VX-970) (NSC 780162) 
Other Agents: Carboplatin (NSC 241240) and Gemcitabine (NSC 613327), commercial supply 
 
IND #: 
 
IND Sponsor: DCTD, NCI 
 
Protocol Type / Version # / Version Date: 
Original / Version 1 /October 20, 2015 
Resubmission / Version 2 / January 29, 2016 
Resubmission / Version 3 / May 24, 2016 
Resubmission / Version 4 / July 11, 2016 
Resubmission / Version 5 / August 3, 2016 
Resubmission / Version 6 / September 29, 2016 
 
CTSU Activation November 4, 2016 
 
Amendment 1 / Version 7 / February 2, 2017 
Amendment 2 / Version 8 / March 12, 2018 
Amendment 2 / Version 9 / May 3, 2018 
Amendment 2 / Version 10 / May 18, 2018 
Amendment 2 / Version 11 / July 17, 2018 
Amendment 3 / Version 12 / August 22, 2018 
Amendment 4 / Version 13 / August 26, 2019 
Amendment 5 / Version 14 / October 18, 2019 November 20, 2019 
Amendment 6 / Version 15 / July 23, 2020 
Amendment 7 / Version 16 / February 25, 2021 
 
 
 

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Protocol Version 25Feb2021 
 
 
rucaparib per FDA approved indications is allowed but is not part of this protocol. 
Bevacizumab therapy while on the clinical trial is not allowed.  
 
** Patients will undergo three biopsies. Patients will all have a pretreatment biopsy 
(up to three weeks prior to initiation of therapy) and be randomly assigned to have 
either the 18-24 h post carboplatin/gemcitabine biopsy on day 2 cycle 1 or the post-
M6620 biopsy in cycle 1 (day 2 6 h after treatment with M6620) and the other 
biopsy on day 2 in cycle 2. 
 
 
 

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TABLE OF CONTENTS 
TITLE: 1 
SCHEMA ......................................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................. 4 
1. OBJECTIVES .............................................................................................................................. 7 
1.1 
Primary Objectives ...................................................................................................7 
1.2 
Secondary Objectives ............................................................................................... 7 
1.3 
Integrated Correlative Study Objectives .................................................................. 7 
2. 
BACKGROUND ................................................................................................................. 8 
2.1 
Ovarian, Peritoneal and Fallopian Tube Cancer ...................................................... 8 
2.2 
M6620 (VX-970) ..................................................................................................... 9 
2.3 
Gemcitabine and Carboplatin ................................................................................ 19 
2.4 
Rationale ................................................................................................................20 
2.5 
Correlative Studies Background ............................................................................ 22 
3. 
PATIENT SELECTION .................................................................................................... 24 
3.1 
Eligibility Criteria .................................................................................................. 24 
3.2 
Exclusion Criteria .................................................................................................. 25 
3.3 
Inclusion of Women and Minorities ...................................................................... 26 
4. 
REGISTRATION PROCEDURES ................................................................................... 26 
4.1 
Investigator and Research Associate Registration with CTEP .............................. 26 
4.2 
Site Registration ..................................................................................................... 28 
4.3 
Patient Registration ................................................................................................ 29 
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 Modification Tables for Phase 1 Dose Escalation/Safety Lead In 
Regimen ................................................................................................................. 34 
6.2 
Dose Modifications for Control Group (Carboplatin/Gemcitabine): ..................... 41 
6.3 
Dose Modification Tables for Expansion Cohort45 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................... 51 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ..................... 51 
7.2 
Adverse Event Characteristics ............................................................................... 56 

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7.3 
Expedited Adverse Event Reporting ...................................................................... 57 
7.4 
Routine Adverse Event Reporting ......................................................................... 59 
7.5 
Secondary Malignancy ........................................................................................... 59 
7.6 
Second Malignancy ................................................................................................ 60 
8. 
PHARMACEUTICAL INFORMATION .......................................................................... 60 
8.1 
CTEP IND Agent(s) .............................................................................................. 60 
8.2 
Commercial Agent(s) ............................................................................................. 63 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ......................................... 66 
9.1 
Integrated Biomarker Studies ................................................................................ 67 
9.2 
Laboratory Correlative Studies ..............................................................................74 
10. 
STUDY CALENDAR ....................................................................................................... 79 
11. 
MEASUREMENT OF EFFECT ........................................................................................ 80 
11.1 
Schedule of Evaluations ......................................................................................... 80 
11.2 
Definitions of Measurable and Non-Measurable Disease ...................................... 80 
11.3 
Guidelines for Evaluation of Measurable Disease ................................................. 81 
11.4 
Measurement of Effect ........................................................................................... 83 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................87 
12.1 
Data Reporting ....................................................................................................... 87 
12.2 
Collaborative Agreements Language ..................................................................... 88 
13. 
STATISTICAL CONSIDERATIONS ...............................................................................90 
13.1 
Study Design/Endpoints ......................................................................................... 90 
13.2 
Sample Size/Accrual Rate ...................................................................................... 92 
13.3 
Stratification Factors .............................................................................................. 94 
13.4 
Analysis of Secondary Endpoints .......................................................................... 94 
13.5 
Reporting and Exclusions ...................................................................................... 96 
13.6 
Adverse Event Stopping Rule ................................................................................ 96 
REFERENCES .............................................................................................................................. 97 
APPENDIX A: PERFORMANCE STATUS CRITERIA ........................................................... 100 
APPENDIX B: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD ....... 101 
APPENDIX C: BROCA GENE LIST ......................................................................................... 103 
APPENDIX D: SOP340507 FOR TUMOR FROZEN NEEDLE BIOPSY SPECIMEN 
COLLECTION AND HANDLING .................................................................................108 
APPENDIX E: SOP340522 TUMOR FROZEN NEEDLE BIOPSY PREPARATION FOR THE 
γH2AX IFA ...................................................................................................................... 120 

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APPENDIX F: PREPARATION OF THU FOR PHARMACOKINETIC STUDIES ............... 146 

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1. 
OBJECTIVES 
 
1.1 Primary Objectives 
 
1.1.1 
Phase 1 Dose Escalation/Safety Lead-in 
o Assess safety and tolerability of the combination therapy carboplatin, gemcitabine 
and M6620 (VX-970) in adult women with platinum sensitive recurrent high 
grade serous or high grade endometrioid ovarian, primary peritoneal or fallopian 
tube cancer. 
 
o Determine the dose of the triple therapy to be used in the dose expansion 
cohort of the study. 
 
1.1.2 
Expansion Cohort 
o Confirm the safety at the maximum tolerated dose (MTD) for the addition of M6620 
(VX-970) to carboplatin and gemcitabine in first or second recurrence of platinum 
sensitive high grade serous or endometrioid ovarian, primary peritoneal or fallopian 
tube carcinoma. 
 
1.2 
Integrated Correlative Study Objectives 
 
1.2.1  
Collection of specimens for biomarker studies to provide preliminary proof of 
mechanism. Assess, in an exploratory fashion, whether the combination of 
gemcitabine and carboplatin activates the ATR/CHK1 pathway at achievable 
concentrations and also whether M6620 inhibits the activated pathway. 
 
1.2.2 To determine whether increased DNA damage as assessed by two different 
multiplex assays correlates with response to combination therapy with M6620 
(VX-970). 
1.2.3 . To determine whether mutations in homologous recombination repair genes 
correlate with response to combination therapy with M6620 (VX-970). To 
ascertain modulation of ATR autophosphorylation and other 
pharmacodynamic readouts for ATR inhibition by M6620 (VX-970). 
1.2.4 To ascertain modulation of ATR autophosphorylation and other 
pharmacodynamic readouts for ATR inhibition by M6620 (VX-970). 
 
1.3 Secondary Objectives 
 
1.3.1 To determine if the MTD for the combination of carboplatin, gemcitabine and M6620 
(VX-970) improves the confirmed response rate in adult women with platinum sensitive 
recurrent high grade serous or high grade endometrioid ovarian, primary peritoneal or 
fallopian tube cancer. 
1.2.5 1.3.2 To determine the impact of the MTD on overall survival (OS), duration of response, 
and progression-free survival (PFS).   
 
 
 

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2. 
BACKGROUND 
 
2.1 Ovarian, Peritoneal and Fallopian Tube Cancer 
 
Overview of Ovarian Cancer- Unmet Clinical Need 
In 2014, ovarian cancer accounted for approximately 21,980 (3%) of new cancer cases 
and 14,270 (6%) cancer deaths in women [1]. It has the highest mortality of all 
gynecologic malignancies. In 75% of newly identified cases, the disease is already 
advanced (stage III or IV) at the time of diagnosis [2]. First line treatment generally 
consists of a surgical procedure to debulk as much tumor as feasible as well as systemic 
chemotherapy, most often a platinum salt (cisplatin or carboplatin) and a taxane (most 
often paclitaxel) administered intravenously or intraperitoneally [2, 3].  Despite this 
initial rigorous treatment, more than 75% of patients experience a recurrence within the 
first 20 months of therapy completion [2]. Current management of recurrent ovarian 
cancer is guided by the interval of time to disease recurrence and is categorized according 
to the response to platinum therapy. Patients who progress during front line 
chemotherapy are defined as having platinum refractory disease and those who progress 
within 6 months after initial therapy are considered platinum resistant. In these cases, the 
response rate to further therapies ranges from 15-25% [4-6]. Those who recur more than 
6 months after completion of initial therapy are considered to be platinum sensitive and a 
platinum-based chemotherapy regimen is used upon recurrence. Platinum sensitivity 
portends a slightly better prognosis with a higher response rate to subsequent therapy as 
well as improved overall survival compared to those with platinum resistant disease [2]. 
 
In general, combination therapy is preferred in platinum sensitive recurrence, with three 
regimens commonly used showing approximately the same response rates, namely 
carboplatin plus pegylated liposomal doxorubicin [7], carboplatin plus paclitaxel [8], or 
carboplatin plus gemcitabine [9]. The ideal platinum based combination is not known 
and the choices depend on physician and patient preferences regarding side effect profile, 
ease of scheduling and possible patient comorbidities. More recent studies have also 
evaluated the role of bevacizumab in ovarian cancer [10-14]. Bevacizumab has been 
shown to improve progression free survival when used in first line therapy with 
maintenance therapy [10, 11], in combination with carboplatin and gemcitabine in 
platinum sensitive recurrence [13] as well as with several FDA approved agents in 
platinum resistant disease [12]. Currently, bevacizumab is only FDA approved in the 
setting of platinum resistant disease. For this reason, bevacizumab is not being 
investigated in this trial. 
 
ATR and DNA Damage response 
The DNA-damage response (DDR) is the term applied to a complex network of signaling 
pathways involved in surveillance and repair of DNA damage and transient cell cycle 

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arrest to ensure genomic stability and cell viability [15-17]. Deficiencies in DDR 
mechanisms have been shown to contribute to tumor development. The primary sensors 
of DNA damage and regulators of DDR are ataxia telangiectasia mutated (ATM) and 
ataxia telangiectasia Rad3-related (ATR) protein kinases. They both contribute to 
maintaining genome integrity in response to various exogenous and endogenous 
genotoxic insults, e.g., cytotoxic chemotherapy, ultraviolet light, ionizing radiation (IR), 
or hypoxia [15, 18, 19]. Although ATR and ATM have broadly overlapping substrate 
specificities, they have non-redundant functions, which are well coordinated during 
DDR. 
 
ATR appears to be primarily activated by single-strand DNA (ssDNA) breaks (SSB) 
during replicative stress while ATM is a main sensor of double-strand DNA (dsDNA) 
breaks (DSB). The key outcomes of ATR activation are inhibition of cell-cycle 
progression and suppression of late replicating origin firing [17]. ATR not only helps to 
stabilize but also restarts stalled replication forks, and suppresses recombination. ATR is 
recruited to the sites of SSB at stalled replication forks resulting from replication stress 
[15, 18]. ATR phosphorylates/activates checkpoint kinase 1 (CHK1) at serine 345 
(CHK1pS345), which stabilizes stalled replication forks until replication stress is resolved 
and DNA damage is repaired. Activated CHK1 phosphorylates and inhibits the cell 
division cycle 25A (CDC25A) phosphatase, which ultimately results in cell cycle arrest 
in intra-S-phase and/or G2-phase and blocks cells from entering mitosis until DNA is 
repaired and completely replicated [18, 20]. ATR function is not entirely restricted to 
CHK1 activation as it has been shown to be independently involved in replication of 
DNA and regulation of a DNA-damage protein network [15]. 
 
Upon detecting DSBs, ATM activates CHK2, which controls p53-dependent G1-phase 
arrest.  Unlike normal cells, cancer cells are often deficient in ATM-CHK2-p53 
signaling. It has been hypothesized that loss of the G1 checkpoint renders tumor cells 
more reliant on the ATR-controlled S/G2 checkpoints for repairing DNA damage and 
survival [15, 21]. Therefore, in tumor cells with defective p53, ATR inhibition may 
exacerbate replication stress leading to accumulation of DSBs, collapse of stalled 
replication forks, and eventually to lethal mitotic catastrophe. In contrast, normal cells 
that exhibit a low level of replicative stress and have functional ATM are expected to 
tolerate ATR inhibition. Indeed, preclinical studies have shown that disruption of the 
ATR pathway can exacerbate replication stress in oncogene-driven tumors and promotes 
cell killing.  In addition, tumor cells, which proliferate rapidly, are more susceptible to 
the cytotoxic effects of chemotherapy and radiation than slowly proliferating normal cells 
[15, 16]. However, the effectiveness of such DNA damage-inducing therapies in cancer 
treatment is attenuated by cells developing drug resistance, leading to tumor recurrence. 
Acquired resistance to cytotoxic therapies in tumors has been linked to the activation of 
DDR.  There is accumulating preclinical evidence that ATR inhibition can sensitize 
tumor cells to the effects of radiation or chemotherapy as described below [22]. 
 
 

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2.2 
M6620 (VX-970) 
 
2.2.1 Mechanism of Action 
 
M6620 (VX-970) (former names VET-0768079 or VE-822) is a highly potent and 
selective ATP- competitive inhibitor of ATR, with an inhibition constant (Ki) <0.2 
nmol/L (nM) [22, 23]. In comparison, M6620 (VX-970) was >100-fold weaker inhibitor 
of ATM (Ki=34 nM) and 
>1000-fold less effective against other closely related kinases, such as DNA-dependent 
protein kinase (DNA-PK) (Ki>4 mcM), mTOR (Ki>1mcM), and PI3K-gamma (Ki=0.22 
mcM) [22]. Overall, among 291 kinases tested, M6620 (VX-970)’s Ki values were 
>500-fold higher for 278 kinases (Ki>200 nM), >50-fold higher for 12 kinases (Ki>15 
nM), and 
>25-fold higher for FLT4 (Ki=8 nM) than its Ki for ATR [23]. A cellular 50% inhibition 
of ATR was attained at a M6620 (VX-970) concentration (IC50) of 0.019 mcM, 
demonstrating 
>100-fold greater selectivity against ATR compared to ATM or DNA-PK (IC50 of 2.6 
mcM or 18.1 mcM, respectively) [22]. 
 
Effect of M6620 (VX-970) on DDR Signaling and DNA Damage 
 
Concurrent treatment of cancer cell lines with M6620 (VX-970) and various DNA-
damaging agents led to sustained M6620 (VX-970)-dose-dependent decreases in levels 
of chemotherapy- induced CHK1pS345, a major substrate of ATR [22, 23]. In the 
presence of DNA damage, primarily DSBs, histone H2AX is phosphorylated at Ser139 
to produce γH2AX (H2AXpS139). Although all three DDR regulatory kinases, ATM, 
ATR and DNA-PK, phosphorylate H2AX to γH2AX, they are variably activated during 
different DNA- damage repair mechanisms (e.g., HR repair, non-homologous end 
joining [NHEJ] repair, base excision repair due induced by stalled replication forks, etc.) 
[24]. In addition, for efficient DNA-damage repair, the DDR regulatory kinases must be 
able to access damaged sites in the chromatin environment. ATM has been shown to 
phosphorylate the heterochromatin protein KAP1 at serine 824 (KAP1pS824) in response 
to DNA damage [25]. Exposure of lung cancer cell lines as well as primary tumors to 
M6620 (VX-970) in combination with DNA-damaging agents enhanced levels of the 
DNA-damage markers, i.e., γH2AX and KAP1pS824, as compared to DNA-damaging 
agent alone [23, 26]. 
Sequential treatment of cells with DNA-damaging agent followed 15 h later by M6620 
(VX-970) resulted in an initial inhibition of phospho-CHK1 (for 1 to 2 h) [23].  
However, over time, phospho-CHK1 reappeared despite continued exposure to M6620 
(VX-970). The rebound of phospho-CHK1 has been attributed to non-specific 
phosphorylation by an undefined kinase. However, despite the transient inhibition of 
phospho-CHK1, the sustained accumulation of γH2AX and KAP1pS824 was observed. 
Together these data suggest that disruption of ATR-mediated DDR signaling by M6620 
(VX-970) leads to sustained accumulation of DNA damage in cancer cells exposed to 
DNA-damaging agents. Failure to repair chemotherapy-induced DNA damage in the 
presence of M6620 (VX-970) has been hypothesized to drive enhanced cytotoxicity in 
cancer cells. These data support using γH2AX and KAP1pS824 as pharmacodynamic 
markers of M6620 (VX-970) activity. 
 

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M6620 (VX-970)-mediated radiosensitivity of pancreatic ductal adenocarcinoma cells 
was associated with inhibition of HR repair [22]. M6620 (VX-970) caused increased 
persistence of γH2AX levels both in vitro and in vivo. Adding M6620 (VX-970) to 
gemcitabine and ionizing radiation (IR) dramatically enhanced antitumor effects, with 
early and late apoptosis and abrogation of IR-induced G2 checkpoint in cell culture 
experiments. It has been suggested that by promoting strong S-phase arrest, 
chemoradiation may further increase dependence of tumor cells on ATR-initiated HR-
mediated repair of DSBs and survival. 
 
2.2.2. Nonclinical Studies 
 
In vitro Antitumor Activity 
 
In the absence of exogenous DNA-damaging agents, M6620 (VX-970) demonstrated 
stronger antiproliferative effects against three cancer cell lines tested (HCT116, HT29, 
and NCI- H23 with IC50s of 35, 48, and 170 nM, respectively) compared to noncancerous 
fibroblast and epithelial cells (IC50=110-200 nM) [23]. However, among the three cancer 
cell lines, potent cytotoxicity by single-agent M6620 (VX-970) was seen only in a 
colorectal cancer [CRC] cell line HCT116: a 50% effect (death in 50% of cells ) was 
observed at a concentration of 61 nM M6620 (VX-970) (EC50). This suggests that certain 
cancer cells may be particularly reliant on ATR for survival even in the absence of an 
exogenous DNA-damaging agent. 
 
In the cell proliferation assay with the HCT116 cell line, M6620 (VX-970) synergized 
with cisplatin (cross-linking agent), gemcitabine (anti-metabolite), irinotecan 
(topoisomerase I inhibitor), and etoposide (topoisomerase II inhibitor) [23]. The most 
dramatic response was observed in combination with cisplatin (a 20-fold lower IC50 
compared to the IC50 of cisplatin alone). Preliminary data from cell proliferation studies 
with M6620 (VX-970) + carboplatin also suggests >10-fold reduction in carboplatin IC50 
for two non-small cell lung cancer (NSCLC) cell lines (H23 and HT1299) tested. 
 
The impact of M6620 (VX-970) on chemotherapy-induced cytotoxicity was further 
examined against a panel of 37 lung cancer cell lines (including squamous NSCLC and 
small cell lung cancer [SCLC] histotypes) and 15 pancreatic cancer cell lines [23]. Most 
lung cancer cell lines responded well to M6620 (VX-970) in combination with cisplatin 
(84% of cell lines) or gemcitabine (76% of cell lines), demonstrating ≥3-fold reduction in 
the IC50 compared to IC50 of the cytotoxic agent alone [23, 27]. Enhanced sensitivity was 
also observed with etoposide (53% of cell lines), irinotecan (49% of cell lines) and 
oxaliplatin (39% of cell lines). About 40% of cell lines were hypersensitized (>10-fold 
reduction in IC50 observed) to cisplatin by M6620 (VX-970). Marked synergy between 
the two agents was also seen against four of seven human NSCLC primary tumors tested 
in vitro [27]. The greatest antitumor synergistic effect was observed in tumors with poor 
response to cisplatin alone. Similarly, most pancreatic cancer lines responded well to 
combination of M6620 (VX-970) with cisplatin or gemcitabine: antitumor IC50 was ≥3-
fold lower for the M6620 (VX-970) 
+ cytotoxic agent in >70% of cell lines as compared to IC50 of cytotoxic agent alone [23]. 
 
In addition, significant radiosensitization effects of M6620 (VX-970) were observed 
against two human pancreatic cancer cell lines with mutant KRAS and mutant p53 
(MiaPaCa-2 and PSN1) (p<0.05), but not against non-cancerous fibroblast cell lines 

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[22]. In addition, M6620 (VX-970) profoundly sensitized pancreatic tumor cells to 
gemcitabine-based chemoradiation. Impact of defective p53 signaling on sensitivity of 
cells to M6620 (VX-970) in combination with a cytotoxic agent (cisplatin, 
gemcitabine, irinotecan, oxaliplatin, or etoposide) was examined in isogenic matched 
lung cancer cells (wild-type p53 A549 versus A549 transfected with p53 shRNA), 
using a cell viability assay [23, 26]. Loss of p53 promoted sensitivity to ATR inhibition 
in combination with all five cytotoxic agents in contrast with the effects in wild-type 
A549. M6620 (VX-970) also synergized with cisplatin resulting in cytotoxicity in 
ATM-null primary skin fibroblasts, but no cytotoxicity was observed against wild-type 
fibroblasts [23]. This suggests that the functional status of the ATM pathway is a 
contributing factor in the cellular response to the inhibition of ATR. 
 
Of note, the response/p53 status relationship was unclear in the panel of heterogeneous 
cancer cell lines exposed to M6620 (VX-970) + chemotherapy [27]. Although not 
significant, there was a trend toward improved response with TP53 mutations (p=0.08) 
for M6620 (VX-970) combined with cisplatin. Furthermore, no clear relationship 
between cellular response to M6620 (VX-970) + cisplatin and p53 status was observed 
in seven primary lung tumors. 
 
In vivo Antitumor Activity 
 
The in vivo activity of M6620 (VX-970) was tested in multiple mouse xenograft models 
derived from human hung cancer cell lines and primary human tumor cells [23, 26]. 
M6620 (VX-970) potentiated antitumor effects of cisplatin, gemcitabine, irinotecan, and 
IR in a dose- dependent as well as schedule-dependent manner. Antitumor efficacy 
correlated with inhibition of phospho-CHK1 and an increase in DNA-damage markers. 
This supports ATR inhibition as a primary mechanism of action for M6620 (VX-970). 
Single-agent M6620 (VX-970) had no significant effect on tumor growth in the 
experimental models. M6620 (VX-970) was generally well tolerated at efficacious doses 
in combination with DNA-damaging agents. Some body weight loss and enhanced 
changes in specific peripheral blood cell populations were observed with intensive and 
sustained dosing of M6620 (VX-970) in combination with cisplatin. 
This effect could be attributed to an increased growth arrest, which was observed in vitro 
in normal cells for combinations of M6620 (VX-970) with DNA-damaging agents. This 
effect was reversed when ATR activity was restored. M6620 (VX-970) sensitized 
pancreatic tumor xenografts to the cytotoxic effects of gemcitabine-based 
chemoradiation [22]. The combination treatment was effective even at gemcitabine doses 
with no single-agent activity. M6620 (VX-970) administered in combination with 
gemcitabine + IR was well tolerated. 
 
In schedule optimization studies, M6620 (VX-970) was administered intravenously (IV) 
at 20 mg/kg (either as a single injection or as two 10 mg/kg injections 3 days apart) 
before (-2 
h) or after cytotoxic agent (+12, 24, or 48 h) in two human pancreatic cancer and NSCLC 
xenograft mouse models.  M6620 (VX-970) effectively enhanced antitumor activity of 
gemcitabine or cisplatin when administered 12 to 24 h after a cytotoxic agent. M6620 
(VX-970) administered before cytotoxic drug or greater than 48 h after a DNA-damaging 
agent had no impact on tumor growth compared to the effect of cytotoxic agent alone. 
 
Therapeutic human dose has been estimated based on the efficacious exposure achieved 

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at 20 mg/kg/week of M6620 (VX-970) (given either as a single IV injection or as two IV 
injections of 10 mg/kg per week) 12-24 h after cytotoxic agent (gemcitabine or cisplatin) 
in mice. 
The target M6620 (VX-970) plasma exposure, which corresponded to this dose, was an 
area under the concentration-time curve (AUC) of 4080 ng×h/mL/week. Allometry 
predicts that a human dose of 2.5 mg/kg (100 mg/m2) will be sufficient to achieve this 
exposure. 
 
Nonclinical Pharmacokinetics 
 
In all non-clinical species (the mouse, rat, dog, and monkey), M6620 (VX-970) 
exhibited a high volume of distribution (Vd); tissue exposure, including tumor, was 
high. In rats, no accumulation or retention was observed in tissues and the elimination 
half-lives (t1/2) were similar across all tissues and whole blood (Investigator’s 
Brochure, 2015). The whole blood t1/2 was 11.6 h in rats and 9.8 h in dogs. M6620 
(VX-970) was extensively bound to plasma proteins; the free fraction of M6620 (VX-
970) was only 2.1% in human blood. 
 
M6620 (VX-970) is primarily eliminated by oxidative metabolism, with a cytochrome 
P450 (CYP) 3A4 isoform being the principal isoform responsible. Strong inducers or 
inhibitors of CYP3A4 may alter M6620 (VX-970) kinetics and blood levels. Based on its 
minimal inhibition or induction effects on CYPs, M6620 (VX-970) is expected to have a 
low potential for drug-drug interactions. M6620 (VX-970) metabolites were excreted in 
the urine and bile. All metabolites observed in human hepatocyte incubations were also 
observed in either rat or dog hepatocyte incubations and in the blood, bile, or urine from 
rats or dogs. The systemic clearance of M6620 (VX-970) following IV administration 
was 26 and 13 mL/min/kg in the rat and dog, respectively. 
 
Nonclinical Safety Pharmacology 
 
An in-house manual patch-clamp human ether-a-go-go-related gene (hERG) assay 
demonstrated moderate inhibition of the hERG channel [23]. However, a telemetry dog 
study did not demonstrate any cardiovascular (CV) effects at exposures greatly exceeding 
the target human exposure. 
 
Nonclinical Toxicology 
 
M6620 (VX-970) was administered PO or IV for up to 28 days in rats and dogs. The oral 
studies used an aggressive dosing regimen (every 2 days) to define the toxicity profile, 
while IV studies (dosed twice per week) were more representative of the planned clinical 
dosing schedule [23]. In the rat, the severely toxic dose in 10% of animals (STD10) was 
30 mg/kg/day IV. The highest non-severely toxic dose (HNSTD) in dogs was 20 
mg/kg/day 
IV. The target organs for M6620 (VX-970) toxicity in rats included testes and 
peripheral blood cell populations (red cell mass, eosinophils, and platelets). Target 
organs in the dog included the liver, testes, and peripheral blood cell populations (red 
cell mass and eosinophils); changes in these organs appeared to be reversible after 
discontinuing of M6620 (VX-970) in both rats and dogs. 
 

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M6620 (VX-970) had no cardiovascular liabilities, was not genotoxic in mutagenicity 
assay, had no hemolytic potential in human blood or compatibility issues in human 
plasma, and was well tolerated in an acute rabbit parenteral injection study. M6620 (VX-
970) does absorb in the ultraviolet (UV) spectrum and has high tissue distribution in rats. 
 
M6620 (VX-970) has yet not been assessed in developmental and reproductive toxicity 
studies. However, VX 970 inhibits DNA-damage repair and will be administered in 
conjunction with cytotoxic chemotherapy, thus the potential for teratogenicity should 
be considered high. 
 
2.2.3 Clinical Studies 
 
The suggested starting dose of M6620 (VX-970) in humans, 18 mg/m2 IV, was 
equivalent to 1/10 of the rat STD10 (30 mg/kg or 180 mg/m2) [23]. This dose represents 
a more conservative estimate than 37 mg/m2 IV which would an estimate corresponding 
to the 1/6 of the dog HNSTD (20 mg/kg or 222 mg/m2). 
 
Vertex Pharmaceuticals, Inc. has sponsored the first-in-human M6620 (VX-970) phase 1 
study withM6620 (VX-970) being administered in combination with DNA-damaging 
agents to patients with advanced solid malignancies (Study 001); the study is ongoing 
[23]. This study evaluates M6620 (VX-970) in combination with either gemcitabine +/- 
cisplatin or cisplatin +/- etoposide. M6620 (VX-970) is dose-escalated (18, 36, 60, 72 
mg/m2 IV) following the standard 3+3 design. To allow for the single-agent M6620 (VX-
970) PK, a 7-day lead-in treatment period of M6620 (VX-970) before cycle 1 has been 
included. Combinations of M6620 (VX-970) with gemcitabine or cisplatin are 
administered on a weekly schedule, with M6620 (VX-970) being dosed 24 h after a 
DNA-damaging agent. 
 
Vertex Pharmaceuticals, Inc. has also sponsored a second trial, study 002, to evaluate the 
safety and tolerability of multiple ascending doses of M6620 (VX-970) administered once 
weekly (Part A1) or twice weekly (Part A2) as a single agent in advanced solid tumors as 
well as the safety and tolerability of M6620 (VX-970) when administered in combination 
with carboplatin (Part B1) and carboplatin and paclitaxel (Part B2) in subjects with 
advanced solid tumors to determine MTD. The study is currently ongoing. 
 
Clinical Pharmacokinetics 
 
Clinical PK have been evaluated both in whole blood and plasma [23]. Preliminary 
clinical PK data are available from the lead-in period for the first two cohorts (M6620 
(VX-970) 18 mg/m2 and 36 mg/m2). Mean exposure (AUC) profiles were similar in 
whole blood and plasma. The terminal elimination t1/2 was approximately 16 h across 
all doses. 
Overall, the Cmax was 1.36x greater and AUC0-∞1.43x greater in whole blood than in 
plasma. The results suggest that plasma is an appropriate matrix to characterize the VX- 
970 PK. M6620 (VX-970) exposures were similar for the agent administered alone and 
in combination with gemcitabine, suggesting no apparent drug-drug interactions. In the 
M6620 (VX-970) single dose studies, the plasma Cmax and AUC0-∞ increase in linear 
fashion with doses up to 480 mg/m2. 
 
Clinical Efficacy 

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Preliminary efficacy data are available for 48 patients treated with M6620 (VX-970) in 
combination with cisplatin (Study 001 Part A; data cutoff date March 21, 2016), 23 patients 
treated with M6620 (VX-970) and gemcitabine (Study 001 Part B; data cutoff date February 
23, 2016), 17 patients treated with M6620 (VX-970) single agent (Study 002 Part A; data 
cutoff date: March 14, 2016), and 17 patients treated with M6620 (VX-970) in combination 
with carboplatin (Study 002 Part B1; data cutoff date: March 14, 2016). In study 002 Part A 
(single agent M6620 (VX-970)), all 17 subjects who received at least 1 dose of single agent 
VX- 970 therapy either once weekly (Part A1) or twice weekly (Part A2) were included. Six 
of the 17 subjects (35.3%) had disease control, defined as CR+PR+SD. One subject with 
colon cancer had a CR.  There were no PRs but 5 of the 17 subjects had stable disease and 
including patients with ovarian, prostate, gallbladder and gastric carcinomas as well as 
peritoneal mesothelioma. PFS ranged from 1 day to 582+ days. 
 
In Study 001 Part A (M6620 (VX-970) and gemcitabine combination therapy), 4 of 48 
patients had a PR and 29 subjects had SD. PFS for all subjects ranged from 1+ to 443 
days. In Study 001 Part B (M6620 (VX-970) plus cisplatin therapy), 16 of 23 patients had 
disease control. These included four PRs, all of which occurred in patients with platinum 
resistant malignancies, and 12 subjects with SD. PFS ranged from 17 to 172 days. In 
Study 002 Part B1 (VX- 970 and carboplatin) 13 of 17 patients had disease control. One 
patient with ovarian cancer had a PR and 12 patients had SD. PFS ranged from 37 to 234 
days. 
 
Clinical Safety 
 
Preliminary safety data for 77 patients receiving M6620 (VX-970) in combination with 
gemcitabine or cisplatin (Study 001) and 36 patients receiving M6620 (VX-970) alone 
or in combination with carboplatin (Study 002) can be found in Investigator’s Brochure 
(2016)[23]. No dose-limiting toxicities (DLTs) were observed during either 7- to 14-day 
or 21-day lead-in periods of M6620 (VX-970) monotherapy in Study 001. 
DLTs 
and serious adverse events are summarized in the tables below. 
 
When treated with M6620 (VX-970) in combination with gemcitabine (Study 001 Part 
A), 26 (52%) subjects had at least one grade ≥ 3 AE that was considered related to the 
study drug treatment. Grade > 3 AEs that were considered related to study drug and 
occurred in at least 10% of subjects were neutropenia, thrombocytopenia, increased 
ALT and fatigue. DLTs of increased ALT, increased AST, increased alkaline 
phosphatase, thrombocytopenia, and fatigue occurred in 4 of 45 patients in the DLT 
evaluable set. 
 
In Study 001 Part B (M6620 (VX-970) and cisplatin combination therapy) 17 subjects 
(63%) had at least one Grade > 3 AE. The majority of Grade > 3 AEs occurred in less 
than 5% of subjects. Grade > 3 AEs that occurred in at least 10% of subjects were 
neutropenia and anemia. Ten subjects (37%) had at least one Grade > 3 AE that was 
considered related to the study drug treatment. Neutropenia was the only Grade > 3 AE 
that was considered related to study drug treatment and occurred in at least 10% of 
subjects. DLTs of hypersensitivity and increased ALT occurred in 2 of 26 (7.7%) 
subjects in the DLT evaluable set. 
 
In study 002 Part A1 (weekly M6620 (VX-970)), the most common AEs regardless of 

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causality were fatigue (45%), nausea, diarrhea, urinary tract infection (36.4% each) and 
anemia, headache, and flushing (27.3% each). No grade >3 AEs were considered related 
to study drug. No subjects had DLTs. In Study 002 Part A2 (twice weekly M6620 (VX-
970)), the only grade >3 AE considered possibly related to study drug was increased 
GGT. No subjects had DLTs. 
 
In Study 002 Part B1 (M6620 (VX-970) and carboplatin combination therapy), 6 
subjects (31.6%) had at least 1 SAE, and 4 subjects (21%) had at least 1 SAE that was 
considered related to study drug. Five subjects (26.3%) had at least 1 grade >3 AE that 
was considered related to study drug treatment. Neutropenia was the only grade > 3 AE 
that was considered related to study drug treatment and occurred in at least 10% of the 
subjects. DLTs of febrile neutropenia, neutropenia, and hypersensitivity occurred in 3 of 
the 19 patients. Four subjects (21%) had AEs leading to study drug discontinuation, 
which included infusion-related hypersensitivity and an infusion-related facial flushing 
(both considered related to study treatment and progressive disease in the liver and 
shortness of breath (both considered not related to study drug. There were no Grade 5 
AEs. 
 
Myelosuppression is an identified risk of M6620 (VX-970) when combined with DNA 
damaging agents. As of April 29, 2016, 3 subjects had serious myelosuppression events 
in combination with carboplatin. 
 
As of March 21, 2016, 6 serious infusion reactions to M6620 (VX-970) occurred at doses 
of VX- 970 ranging from 90 to 210 mg/m2. In all cases the reaction occurred during the 
second infusion of M6620 (VX-970) and caused symptoms that included flushing, 
erythema, and nausea, in addition to blood pressure abnormalities and mental status 
changes. 
 
A summary of the DLTs and most common adverse events regardless of causality are 
listed in the following tables. 
 
Summary of DLTs in Studies 001 and 002 
Regimen 
DLTs 
Percent (%) 
M6620 (VX-970) and 
gemcitabine 
(Study 001Part A) 
AST 
4.4 
ALT 
4.4 
Alkaline phosphatase 
2.2 
Thrombocytopenia 
2.2 
Fatigue 
2.2 
M6620 (VX-970) and 
cisplatin 
(Study 001 Part B) 
Hypersensitivity 
3.8 
ALT 
3.8 
M6620 (VX-970) (Study 
002) 
Neutropenia 
5.2 
Hypersensitivity 
5.2 
Febrile Neutropenia 
5.2 
 

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Summary of Serious AEs Regardless of Causality in Studies 001 and 002 
Regimen 
AEs 
Percent (%) 
M6620 (VX-970) and 
gemcitabine 
(Study 001 Part A) 
Pyrexia 
12.0 
Influenza-like Illness 
2.0 
Infections 
7.2 
Dehydration 
4.0 
Hyponatremia 
2.0 
Musculoskeletal pain 
4.0 
Pathological fracture 
2.0 
Atelectasis 
2.0 
Pleuritic pain 
2.0 
Pulmonary embolism 
2.0 
Thrombocytopenia 
4.0 
Anemia 
2.0 
Febrile Neutropenia 
2.0 
Left Ventricular hypertrophy 
2.0 
Pericardial effusion 
2.0 
Vomiting 
4.0 
Hypersensitivity 
4.0 
Body temperature increased 
2.0 
Non-small cell lung cancer 
2.0 
Hydronephrosis 
2.0 
Deep vein thrombosis 
2.0 
M6620 (VX-970) and 
cisplatin 
(Study 001 Part B) 
Abdominal pain 
3.7 
Diarrhea 
3.7 
Small bowel obstruction 
3.7 
Hypersensitivity 
7.4 
Dyspnea 
3.7 
Hypoxia 
3.7 
Pyrexia 
3.7 
Skin infection 
3.7 
ALT 
3.7 
AST 
3.7 
M6620 (VX-970) (Study 002 
Part B1) 
Febrile Neutropenia 
5.3 
Neutropenia 
5.3 
Thrombocytopenia 
5.3 
Pleuritic Paine 
5.3 
Pulmonary Embolism 
5.3 
Hypersensitivity 
5.3 
Lower respiratory tract 
5.3 

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infection 
Infusion related reaction 
5.3 
Tumor pain 
5.3 
 
One death was reported with single-agent therapy and 19 deaths were reported with 
combination therapy. None of these deaths were attributable to the study treatment (23). 
 
Safety Summary and Guidance for Investigators (Investigator’s Brochure, 2016) 
 
• 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. 
 
• To minimize the possibility of phlebitis, M6620 (VX-970) should be 
administered through a large-bore catheter into a large-caliber peripheral vein. 
The intravenous infusion site should be monitored closely for the development 
of erythema, induration, purulence, tenderness, or warmth. If any subject 
develops 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. 
 
• Because the drug-interaction profile of M6620 (VX-970) has not been fully 
characterized, caution should be used when co-administering medications with 
M6620 (VX-970). Because M6620 (VX-970) is primarily metabolized by 
CYP3A4, concomitant administration with strong inhibitors or inducers of 
CYP3A4 should be avoided. 
 
• Developmental and reproductive toxicity studies have not been conducted yet. 
Therefore, patients should take stringent measures to avoid bearing children while 
on study drug and for 6 months after discontinuation of M6620 (VX-970). 
 
• Serious acute hypersensitivity reactions have occurred in a few subjects receiving 
M6620 (VX-970). These reactions have occurred within minutes of re-exposure 
to M6620 (VX-970), and in cases to date have occurred during the second 
infusion. They may include hypotension and mental status changes. All subjects 
have fully recovered with standard treatment for this reaction, including 
immediate discontinuation of the inciting infusion and administration of IV 
corticosteroid and antihistamine, as well as IV fluids and oxygen when clinically 
indicated. 
 
• There is a potential increase in toxicity of DNA- damaging agents paired with 
M6620 (VX-970) in patients with evidence of germline defects in their DDR, 
e.g., patients with Li Fraumeni syndrome or ataxia telangiectasia. M6620 (VX-
970) should be used with caution in these patients. 
 
 
 

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2.3 
Gemcitabine and Carboplatin 
 
Gemcitabine 
 
Gemcitabine is a pyrimidine based antimetabolite with activity against recurrent ovarian 
cancer. The diphosphate metabolite of gemcitabine inhibits ribonucleotide reductase, 
depleting deoxyribonucleotide levels, and the triphosphate metabolite acts as a substrate 
for DNA polymerases, causing chain termination [28]. In the presence of these types of 
replication stresses, the ATR/CHK1 signaling pathway promotes cell survival by 
blocking additional origin firing and stabilizing the stalled replication forks [29]. 
Consistent with a role for ATR/CHK1 protecting against gemcitabine toxicity, 
gemcitabine induces CHK1 activation in various cell lines; and targeted depletion of 
components of this pathway sensitizes these tumor cells to gemcitabine [29, 30]. 
 
Gemcitabine has a wide range of activity in a variety of tumor types, including ovarian 
cancer. It is also a drug that can be given in patients with underlying mild to moderate 
hepatic dysfunction. 
 
Gemcitabine will be obtained according to local clinical trial agreement and in 
accordance with local guidelines. Preparation and administration should follow local 
prescribing information and local practice. Please see gemcitabine prescribing 
information for more details on the approved indications, known precautions, warnings, 
and adverse reactions of gemcitabine (current version of prescribing information is 
provided in the Pharmacy Binder). 
 
Pharmacokinetic evaluation of gemcitabine indicates that gemcitabine reaches a plateau 
value 15 minutes after the start of infusion. The elimination of gemcitabine is rapid, with 
a median half-life of 8 minutes, and is dose dependent. Difluorodeoxyuridine (dFdU), 
the gemcitabine deaminated uridine metabolite that is the only detectable metabolite in 
the serum, has a half-life of 14 hours. The peak dFdU concentration generally occurs 
about 5-15 minutes after the end of the infusion. Clearance of gemcitabine and dFdU is 
biphasic, with a prolonged terminal elimination phase. The prolonged phase of dFdU 
elimination is likely a result of renal absorption, a reduced rate of renal excretion at low 
concentration, and the slow release of the metabolite from tissue stores. 
 
Carboplatin 
 
Carboplatin is a platinum coordination compound that causes predominantly intra- and 
interstrand DNA cross-links rather than DNA-protein cross-links. Carboplatin is 
approved for the treatment of ovarian cancer in the U.S. and for the treatment of ovarian 
cancer and small cell lung cancer in the E.U., where it has also been used as a standard 
for triple negative breast cancer (TNBC). Carboplatin administration is discussed in 
Section 8.2, Treatment Administration and Schedule. 
 
Carboplatin will be obtained according to local clinical trial agreement and in 
accordance with local guidelines. Carboplatin should be prepared and stored according 
to local prescribing information and local practice. Please see carboplatin prescribing 
information for more details on the approved indications, known precautions, warnings, 
and adverse reactions of carboplatin (the current version of prescribing information is 
provided in the Pharmacy Binder). 

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Needles or intravenous administration sets containing aluminum parts that may 
come in contact with carboplatin injection should not be used for the preparation 
and administration of the drug. Aluminum can react with carboplatin causing 
precipitate formation and loss of potency. 
 
Dosing of carboplatin will be based on the Calvert formula: carboplatin dose (mg) = 
(Target AUC) x (GFR + 25). For the purposes of this protocol, the glomerular filtration 
rate (GFR) is considered to be equivalent to the creatinine clearance (calculated by the 
method of Cockcroft and Gault, 1976). 
 
To calculate creatinine clearance (CrCl) from serum creatinine 
Use current [actual] weight: 
CrCl = (140 – age) x (weight in kg) 
(72 x serum creatinine) x (0.85 [for females]) 
 
To calculate dose of carboplatin (total mg, not mg/m2): 
mg carboplatin = (AUC) x (CrCl + 25) 
 
Carboplatin dose should be calculated prior to each dose using actual weight and current 
serum creatinine level according to local prescribing information and local practice. 
 
Please see carboplatin prescribing information for more details on the known precautions, 
warnings, and adverse reactions of carboplatin. 
 
2.4 
Rationale 
 
Combination Carboplatin and Gemcitabine in Platinum Sensitive Ovarian Cancer 
 
As indicated in Section 2.1, the combination of carboplatin and gemcitabine is a 
commonly used FDA approved regimen for platinum-sensitive recurrent ovarian, 
peritoneal and fallopian tube malignancies [9]. It is often preferred over carboplatin and 
paclitaxel, as it is associated with less peripheral neuropathy, which is a significant issue 
in a large proportion of women with recurrent disease. The combination of carboplatin 
and gemcitabine was FDA approved in 2006 for platinum sensitive recurrent ovarian 
cancer based on a multicenter international randomized clinical trial of 356 women with 
first recurrence of platinum sensitive ovarian cancer [9]. Patients were randomized to 
receive either gemcitabine 1000 mg/m2 on days 1, 8 and carboplatin AUC 4 on day 1 of a 
21 day cycle or carboplatin AUC 5 administered on day 1 of each 21 day cycle. The 
combination therapy led to a significant improvement in PFS. Median PFS was 8.6 
months for the combination group and 5.8 months for the carboplatin only group. The 
overall response rate in the combination group was 46%. Because this combination 
regimen is considered a standard of care for platinum sensitive ovarian cancer, it has been 
chosen as the comparator group for this study. 
 
An early event in tumorigenesis involves abrogation of DNA damage responses. As a 
consequence tumors exhibit increased genomic instability with defects in DNA repair 
pathways and cell cycle regulation. In particular, mutations in the TP53 render cancer 
cells deficient in the G1 phase checkpoint DNA damage repair and therefore, more reliant 
on the S and G2 phase checkpoints for survival. Because it has been reported that TP53 

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mutations occur in over 95% of serous ovarian cancers, targeting the ATR pathway in 
this tumor type is of particular interest. In contrast, normal tissue has functional p53 and 
G1 phase checkpoint repair, making G2 checkpoint abrogation a means of enhancing the 
therapeutic index of cytotoxic agents with minimal effects on normal tissue. 
 
Gemcitabine and the ATR Pathway 
 
As indicated in the prior section, gemcitabine is a pyrimidine-based antimetabolite with 
activity against recurrent ovarian cancer. In the presence of this type of replication stress, 
the ATR/CHK1 signaling pathway promotes cell survival by blocking additional origin 
firing and stabilizing the stalled replication forks [29].  Consistent with a role for the 
ATR pathway in protecting against gemcitabine toxicity, gemcitabine induces CHK1 
activation in various cell lines, and inhibition of CHK1 or targeted deletion of 
components of the CHK1 pathway sensitizes these tumor cells to gemcitabine [29, 30]. 
Moreover, down regulation of ATR, Chk1, or RAD9 using siRNA each sensitizes a 
variety of cells to gemcitabine [30, 31]. In further studies performed by the Karnitz 
laboratory, the effects of ATR knockdown were explored in ovarian cancer cell lines and 
it was found that the ATR inhibitor VE-821 sensitized to a wide variety of genotoxic 
stresses, including gemcitabine and cisplatin [32]. Since many high grade serous ovarian 
cancers have HR defects, including but not limited to BRCA1 or BRCA2 mutations, the 
effect of ATR inhibition was investigated as well. ATR inhibition further sensitized cells 
with HR defects to cisplatin [32]. 
 
Effect of M6620 (VX-970) on DNA Damage 
 
In preliminary studies performed by Vertex, treatment of cell lines with various DNA 
damaging agents, including cisplatin and gemcitabine, led to increased phospho-Ser317, 
345-Chk1, a marker of ATR activity, and activation of proteins that are recruited to sites of 
DNA damage (phosho-KAP1 and phospho-Ser139-H2AX). Concurrent treatment of these 
cell lines with M6620 (VX-970) and a DNA-damaging agent led to sustained, M6620 
(VX-970) dose- dependent decreases in phosphorylations of Chk1, H2AX and KAP1 
(compared with DNA damaging agent alone). The failure to repair DNA damage in the 
presence of VX- 970 is believed to be the driver for the enhanced cytotoxicity in cancer 
cells that is observed when M6620 (VX-970) is combined with DNA damaging agents. 
Furthermore, these data support the potential for using DNA damage markers as 
pharmacodynamic markers of M6620 (VX-970) activity [23]. 
 
Optimization of Schedule 
 
The effect of timing of M6620 (VX-970) in combination with DNA damaging agents 
was assessed with gemcitabine in pancreatic cancer cell lines. Cells were treated with 
gemcitabine for 24 hours in combination with M6620 (VX-970), with M6620 (VX-970) 
added at various time points both during and after gemcitabine treatment. Cell viability 
was measured by MTS assay (96 hours) and the data were subjected to Bliss analysis. 
Synergy was maximal when VX- 970 was administered 24 hours after starting 
gemcitabine treatment; later administration was less effective. No synergy was seen 
when M6620 (VX-970) was administered 48 or more hours after gemcitabine treatment 
was started. The schedule dependence is attributed to an accumulation of cells in S-
phase, and concomitant increase in ATR activity (as measured by Chk1 phosphorylation) 
that occurs in response to gemcitabine treatment. 

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The data suggest that administering M6620 (VX-970) after treatment with a DNA 
damaging agent, to coincide with maximal S-phase accumulation is optimal [23]. 
 
2.5 
Correlative Studies Background 
 
2.5.1 Multiplex Quantitative IFA Assay (Expansion Cohort) 
 
PADIS, Frederick National Laboratory for Cancer Research (FNLCR)  has developed a panel of DNA 
damage repair markers for use as a multiplex immunofluorescence assay to monitor drug effect in 
formalin-fixed, paraffin-embedded (FFPE) cell pellets. The multiplex DDR2 assay expands the scope 
of the previously validated immunofluorescence assay for histone H2AX phosphorylated at Ser139 
(γH2AX) to include three additional biomarkers: Rad51, Nbs1 phosphorylated at Ser343 (pS343-
Nbs1), and pATR-Thr1989. γH2AX is well established as a marker of DNA double-strand breaks and 
is widely used as a tool in measuring DNA damage responses following drug exposure in both biopsy 
and circulating tumor cell samples. However, γH2AX also increases during DNA fragmentation 
induced by apoptosis, so induction of the marker at later time points cannot be defined purely as a 
DNA damage response. 
Nbs1 is part of the Mre11-Rad50-Nbs1 complex (MRN), which is essential in early DNA 
damage recognition, recruitment of ATM to the site of damage, repair of double-strand 
breaks and cell cycle checkpoint activation. The phosphorylation of Nbs1 is critical to 
the double-strand break DNA damage response. Similar to γH2AX, Nbs1 is 
phosphorylated at Ser343 primarily by ATM early in the response to DNA damage. 
Once phosphorylated, pSer343-Nbs1 plays a role in activation of cell cycle checkpoints 
and has a direct role in repair of damaged DNA. Rad51 is essential to the HR repair 
pathway, serving as a recombinase that facilitates strand homology searching and 
forming foci at double-strand break sites which can be quantified to assess ongoing HR. 
pThr1989-ATR is an autophosphorylation site critical for ATR function and PADIS has 
developed a phospho-specific rabbit monoclonal antibody for use as a pharmacodynamic 
biomarker of ATR activation during DNA damage responses. 
 
This multiplex immunofluorescence assay is incorporated into the protocol as an 
integrated biomarker. The purpose is to provide proof of mechanism that the predicted 
DNA repair pathways have been activated by carboplatin + gemcitabine and have been 
inhibited by M6620 (VX-970). Comparison of tumor samples harvested prior to therapy 
and again 24 hours after initiation of carboplatin/gemcitabine therapy will allow 
assessment of the hypothesis that ATR and the DNA damage response have been 
activated. Comparison of the increment in signal observed after carboplatin/gemcitabine 
vs. carboplatin/gemcitabine followed by M6620 (VX-970) will allow assessment of the 
hypothesis that ATR has been inhibited by M6620 (VX-970) in situ. These hypotheses 
are described in greater detail in Section 9 of this protocol. 
 
2.5.2 BROCA Analysis 
Ovarian cancer has a significant heritable component. A woman with a first degree 
relative diagnosed with ovarian cancer has approximately a 3-fold increased risk of 
developing ovarian cancer compared to the general population. Approximately 10-15% 
of ovarian cancer patients are BRCA1 or BRCA2 mutation carriers [33]. Defects in 
BRCA1 or BRCA2 function result in defective HR repair, leading to i) heightened 
sensitivity to platinum agents and PARP inhibitors and ii) improvement in overall 
survival after these treatments. Preclinical data from the Karnitz laboratory also revealed 
that disabling the HR pathway by depleting BRCA1 led to further sensitization to 
platinum in combination with an ATR inhibitor [32]. Of note, a large subset of sporadic 

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ovarian cancers (up to 50% of all ovarian cancers) exhibits defective HR repair pathway; 
and these sporadic tumors appear to behave similarly to those with germline BRCA1 and 
BRCA2 mutations [34]. Indeed, this so-called “BRCA-ness” phenotype can arise due to 
BRCA1/2 mutations in the tumor, reduced levels of BRCA1 or BRCA2 protein due to 
promoter methylation, or mutations in up to a dozen other genes encoding proteins in the 
HR pathway such as RAD51C and RAD51D [35][36].  
 
BROCA is a validated, highly sensitive approach (based on targeted capture and 
massively parallel sequencing of selected genomic regions) for sequencing a panel of 
over 21 tumor suppressor genes, including BRCA1, BRCA2, and other genes known to be 
mutated in inherited breast or ovarian carcinoma [36]. We will utilize this approach to 
analyze tumor and germline DNA for mutations in a panel of genes involved in various 
aspects of DNA repair or its regulation [36]. In women in the standard treatment group 
(carboplatin and gemcitabine), this will be assessed using germline DNA and archival 
tumor DNA. This will be done at the University of Washington under the direction of 
Elizabeth Swisher. The list of current genes in the BROCA test is attached in Appendix 
C. 
 
2.5.3 Multiplexed Mass Spectrometry-Based Assay for Quantification of Phospho-signaling 
in Response to DNA Damage 
A lack of analytically robust and multiplexed assays has hampered studies of the large, 
branched phospho-signaling network responsive to DNA damage. The Paulovich 
laboratory at the Fred Hutchinson Cancer Research Center has developed and fully 
analytically characterized a 62-plex assay quantifying protein expression and post-
translational modification (phosphorylation and ubiquitination) after induction of DNA 
damage. The linear range was over 3 orders of magnitude, the median inter-assay 
variability was 10% CV and the vast majority (∼85%) of assays were stable after 
extended storage. The multiplexed assay was applied in proof-of-principle studies to 
quantify signaling after exposure to genotoxic stress (ionizing radiation and 4-
nitroquinoline 1-oxide) in immortalized cell lines and primary human cells. The effects 
of genomic variants and pharmacologic kinase inhibition (ATM/ATR) were profiled 
using the assay. The DDR1 panel includes phospho-Thr1989-ATR, phospho-Ser317-
CHK1 (an ATR substrate), phospho-Ser343-NBS1 (an ATM/ATR site), phospho-
Ser1524-BRCA1 (an ATM/ATR site), phospho-Ser376-PALB2 (an ATR/ATM site), 
phospho-Ser635-RAD51D (an ATR/ATM site) and phospho-Ser730-FANCI (an 
ATM/ATR site). 
The purpose of this exploratory endpoint is to provide proof of mechanism that the 
predicted DNA repair pathways have been activated by carboplatin + gemcitabine and 
have been inhibited by M6620 (VX-970). Comparison of tumor samples harvested prior 
to therapy and again 24 hours after initiation of carboplatin/gemcitabine therapy will 
allow assessment of the hypothesis that ATR and the DNA damage response have been 
activated. Comparison of the increment in signal observed after carboplatin/gemcitabine 
vs. carboplatin/gemcitabine followed by M6620 (VX-970) will allow assessment of the 
hypothesis that ATR has been inhibited by M6620 (VX-970) in situ.  
 
 
 

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3. 
PATIENT SELECTION 
 
3.1 Eligibility Criteria 
 
3.1.1 
Histologically confirmed high grade serous or endometrioid ovarian, peritoneal or 
fallopian tube malignancy that is metastatic and for which curative measures do not exist. 
The histology can be confirmed from tissue that was taken at the time of diagnosis. A 
biopsy at the time of recurrence prior to enrollment on study is not required. 
 
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. 
 
3.1.3 
Patients enrolled in the expansion cohort will be required to have archival tumor tissue 
available for analysis and be willing to have a tumor biopsy at baseline (after registration 
and prior to starting study treatment), at Cycle 1 Day 2 and at Cycle 2 Day 2. 
Patients must have platinum sensitive disease and be in their first or second platinum sensitive 
recurrence. Platinum sensitive disease is defined as recurrence that occurred greater than six 
months after completion of their last line of platinum based therapy. No non-platinum 
regimens allowed. Prior therapy with PARP inhibitors as well as bevacizumab is allowed. 
 
3.1.4 
No more than two prior platinum based regimens. One regimen is defined as the interval 
of treatment from start of platinum based doublet to finish of that treatment course for 
the initial therapy or for the recurrent disease episode. If the nonplatinum agent is altered 
due to any reason other than disease progression, it counts as one regimen. For example, 
if a patient started on carboplatin and paclitaxel but developed a taxol reaction and was 
switched to carboplatin and Abraxane, this counts as one prior regimen.  
 
3.1.5 
Age ≥18 years. 
Because no dosing or adverse event data are currently available on the use of M6620 
(VX-970) in combination with carboplatin and gemcitabine in patients <18 years of age, 
children are excluded from this study, but will be eligible for future pediatric trials. 
 
3.1.6 
ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A). 
 
3.1.7 
Life expectancy of greater than 6 months. 
 
3.1.8 
Patients must have normal organ and marrow function as defined below: 
 
− 
Leukocytes 
≥3,000/mcL 
− 
Absolute Neutrophil Count (ANC) 
≥1,500/mcL 
− 
Platelets 
≥100,000/mcL 
− 
Total Bilirubin 
Within normal institutional limits 
− 
AST(SGOT)/ALT(SGPT) 
≤ 2 × institutional upper limit of normal (ULN) 
− 
Creatinine 
 
Within normal institutional limits 
OR 
Creatinine Clearance 
≥ 50 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. 

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3.1.9 
Negative serum pregnancy test result for females of child bearing potential 
 
Note: The effects of M6620 (VX-970) on the developing human fetus are unknown. For 
this reason and because DNA-damage response (DDR) inhibitors as well as other 
therapeutic agents used in this trial may have teratogenic potential, 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 M6620 (VX-970) administration. Should a woman 
become pregnant or suspect she is pregnant while she is participating in this study, she 
should inform her treating physician immediately. 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 Of note, if appropriate per the FDA approved indications, patients may receive PARP 
inhibitor maintenance therapy after the primary endpoint has been reached, if desired. This 
therapy is not a part of the clinical trial and should be discussed and performed at the 
discretion of the patient and treating physician.  
 
 
3.3 Exclusion Criteria 
 
3.3.1 
Patients with platinum resistant disease or platinum sensitive disease that is past the first 
or second recurrence.  
 
3.3.2 
Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the 
study or those who have not recovered from adverse events due to agents administered 
more than 4 weeks earlier, excluding alopecia. Patients with treatment related effects, 
such as peripheral neuropathy, that are grade 1 or less are eligible. 
 
3.3.3 
Prior exposure to gemcitabine. 
 
3.3.4 
Patients who are concurrently receiving any other investigational agents. 
 
3.3.5 
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. 
 
3.3.6 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to M6620 (VX-970), carboplatin, gemcitabine or to these specific 
compounds. 
 
3.3.7 
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 Information Handout and Wallet Card) should be 
provided to patients. 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 

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medications need to be prescribed or if the patient is considering a new over-the-counter 
medicine or herbal product. 
 
3.3.8 
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. 
 
3.3.9 
Pregnant women are excluded from this study because M6620 (VX-970) as a DNA-
damage response (DDR) inhibitor may have the potential for teratogenic or 
abortifacient effects. Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with M6620 (VX-970), 
breastfeeding should be discontinued if the mother is treated with M6620 (VX-970). 
These potential risks also apply to the other agents used in this study, such as 
carboplatin and gemcitabine. 
 
3.3.10 Patients with Li Fraumeni syndrome are excluded from the study as M6620 (VX-970) 
is a DDR inhibitor. 
 
3.3.11  Addition of bevacizumab to the treatment in this study is not allowed. If the treating physician 
feels that the addition of bevacizumab is in the best interest of the patient, the patient should 
be treated with an FDA approved regimen outside of the present study.  
 
 
3.4 Inclusion of Women and Minorities 
 
This study will be available to all eligible patients regardless of race or ethnic group. Because 
this is a clinical trial in primary peritoneal, ovarian and fallopian tube malignancies, all patients 
in this study will be women. 
 
 

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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 the following:  
• 
An active Federalwide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site 
 
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 9948 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 number in the search field at the top of the protocol tree, 
or 
• Click on the By Lead Organization folder to expand, then select LAO-MN026 
and protocol # 9948 
• 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 automatically load to RSS.) 

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4.2.2 
Requirements for Protocol 9948 Site Registration 
• 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.) 
• Site Initiation Teleconference 
 
4.2.3 
Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS. 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 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. 
 
4.2.4 
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 using your CTEP IAM username and 
password. 
• Click on the Regulatory tab at the top of your screen. 
• Click on the Site Registration sub 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 
 
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, 

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Medidata Rave. 
 
 
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: Be on an ETCTN Corresponding or Participating Organization 
roster with the role of Registrar.  Registrars must hold a minimum of an AP 
registration type. 
• 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. 
 
4.4 General Guidelines 
 
Following registration, patients should begin protocol treatment within 21 days. Issues 
that would cause treatment delays should be discussed with the Principal Investigator. If 
a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled. The Study Coordinator should be notified of 
cancellations as soon as possible. 
 
 
 

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5. TREATMENT PLAN 
 
5.1 Agent Administration 
 
Treatment will be administered on an outpatient basis. To minimize the possibility of 
phlebitis, M6620 (VX-970) should be administered through a large-bore catheter into a 
large- caliber peripheral vein. The intravenous infusion site should be monitored closely 
for the development of erythema, induration, purulence, tenderness or warmth. M6620 
(VX-970) should not come into contact with 0.9% sodium chloride due to 
incompatibility. Infuse using an infusion set containing low-sorption or non-PVC, 
DEHP-free tubing and an in-line 0.2 micro filter. 
 
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. 
 
Phase 1 Dose Escalation/Safety Lead-In Regimen Description 
Dose Level 
M6620 (VX-970) 
Gemcitabine 
Carboplatin 
-2 
90 mg/m2, day 2, 9 
480 mg/m2, day 1, 8 
AUC 4, day 1 
-1 
90 mg/m2, day 2, 9 
560 mg/m2, day 1, 8 
AUC 4, day 1 
1* 
90 mg/m2, day 2, 9 
640 mg/m2, day 1, 8 
AUC 4, day 1 
2 
90 mg/m2, day 2, 9 
800 mg/m2day 1, 8 
AUC 4, day 1 
3 
120 mg/m2, day 2, 9 
800 mg/m2, day 1, 8 
AUC 4, day 1 
* Starting dose level 
 
 
Regimen Description – Expansion Cohort 
(Experimental Group: M6620 (VX-970) + Gemcitabine + 
Carboplatin) 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Gemcitabine 
See antiemetic regimen 
and section 8.2. 
640    
mg/m2/day in 
250 mL 0.9% 
NaCl 
IV over 
approximately 
30 minutes 
or according 
to institutional 
standards 
Days 1, 8 
21 days 
(3 weeks) 
Carboplatin 
Dosed using Calvert 
Formula with Cockcroft- 
Gault, actual body weight 
and maximum CrCL of 
AUC 4 
(Cockcroft- 
Gault) in 250 
mL 0.9% 
IV infusion 
over 
approximately 
30 minutes 
or according 
to institutional 
standards 
Days 1 
 

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125 mL/min. Creatinine 
clearance should be 
estimated using a 
minimum serum 
creatinine value of 0.7 
mg/dL. Dose rounding to 
the nearest 10 mg. 
NaCl 
M6620 
(VX-970) 
90 
mg/m2 IV in 
D5W to a 
concentration 
between 0.075 
mg/ml to 
1 mg/ml 
IV infusion 
over 60 (+/-
15) minutes. 
Days 2, 9 
*Doses of gemcitabine and M6620 (VX-970)  have been determined from the phase 1 dose 
escalation/safety lead-in. 
 
Pretreatment Medication 
Agent 
Dose 
Route 
Day 
Dexamethasone 
20 mg 
PO or IV 
PO route preferred, 
if unable to tolerate, 
administer same dose IV 
Day 1 
Dexamethasone 
10 mg 
PO or IV, 
PO route preferred, 
if unable to tolerate, 
administer same dose IV 
Day 2, 9 
Granisetron 
(Kytril) 
1 mg 
PO or IV 
PO route preferred, 
if unable to tolerate, 
administer same dose IV 
Days 1, 8 
Palonosetron 
(Aloxi) 
0.25 mg/day 
IV push 
Day 2, 9 
Fosaprepitant 
(Emend) 
150 mg/day 
IV 
Day 2 
Prochlorperazine 
10 mg 
PO every 6 hours 
as needed for 
nausea and vomiting 
Take home script 
Lorazepam 
1 mg/dose 
If nausea unrelieved 
by prochlorperazine 
Take home script 
Ondansetron 
8 mg/dose 
PO daily for 2 days, 
start in AM with breakfast 
the day after treatment 
Take home script 
Dexamethasone 
4mg 
PO daily for 2 days, 
start in AM with breakfast 
the day after treatment 
Optional take home 
script to begin on day 
3 and day 10 
Note: Antiemetics can also be used per institutional guidelines or modified as needed per treating 
physician 
 
 

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5.2 General Concomitant Medication and Supportive Care Guidelines 
 
5.2.1 
M6620 is metabolized by cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4); 
exposure to M6620 may be affected by concomitantly administered drugs that are strong 
inhibitors or inducers of CYP3A4.  Because there is a potential for interaction of M6620 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. [For example, the potential targets for drug interaction can 
involve, but are not limited to CYP450, glucuronidation, P-glycoprotein, protein binding, or 
reduced absorption from proton-pump inhibitors.  Check the study agent Investigator’s 
Brochure for potential sources of drug interactions].  The study team should check a 
frequently-updated medical reference for a list of drugs to avoid or minimize use of.  
Appendix D (Patient Drug Interactions Handout and Wallet Card) should be provided to 
patients. 
 
5.2.2 
If any subject develops phlebitis or signs of inflammation which the subject 
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.  If any subject develops pruritus or evidence of an allergic reaction, standard 
measures may be employed to ameliorate these symptoms or prevent recurrence (e.g., 
premedication with acetaminophen 325 mg, PO approximately 30 minutes before the 
infusion, 200 mg hydrocortisone IV approximately 60 minutes before infusion, and 25 
mg diphenhydramine IV approximately 30 minutes before infusion).  Alternative 
antihistamine and steroid combinations may be considered, as long as they are not 
prohibited by protocol.  If standard procedures to limit symptoms of injection site 
reaction or pruritus are insufficient, the infusion time may be extended beyond 60 
minutes, but no more than 90 minutes. 
 
5.2.3 
To decrease the risk of phlebitis, M6620 should be administered through a large-
bore catheter into a large-caliber peripheral vein.  The intravenous infusion site should be 
monitored closely for the development of erythema, induration, purulence, tenderness, or 
warmth. 
 
 
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; 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s); 
 
• 
Patient decides to withdraw from the study; 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator; 

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• 
If a patient has a complete response to therapy and has continued two cycles beyond 
complete response, discussion between treating physician and investigator regarding 
discontinuation of therapy may be considered. 
 
5.4 Duration of Follow Up 
 
Patients who begin study treatment will be followed for 3 years after removal from study 
treatment or until death, whichever occurs first. Patients will be followed periodically 
until death by telephone call or letter, as well as by using public health records, for 
example, a local newspaper. 
 
5.5 Criteria for Removal from Study 
 
Patients will be removed from study treatment when any of the criteria listed in Section 
5.3 applies. Patients will be removed from the study 3 years from study treatment, death 
or withdrawal of consent, whichever comes first. The reason for discontinuation of study 
treatment and the date the patient was discontinued treatment must be documented in the 
Case Report Form; the reason for removal from study treatment and the date must be 
documented in the Case Report Form. 
 
Patients who are eligible for PARP inhibitor maintenance therapy may receive this 
therapy per FDA approval. This is not part of the present study but may be done once 
the patient has come off study after assessment of the primary endpoint. 
 
 
 

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6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 Dose Modification Tables for Phase 1 Dose Escalation/Safety Lead In Regimen 
 
Phase 1 Safety Lead-In Regimen Description 
Dose Level 
M6620 (VX-970) 
Gemcitabine 
Carboplatin 
-2 
90 mg/m2 day 2, 9 
480 mg/m2 day 1, 8 
AUC 4, day 1 
-1 
90 mg/m2 day 2, 9 
560 mg/m2 day 1, 8 
AUC 4, day 1 
1** 
90 mg/m2 day 2, 9 
640 mg/m2 day 1, 8 
AUC 4, day 1 
2 
90 mg/m2 day 2, 9 
800 mg/m2 day 1, 8 
AUC 4, day 1 
3 
120 mg/m2 day 2, 9 
800 mg/m2 day 1, 8 
AUC 4, day 1 
 
** starting dose level. 
At Time of Treatment 
Nausea/ 
Vomiting* 
Management/ 
Next Dose for 
M6620 (VX-
970) 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3 
Hold** until ≤ Grade 2. 
Resume at one dose level 
lower, if at dose level 3 or 
4 and if indicated.*** If at 
dose level 2 or lower, 
continue at same dose. 
Hold** until ≤ Grade 2. 
At first occurrence, 
reduce gemcitabine by 
one dose level.*** If at 
dose level 3 or 4, reduce 
gemcitabine to dose level 
1 at first occurrence. At 
second occurrence, 
resume at same dose. 
Hold** until ≤ 
Grade 2. Resume at 
same dose at first 
occurrence. At 
second occurrence, 
reduce dose to AUC 
3, at third 
occurrence, reduce 
to AUC 2. 
Grade 4 
Hold** until ≤ Grade 2. 
Resume at one dose level 
lower, if at dose level 3 or 
4 and if indicated.*** If at 
dose level 2 or lower, 
continue at same dose. 
Hold** until ≤ Grade 2. 
At first occurrence, 
reduce gemcitabine by 
one dose level.*** If at 
dose level 3 or 4, reduce 
gemcitabine to dose level 
1 at first occurrence. At 
second occurrence, 
reduce to dose level -
1 
Hold** until ≤ 
Grade 2. Resume at 
same dose at first 
occurrence. At 
second occurrence, 
reduce dose to AUC 
3, at third 
occurrence, reduce 
to AUC 2. 
* Nausea and vomiting after maximal therapy (see premedication suggestions and institutional 
guidelines for optimal management of nausea and vomiting). 
** Patients with grade 3 toxicity requiring a delay of > 2 weeks should be discussed with the PI. 
Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity requiring a 
delay of > 2 weeks, study should be discontinued. 
*** Patients requiring > two dose reductions should be discussed with PI. Patients may 
continue therapy if receiving benefit. 
Recommended management: antiemetics. 

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At Time of Treatment 
Diarrhea 
Management/ 
Next Dose for 
M6620 (VX-
970) 
Management/ 
Next Dose for Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3  
Hold* until < Grade 2. 
Resume at one dose 
level lower, if at dose 
level 3 or 4 and if 
indicated.** If at dose 
level 2 or lower, 
continue at same dose. 
Hold* until < Grade 2. 
Resume at one dose level 
lower, if indicated.** If at 
dose level 3 or 4, reduce 
gemcitabine to dose level 1 
at first occurrence and dose 
level -1 at second 
occurrence. Third 
recurrence, reduce to dose 
level -2.  
Hold* until < Grade 2. 
Resume at same dose 
at first occurrence. At 
second occurrence, 
reduce dose to AUC 3, 
at third occurrence, 
reduce to AUC 2. 
Grade 4 
Hold* until < Grade 
2. Resume at one 
dose level lower, if 
at dose level 3 or 4 
and if indicated.** If 
at dose level 2 or 
lower, continue at 
same dose. 
Hold* until < Grade 2. 
Resume at one dose level 
lower, if indicated.** If at 
dose level 3 or 4, reduce 
gemcitabine to dose level 1 
at first occurrence and dose 
level -1 at second 
occurrence. Third 
recurrence, reduce to dose 
level -2. 
Hold* until < Grade 2. 
Resume at same dose 
at first occurrence. At 
second occurrence, 
reduce dose to AUC 3, 
at third occurrence, 
reduce to AUC 2. 
* Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with the 
PI. Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity 
requiring a delay of > 2 weeks, study should be discontinued. 
** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit.  
Recommended management: Loperamide antidiarrheal therapy. 
Dosage schedule: 4 mg at first onset, followed by 2 mg with each loose motion until diarrhea- 
free for 12 hours (maximum dosage: 16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used 
 
 
 

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Dose Modifications for Neutropenia at Time of Treatment on Day 1 of Any Cycle 
Neutropenia 
Management/ 
Next Dose for 
M6620 
(VX-970) 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. 
Resume at 
same dose level. 
Hold until ≤ Grade 1. 
Resume at 
same dose level. 
Hold until ≤ Grade 1. 
Resume at same dose 
level. 
Grade 3 
Hold* until < Grade 1. 
Resume at one dose level 
lower, at dose level 3 or 
4 and if indicated.** If at 
dose level 2 or lower, 
continue at same dose. 
Hold* until < Grade 1. 
Resume at one dose level 
lower, if indicated.** If at 
dose level 3 or 4, reduce 
gemcitabine to dose level 1 
at first occurrence, keep at 
dose level 1 for second 
occurrence, reduce to dose 
level -1 at third 
occurrence. 
Hold* until < Grade 1. 
Resume at same dose 
at first occurrence. At 
second occurrence, 
reduce dose to AUC 3; 
at third occurrence, 
reduce to AUC 2. 
Grade 4 
Hold* until < Grade 1. 
Resume at one dose 
level lower, at dose 
level 3 or 4 and if 
indicated.** If at dose 
level 2 or lower, 
continue at same dose. 
Hold* until < Grade 1. 
Resume at one dose 
level lower, if 
indicated.** If at dose 
level 3 or 4, reduce 
gemcitabine to dose 
level 1 at first 
occurrence, reduce to  
dose level -1 for second 
occurrence, reduce to 
dose level -2 at second 
occurrence 
Hold* until < Grade 1. 
Resume at one dose 
level lower, if 
indicated.** Resume 
at same dose at first 
occurrence. At second 
occurrence, reduce 
dose to AUC 3; at 
third occurrence, 
reduce to AUC 2. 
Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with the PI. 
Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity requiring a 
delay of > 2 weeks, study should be discontinued. 
** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 
Recommended management: If dose delay occurs due to grade 2 or 3 neutropenia, growth factor 
(G-CSF or GM-CSF) can be used at the discretion of the treating physician with subsequent 
cycles. 
 
 
 

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Dose Modifications for Neutropenia at Time of Treatment on Day 8 of Any Cycle 
Neutropenia 
Management/ 
Next Dose for 
M6620 
(VX-970)* 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin** 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3 
Omit current cycle day 8 
dose 
Omit current cycle day 8 
dose 
No change in dose 
Grade 4 
Omit current cycle day 8 
dose 
Omit current cycle day 8 
dose 
Omit current cycle 
day 8 
dose 
Recommended management: If dose delay occurs due to grade 2 or 3 neutropenia, growth 
factor (G-CSF or GM-CSF) can be used at the discretion of the treating physician with 
subsequent cycles. 
* M6620 (VX-970) dose is given on day 9; however, the CBC from day 8 will be used to 
determine the day 9 dose 
**Carboplatin is not given on day 8 or day 9 of the cycle. 
 
Dose Modifications for Thrombocytopenia at Time of Treatment on Day 1 of Any Cycle 
Thrombocytopenia 
Management/ 
Next Dose for 
M6620 (VX-
970)*** 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. 
Resume at same dose 
level. 
Hold until ≤ Grade 1. 
Resume at same dose 
level. 
Hold until ≤ Grade 
1. Resume at same 
dose. 
Grade 3 
Hold* until < Grade 1. 
Resume at one dose level 
lower, at dose level 3 or 4 
and if indicated.** If at 
dose level 2 or lower, 
continue at same dose.   
Hold* until < Grade 1. 
Resume at one dose 
level lower, if 
indicated.** If at dose 
level 3 or 4, reduce 
gemcitabine to dose 
level 1 at first 
occurrence,, reduce to 
dose level -1 at second 
occurrence and reduce 
to  dose level -2 at 
second 
occurrence. 
Hold* until < 
Grade 1. Resume 
at same dose at 
first occurrence, 
AUC 3 at second 
occurrence,  
reduce to AUC2 
at third 
recurrence if 
indicated.** 
Grade 4 
Hold* until < Grade 1. 
Resume at one dose 
level lower, at dose 
level 3 or 4 and if 
indicated.** If at dose 
level 2 or lower, 
continue at same dose. 
Hold* until < Grade 1. 
Resume at one dose 
level lower, if 
indicated.** If at dose 
level 3 or 4, reduce 
gemcitabine to dose 
level 1 at first 
occurrence, reduce to 
Hold* until < 
Grade 1. Reduce 
to AUC 3 at first 
occurrence, AUC 
2 at second 
occurrence, 
maintain at 
AUC2 at third 

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dose level -1 at second 
occurrence and reduce 
to  dose level -2 at 
second 
occurrence.  
recurrence if 
indicated.** 
* Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with the 
PI. Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity 
requiring a delay of > 2 weeks, study should be discontinued.** Patients requiring > two dose 
reductions should be discussed with PI. Patients may continue therapy if receiving benefit. 
*** M6620 (VX-970) dose is given on day 2; however, the platelet count from day 1 will 
be used to determine the day 2 dose 
 
Dose Modifications for Thrombocytopenia at Time of Treatment on Day 8 of Any Cycle 
Thrombocytopenia 
Management/ 
Next Dose for 
M6620 (VX-
970)** 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin*** 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3 
Omit current cycle day 8 
dose. Resume at one 
dose lower, at dose level 
3 or 4 and if indicated* 
If at dose level 2 or 
lower, continue at same 
dose. 
Omit current cycle day 8 
dose. Resume at one 
dose lower, if indicated.* 
If at dose level 3 or 4, 
reduce gemcitabine to 
dose level 1 at first 
occurrence and dose 
level -1 at second 
occurrence. 
No change in dose 
Grade 4 
Omit current cycle day 8 
dose. Resume at one 
dose lower, at dose level 
3 or 4 and if indicated* 
If at dose level 2 or 
lower, continue at same 
dose. 
Omit current cycle day 8 
dose. Resume at one 
dose lower, if indicated.* 
If at dose level 3 or 4, 
reduce gemcitabine to 
dose level 1 at first 
occurrence and dose 
level -1 at second 
occurrence. 
No change 
in dose 
* Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with the 
PI. Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity 
requiring a delay of > 2 weeks, study should be discontinued.. 
** M6620 (VX-970) dose is given on day 9; however, the platelet count from day 8 will 
be used to determine the day 9 dose 
*** No carboplatin is given on day 8 
 
Dose Modifications for Other Non-Hematological Toxicities at Time of Treatment on 
Days 1 or 8* 

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Event 
Management/ 
Next Dose for 
M6620 (VX-
970)**** 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3 
or 4 
Hold** until < Grade 2. 
Resume at one dose level 
lower, at dose level 3 or 4 
and if indicated.*** If at 
dose level 2 or lower, 
continue at same dose. 
Hold** until < Grade 2. 
Resume at one dose level 
lower, if indicated.*** If at 
dose level 3 or 4, reduce 
gemcitabine to dose level 1 
at first occurrence, keep at 
dose level 1 for second 
occurrence, reduce to dose 
level -1 at third occurrence, 
and keep at dose level -1 at 
fourth occurrence. 
Hold** until < 
Grade 2. Resume 
at same dose at 
first occurrence, at 
AUC 3 at second 
occurrence, at 
AUC3 at third 
recurrence if 
indicated.** 
* Does not include alopecia and fatigue 
** Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with the 
PI. Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity requiring 
a delay of > 2 weeks, study should be discontinued. 
*** Patients requiring > two dose reductions should be discussed with PI. Patients may 
continue therapy if receiving benefit. 
**** M6620 (VX-970) dose is on day 2, 9, but dose can be determined based on toxicity 
assessment performed on day 1 and 8 as well as on days 2 and 9. 
 
Dose Modifications Based on Interim Toxicity 
Event 
Management/ 
Next Dose for 
M6620 (VX-
970) 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3 
or 4 
Hold* until < Grade 2. 
Resume at one dose level 
lower, at dose level 3 or 4 
and if indicated.** If at 
dose level 2 or lower, 
continue at same dose. 
Hold* until < Grade 2. 
Resume at one dose level 
lower, if indicated.** If at 
dose level 3 or 4, reduce 
gemcitabine to dose level 1 
at first occurrence, keep at 
dose level 1 for second 
occurrence, reduce to dose 
level -1 at third occurrence, 
and keep at dose level -1 at 
fourth occurrence. 
Hold* until < Grade 
2. Resume at same 
dose at first 
occurrence, reduce to 
AUC 3 at second 
occurrence, maintain 
at AUC3 at third 
recurrence and 
reduce to AUC 2 at 
fourth occurrence if 
indicated.** 
* Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with the PI. 
Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity requiring a 
delay of > 2 weeks, study should be discontinued. 
** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 

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6.2 Dose Modification Tables for Expansion Cohort 
Three patients were enrolled at dose level 1 (carboplatin AUC 4, gemcitabine, 640 mg/m2, M6620 90 
mg/m2) and no DLTs were identified. Dose level 2 (carboplatin AUC4, gemcitabine 800 mg/m2 and 
M6620 90 mg/m2) was opened to three patients and one of the three developed grade 4 
thrombocytopenia. Therefore, two additional patients were added at dose level 2. Of these, one 
additional patient also developed a DLT, namely grade 4 thrombocytopenia. Thus, dose level 2 was 
determined to have exceeded the MTD.  Therefore, an additional three patients were enrolled at dose 
level 1. One of these three patients developed a DLT (grade 4 thrombocytopenia), bringing the total 
DLTs at dose level 1 to 1 of 6 patients. Therefore, the MTD was deemed to be dose level 1, 
carboplatin AUC 4 day 1, gemcitabine 640mg/m2 day 1, 8 and M6620 90 mg/m2 day 2,9. 
 
Dose Modification Table 
Dose Level 
M6620 (VX-970) 
Gemcitabine 
Carboplatin 
MTD 
90 mg/m2 day 2, 9* 
640 mg/m2 day 1, 
8* 
AUC 4, day 1 
-1 
90 mg/m2 day 2, 9 
560mg/m2 day 1, 8 
AUC 3, day 1 
-2 
90 mg/m2 day 2, 9 
480 mg/m2 day 1, 8 
AUC 2, day 1 
 
At Time of Treatment 
Nausea/ 
Vomiting* 
Management/ 
Next Dose for 
M6620 
(VX-970) 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3  
Hold** until 
≤ Grade 2. 
Resume at same 
dose. 
Hold** until 
≤ Grade 2. 
Resume at one dose 
level lower, if 
indicated.*** 
Hold** until 
≤ Grade 2. 
Resume at the 
same dose for the 
first occurrence 
and reduce by one 
dose level at 
second recurrence, 
if indicated. *** 
Grade 4 
Hold** until 
≤ Grade 2. 
Resume at same 
dose.  
Hold** until 
≤ Grade 2. 
Resume at one dose 
level lower, if 
indicated.*** 
Hold** until 
≤ Grade 2. 
Resume at the 
same dose for the 
first occurrence 
and reduce by one 
dose level at 
second recurrence, 
if indicated. *** 
* Nausea and vomiting after maximal therapy (see premedication suggestions and 
institutional guidelines for optimal management of nausea and vomiting). 
** Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be 
discussed with the PI. Patients may continue therapy if receiving benefit. Patients 
with a grade 4 toxicity requiring a delay of > 2 weeks, study should be 
discontinued.. 

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*** Patients requiring > two dose reductions should be discussed with PI. Patients 
may continue therapy if receiving benefit. 
Recommended management: antiemetics. 
 
At Time of Treatment 
Diarrhea 
Management/ 
Next Dose for 
M6620 (VX-
970) 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3 
Hold* until < Grade 2. 
Resume at same dose. 
Hold* until < Grade 2.  
Reduce by one dose 
level for the first 
occurrence and resume at 
that same dose level for 
the second occurrence, if 
indicated.** 
Hold* until < Grade 2. 
Resume at the same 
dose at first occurrence 
and reduce by one dose 
level for second 
occurrence, if 
indicated.** 
Grade 4 
Hold* until < Grade 
2. Resume at same 
dose. 
Hold* until < Grade 2.  
Reduce by one dose 
level for the first 
occurrence and resume at 
that same dose level for 
the second occurrence, if 
indicated.** 
Hold* until < Grade 
2. Resume at the 
same dose at first 
occurrence and 
reduce by one dose 
level for second 
occurrence, if 
indicated.** 
* Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with the 
PI. Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity 
requiring a delay of > 2 weeks, study should be discontinued. 
** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 
Recommended management: Loperamide antidiarrheal therapy 
Dosage schedule: 4 mg at first onset, followed by 2 mg with each loose motion until diarrhea- 
free for 12 hours (maximum dosage: 16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Dose Modifications for Neutropenia on Day 1 at Time of Treatment of Any Cycle 
Neutropenia 
Management/ 
Next Dose for M6620 
(VX-970)*** 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in 
dose 

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Grade 2 
Hold until ≤ Grade 1. 
Resume at same dose level. 
Hold until ≤ Grade 1. 
Resume at same dose level. 
Hold until ≤ 
Grade 1. Resume 
at same dose 
level. 
Grade 3 
Hold* until < Grade 1. 
Resume at same dose.** 
Hold* until < Grade 1. 
Resume at same dose for 
the first occurrence and 
reduce by one dose level 
for second 
occurrence, if indicated.** 
Hold* until < 
Grade 1. Resume 
at same dose for 
first occurrence 
and reduce by 
one dose level at 
second 
occurrence. 
Grade 4 
Hold* until < Grade 1. 
Resume at same dose.** 
Hold* until < Grade 1. 
Reduce by one dose level 
for first occurrence, resume 
at the same dose for second 
occurrence, if 
indicated.** 
Hold* until < 
Grade 1. Resume 
at same dose for 
first occurrence 
and reduce by 
one dose level at 
second 
occurrence. 
* * Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with the 
PI. Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity requiring 
a delay of > 2 weeks, study should be discontinued. 
** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 
*** Although M6620 (VX-970) is given on day 2, neutrophil count from day 1 will be used to 
determine the day 2 dose. 
Recommended management: If dose delay occurs due to grade 2 or 3 neutropenia, growth 
factor (G-CSF or GM-CSF) can be used at the discretion of the treating physician with 
subsequent cycles. 
 
Dose Modifications for Neutropenia on Day 8 at Time of Treatment of Any Cycle 
Neutropenia 
Management/ 
Next Dose for M6620 
(VX-970)* 
Management/ 
Next Dose for Gemcitabine 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Omit dose 
Omit dose 
Grade 4 
Omit dose 
Omit dose  
* Although M6620 (VX-970) is given on day 9, neutrophil count from day 8 will be used to 
determine 
the day 9 dose. 
Recommended management: If dose delay occurs due to grade 2 or 3 neutropenia, growth 
factor (G-CSF or GM-CSF) can be used at the discretion of the treating physician with 
subsequent cycles. 
 
Dose Modifications for Thrombocytopenia on Day 1 at Time of Treatment of Any Cycle 

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Thrombocytopenia 
Management/ 
Next Dose for 
M6620 (VX-
970)*** 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. 
Resume at same dose 
level. 
Hold until ≤ Grade 1. 
Resume at same dose 
level. 
Hold until ≤ Grade 
1.  Resume at same 
dose level. 
Grade 3 
Hold* until < Grade 1. 
Resume at same dose.** 
Hold* until < Grade 1. 
Resume at the same dose 
for the first occurrence, 
resume at one dose lower 
for second occurrence if 
indicated. ** 
Hold* until < 
Grade 1.  Resume 
at one lower dose if 
indicated. ** 
Grade 4 
Hold* until < Grade 1. 
Resume at same dose.** 
Hold* until < Grade 1. 
Resume at one lower 
dose if indicated. ** 
Hold* until 
< Grade 1.  
Resume at 
one lower 
dose if 
indicated. 
** 
* * Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with 
the PI. Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity 
requiring a delay of > 2 weeks, study should be discontinued 
** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 
*** Platelet count from day 1 will be used to determine the day 2 dose of M6620 (VX-970) 
 
Dose Modifications for Thrombocytopenia on Day 8** at Time of Treatment of Any 
Cycle 
Thrombocytopenia 
Management/ 
Next Dose for M6620 (VX-
970) (day 9) 
Management/ 
Next Dose for Gemcitabine 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Omit dose. Resume same dose* Omit dose. Resume at one dose 
lower, if indicated* 
Grade 4 
Omit dose. Resume at same 
dose* 
Omit dose. Resume at one dose 
lower, if indicated* 
** Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with the 
PI. Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity requiring 
a delay of > 2 weeks, study should be discontinued ** Platelet count from day 8 will be used to 
determine the day 9 dose of M6620 (VX-970) 
 
Dose Modifications for Other Non-Hematological Toxicities At Time of Retreatment on 
Days 1, 2, 8 or 9* 
Event 
Management/ 
Next Dose for 
M6620 (VX-
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 

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970)**** 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3* 
Day 1: Hold** until ≤ 
Grade 2. Resume at 
same dose.*** 
Day 1: Hold** until < Grade 
2. Resume at one dose level 
lower. Day 8: Omit dose. 
Day 1: Hold** until 
< Grade 2. Resume 
at same dose for first 
occurrence; reduce 
one dose level for 
second occurrence, 
if indicated. *** 
Grade 4* 
Day 1: Hold** until ≤ 
Grade 2. Resume at 
same dose.*** 
Day 1: Hold** until < Grade 
2. Resume at one dose level 
lower.*** 
Day 8: Omit dose  
Day 1: Hold** until 
< Grade 2. Resume 
at same dose for first 
occurrence; reduce 
one dose level for 
second occurrence, 
if indicated. *** 
* Excludes alopecia and fatigue 
*** Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with 
the PI. Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity 
requiring a delay of > 2 weeks, study should be discontinued. 
***Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 
**** M6620 (VX-970) should not be given if the day 1 or 8 chemotherapy was held or 
omitted. M6620 (VX-970) should only be given if it was preceded by chemotherapy the 
day prior. 
 
Dose Modifications Based on Interim Toxicity 
Event 
Management/ 
Next Dose for 
M6620 (VX-
970) 
Management/ 
Next Dose for 
Gemcitabine 
Management/ 
Next Dose for 
Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3 
Hold* until < Grade 2. 
Resume at same dose. 
Hold* until < Grade 2. 
Resume at one dose level 
lower, if indicated.** 
Hold* until < Grade 
2. Resume at one 
dose level lower, if 
indicated.** 
Grade 4 
Hold* until < Grade 2. 
Resume at same dose, if 
indicated.**  
Hold* until < Grade 2. 
Resume at one dose level 
lower and is indicated.**  
Hold* until < 
Grade 2. 
Resume at one dose 
level lower and is 
indicated.**  

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** Patients with a grade 3 toxicity requiring a delay of > 2 weeks should be discussed with 
the PI. Patients may continue therapy if receiving benefit. Patients with a grade 4 toxicity 
requiring a delay of > 2 weeks, study should be discontinued **Patients requiring > two dose 
reductions should be discussed with PI. Patients may continue therapy if receiving benefit. 
 
Carboplatin Hypersensitivity Reaction: In the case of a carboplatin hypersensitivity reaction 
in any treatment group or cycle, omit remainder of carboplatin for the current cycle and attempt 
carboplatin desensitization day 1 of next cycle per institutional protocol. In the acute setting, 
please treat per institutional guidelines with IV corticosteroids, fluids, antihistamines and oxygen 
as needed. Rechallenge should be restricted to patients with mild to moderate reactions that do 
not include features of anaphylaxis. Carboplatin desensitization can be done per institutional 
protocol. Desensitization at Mayo Clinic includes medication with dexamethasone, 
diphenhydramine, famotidine, and hydrocortisone as well as beginning with low doses of 
carboplatin (0.0001 mg/dose in 100 mL 0.9% NaCl over 15 minutes) and titrating that upwards 
(0.0001 mg/dose, 0.001 mg/dose, 0.01 mg/dose, 0.1 mg/dose over 15 minutes) to 24.9 mg/dose 
over 3 hours. If this is tolerating the remaining carboplatin is infused in 250 mL 0.9% NaCl over 
4 hours. Diphenhydramine and hydrocortisone is given every 4 hours during the desensitization. 
An anaphylaxis tray should be available at the bedside and the patient is staffed 1:1 during the 
first 8 hours of the infusion. If unable to rechallenge or patient refusal, patient will discontinue 
all protocol therapy. 
 
M6620 (VX-970) Acute Hypersensitivity Reaction: Infusion reactions are common with 
intravenous administration of drugs used to treat cancer and have been seen with M6620 (VX-
970) administration. These reactions occur during or shortly after administration of the drug and 
are diverse. They may include pruritus, flushing, chills/rigors, urticaria/rash, headache, 
bronchospasm/dyspnea, and hypotension or hypertension, among others. If any subject develops 
pruritus, flushing, or any other symptom suggestive of an infusion reaction, standard measures 
may be employed to manage these symptoms (e.g., antihistamines and/or steroids not prohibited 
by the protocol). To prevent recurrence of these symptoms in subsequent administrations, 
appropriate desensitizing measures prior to the administration of the study drugs may be 
employed (e.g., premedication with 200 mg hydrocortisone approximately 60 minutes before 
infusion, and 10 mg of chlorphenamine approximately 30 minutes before infusion; alternative 
antihistamine and steroid combinations may be considered). If standard procedures to limit 
symptoms of an infusion reaction are insufficient, then the infusion time may be extended 
beyond 60 minutes but no more than 90 minutes. Management of an infusion reaction may occur 
pre-emptively, if symptoms of an infusion reaction have been observed in subjects at a particular 
dose level of M6620 (VX-970). 
 
Serious acute hypersensitivity reactions have occurred in a few subjects receiving M6620 (VX-
970) as well. These reactions occurred within minutes of re-exposure to M6620 (VX-970), and in 
cases reported to date, they have occurred during the second infusion. They may include 
hypotension and mental status changes. All subjects have fully recovered with standard treatment 
for this reaction, including immediate discontinuation of the inciting infusion and administration 
of IV corticosteroid. If the reaction included significant hypotension and mental status changes, 
the patient cannot be rechallenged.  The patient will no longer be able to continue on study; 
however, continued treatment with carboplatin and gemcitabine should be considered if a benefit 
is noted, per the discretion of the treating physician. 
 
 
 

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7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 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, 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). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in the parentheses 
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
 
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). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
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INVESTIGATIONS - GGT increased; Hemoglobin increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Dehydration; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle weakness 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (malignant neoplasm progression) 
NERVOUS SYSTEM DISORDERS - Lethargy; Spinal cord compression; Syncope 
PSYCHIATRIC DISORDERS - Confusion 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Atelectasis; Dyspnea 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
 
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 Commercial Agent(s) 
 
7.1.2.1 
Gemcitabine 
 
Consult the package insert for the most current and complete information. 
 
Common known potential toxicities, > 10%: 
Cardiovascular: Peripheral edema, edema 
Central nervous system: Pain, fever, somnolence 
Dermatologic: Rash, alopecia, pruritus 
Gastrointestinal: Nausea/vomiting, constipation, diarrhea, stomatitis 
Hematologic: Anemia, leukopenia, thrombocytopenia, neutropenia, hemorrhage, 
myelosuppression is the dose-limiting toxicity 
Hepatic: Transaminases increased, alkaline phosphatase increased, bilirubin increased 
Renal: Proteinuria, hematuria, BUN increased 
Respiratory: Dyspnea 
Miscellaneous: Flu-like syndrome, infection 
 
Less common known potential toxicities, 1% - 10%: 
Local: Injection site reactions 
Neuromuscular & skeletal: Paresthesia 
Renal: Creatinine increased 
Respiratory: Bronchospasm 
 
Rare known potential toxicities, <1% (Limited to important or life-threatening): 
Adult respiratory distress syndrome, anaphylactoid reaction, anorexia, arrhythmias, bullous 
skin eruptions, cellulitis, cerebrovascular accident, CHF, chills, cough, desquamation, 
diaphoresis, gangrene, GGT increased, headache, hemolytic uremic syndrome (HUS), 
hepatotoxic reaction, hypertension, insomnia, interstitial pneumonitis, liver failure, 
malaise, MI, peripheral vasculitis, Petechiae, pulmonary edema, pulmonary fibrosis, 
radiation recall, renal failure, respiratory failure, rhinitis, sepsis, supraventricular 
arrhythmia, weakness 
 
7.1.2.2 
Carboplatin 
 

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Consult the package insert for the most current and complete information. Percentages 
reported with single-agent therapy. Note: Myelosuppression is dose related, schedule 
related, and infusion-rate dependent (increased incidences with higher doses, more 
frequent doses, and longer infusion times) and, in general, rapidly reversible upon 
discontinuation. 
 
Common known potential toxicities, > 10%: 
Central nervous system: Pain 
Endocrine & metabolic: Hyponatremia, hypomagnesemia, hypocalcemia, hypokalemia 
Gastrointestinal: Vomiting, abdominal pain, nausea 
Hematologic: Myelosuppression (dose related and dose limiting; nadir at ~21 days; 
recovery by ~28 days), leukopenia, anemia, neutropenia, thrombocytopenia 
 
Hypersensitivity: Hypersensitivity 
Neuromuscular & skeletal: Weakness 
Renal: Creatinine clearance decreased, BUN increased 
 
Less common known potential toxicities, 1% - 10%: 
Central nervous system: Peripheral neuropathy, neurotoxicity 
Dermatologic: Alopecia 
Gastrointestinal: Constipation, diarrhea, stomatitis/mucositis, taste dysgeusia 
Hematologic: Hemorrhagic/bleeding complications 
Hepatic: Bilirubin increased, increased serum alkaline phosphatase, increased serum AST 
Infection: Infection 
Local: Pain at the injection site 
Neuromuscular & skeletal: Peripheral neuropathy 
Ocular: Visual disturbance 
Otic: Ototoxicity 
Renal: Creatinine increased 
 
Rare known potential toxicities, <1% (Limited to important or life-threatening): 
Anaphylaxis, anorexia, bronchospasm, cardiac failure, cerebrovascular accident, 
dehydration, embolism, erythema, febrile neutropenia, hemolytic anemia (acute), 
hemolytic uremic syndrome, hyper-/hypotension, injection site reaction (pain, redness, 
swelling), limb ischemia (acute), malaise, metastases, pruritus, skin rash, tissue necrosis 
(associated with extravasation), urticaria, vision loss.

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7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only: 
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
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 
 

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1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
 
 
7.3.4 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS. However, they still must be reported through the routine reporting 
mechanism (Section 7.4): 
 
 
CTCAE SOC 
Adverse Event 
Grade 
Skin and subcutaneous disorders 
Alopecia 
Grade 2 
Investigations 
Neutropenia 
Grade 3 
Investigations 
Thrombocytopenia 
Grade 3 
Due to the expected high frequency of the above events, these do not require expedited reporting 
but will be reported through the routine reporting mechanism. 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of 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]) 

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• 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 and/or 
commercial agents administered in this study can be found in Section 7.1. 
 
8.1 CTEP IND Agent(s) 
 
 
8.1.1 M6620 
 
Other Names: VRT-0768079, MSC2527093A, VX-970 
 
Chemical Name: 5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-
yl)pyrazin-2- amine 
 
 
Classification: ATR inhibitor  
 
 
CAS Registry Number: 1232416-25-9 
 
Molecular Formula: C24H25N5O3S                 M.W.: 463.55 Da 
 
Mode of Action: Ataxia telangiectasia mutated and Rad3-related (ATR) kinase is an apical regulator 
of checkpoint pathways triggered by DNA damage.  The DNA damage response (DDR) is regulated 
by ATR kinase and ataxia telangiectasia mutated (ATM) kinase, which are recruited to distinct DNA 
damage structures.  M6620 (VX-970) disrupts ATR-mediated DNA damage response signaling and 
leads to sustained accumulation of DNA damage in cancer cells co-treated with DNA-damaging 
agents. 
 
Description: The drug substance for M6620 (VX-970) is the free base. 
 
How Supplied: M6620 (VX-970) is supplied by Merck KGaA/EMD Serono, Inc. and distributed by 
the Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 200 mg vials containing a 
sterile solution (20 mg/mL).  M6620 (VX-970) solution for injection is a yellow liquid formulated in 
20% betadex sulfobutyl ether sodium (w/v) and 86 mM acetate buffer, 10 mL total volume, supplied 
in clear glass vials in cardboard boxes with foam inserts. 
 
Preparation: M6620 (VX-970) solution for injection must be diluted with 5% dextrose in water 
solution prior to administration.  Do not use 0.9% Sodium Chloride due to incompatibility with 

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M6620 (VX-970).  To prepare the infusion solution add the dose volume of M6620 (VX-970) to a 
non-polyvinyl chloride (non-PVC), di(2-ethylhexyl) phthalate (DEHP)-free EVA infusion bag 
containing 5% dextrose in water. Gently invert the IV bag 5-10 times to mix the solution.  Confirm 
the solution is clear and free of precipitates and/or particulates.  The final concentration must be 
between 0.075 mg/mL to 1 mg/mL.  Place the IV bag into an opaque cover to protect from light.   
 
Storage: Store intact vials protected from light inside cardboard boxes at room temperature, 25°C 
(77°F), with excursions allowed between 15 and 30°C (59 and 86°F).   
 
If a storage temperature excursion is identified, promptly return M6620 (VX-970) to between 15 and 
30°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability testing of the intact vials is on-going.  Prepared solutions must be protected from 
light and used within 4 hours from time of preparation if stored at room temperature or 24 hours if 
stored refrigerated (2-8°C).  
 
Route of Administration: Intravenous (IV) infusion. 
 
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. 

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8.1.2 
Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by 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 eligible participating investigators at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 
(Statement of Investigator), NCI 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 participating investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
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, a “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 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators 
and research staff through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status and a “current” password and an 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/ 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.govPMB 
policies and 
guidelines:http://ctep.cancer.gov/branches/pmb/agent_management.htm 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ CTEP Associate Registration and IAM account 
help: 

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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) 
IB Coordinator: IBCoordinator@mail.nih.gov 
 
 
8.2 
Commercial Agent(s) 
 
8.2.1 Gemcitabine (Gemzar®) 
 
Background: Gemcitabine is a pyrimidine antimetabolite that inhibits DNA synthesis by 
inhibition of DNA polymerase and ribonucleotide reductase, specific for the S-phase of 
the cell cycle. Gemcitabine is phosphorylated intracellularly by deoxcytidine kinase to 
gemcitabine monophosphate, which is further phosphorylated to active metabolites 
gemcitabine diphosphate and gemcitabine triphosphate. Gemcitabine diphosphate 
inhibits DNA synthesis by inhibiting ribonucleotide reductase; gemcitabine triphosphate 
incorporates into DNA and inhibits DNA polymerase. 
 
Formulation: Commercially available for injection: Powder for reconstitution: 200 mg 
and 1 gram vials. Solution for injection: 38 mg/mL 200 mg, 1 gm, and 2 gm vials. MUST 
BE DILUTED BEFORE USE. 
 
Preparation, Storage, and Stability: 
Powder for reconstitution: 
Store intact vials at room temperature. Reconstitute the 200 mg vial with preservative 
free 0.9% NaCl 5 mL or the 1000 mg vial with preservative free 0.9% NaCl 25 mL. 
Resulting solution is 38 mg/mL. Dilute with 50-500 mL 0.9% NaCl or D5W to 
concentrations as low as 0.1 mg/mL. Reconstituted vials are stable for up to 35 days and 
infusion solutions diluted in 0.9% NaCl are stable up to 7 days at 23ºC when protected 
from light; however, the manufacturer recommends use with 24 hours for both 
reconstituted vials and infusion solutions. Do not refrigerate. 
 
Solution for injection: 
Store intact vials at refrigeration temperature between 2º to 8ºC (36º to 46ºF). Do 
not freeze. Each vial contains a gemcitabine concentration of 38 mg/mL. The 
appropriate amount of drug should be further diluted with 50-500 mL 0.9% NaCl 
or D5W to concentrations as low as 0.1 mg/mL. When prepared as directed, diluted 
gemcitabine solutions are stable for 24 hours at controlled room temperature. 
 
Administration: Refer to the drug treatment section of the protocol for specific 
administration directions and infusion rates. Gemcitabine is normally infused IV over 30 
minutes. Note: Prolongation of the infusion time > 60 minutes has been shown to 
increase toxicity. Gemcitabine is being investigated in clinical trials for fixed dose rate 
infusion administration at doses from 1000 mg/m2 to 2200 mg/m2 at a rate of 10 
mg/m2/minute. Prolonged infusion times increase the accumulation of the active 
metabolite, gemcitabine triphosphate. Patients who receive gemcitabine fixed dose rate 
infusions experience more grade three and four hematologic toxicities. 
 
Pharmacokinetic information: 

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Distribution: Infusions <70 minutes: 50 L/m2; Long infusion times: 370 L/m2 
Protein binding: Low 
Metabolism: Metabolized intracellularly by nucleoside kinases to the active 
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleoside metabolites 
Half-life elimination: 
Gemcitabine: Infusion time ≤ hour: 32-94 minutes; infusion time 3-4 hours: 4-10.5 
hours 
Metabolite (gemcitabine triphosphate), terminal phase: 1.7-19.4 hours 
Time to peak, plasma: 30 minutes after completion of infusion 
Excretion: Urine (92% to 98%; primarily as inactive uridine metabolite); feces 
(<1%) 
 
Potential Drug Interactions: 
Increased Effect/Toxicity: Gemcitabine may increase the levels/effects of 
fluorouracil. Gemcitabine may enhance the adverse pulmonary effects of 
bleomycin. 
Ethanol/Nutrition/Herb Interactions Ethanol: Avoid ethanol (due to GI 
irritation). 
 
Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain supplies 
from normal commercial supply chain or wholesaler. 
 
 
8.2.2 Carboplatin (Paraplatin®, CBDCA) 
 
Background: Carboplatin is an alkylating agent which covalently binds to DNA; 
interferes with the function of DNA by producing interstrand DNA cross-links. 
 
Product description: Commercially available for injection as: 
Solution Reconstituted: 150 mg; Solution 10 mg/mL (5 mL, 15 mL, 45 mL, 60 mL) 
 
Solution preparation: Refer to package insert for complete preparation and dispensing 
instructions. Store intact vials at room temperature at 25ºC (77ºF); excursions permitted to 
15ºC to 30ºC (59ºF to 86ºF). Protect from light. Further dilution to a concentration as low as 
0.5 mg/mL is stable at room temperature (25ºC) for 8 hours in 0.9% NaCl or D5W; Stability 
has also been demonstrated for dilutions in D5W in PVC bags at room temperature for 8 days; 
however the manufacturer states to use within 8 hours due to lack of preservative. 
 
Pharmacokinetic information: 
Distribution: Vd: 16 L; into liver, kidney, skin, and tumor tissue. 
Protein binding: 0%; however the platinum from carboplatin becomes irreversibly 
bound to plasma proteins. 
Metabolism: Minimally hepatic to aquated and hydroxylated compounds. 
Half-life elimination: CrCl > 60 mL/min: Carboplatin: 2.6-5.9 hours (based on 
dose of 300-500 mg/m2); Platinum (from carboplatin): > 5 days. 
Excretion: Urine (~70% as carboplatin within 24 hours; 3% to 5% as platinum 
within 1-4 days). 
 
Potential Drug Interactions: 

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Increased Effect/Toxicity: Aminoglycosides increase risk of ototoxicity and/or 
nephrotoxicity. When administered as sequential infusions, observational studies 
indicate a potential for increased toxicity when platinum derivatives (carboplatin, 
cisplatin) are administered before taxane derivatives (docetaxel, paclitaxel). 
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in estrogen- 
dependent tumors. 
 
Route of administration: Refer to the treatment section for specific administration 
instructions. When administered as a part of a combination chemotherapy regimen, 
sequence of administration may vary by regimen; refer to specific protocol for sequence 
recommendation. Needles or IV administration sets that contain aluminum should not be 
used in the preparation or administration of carboplatin; aluminum can react with 
carboplatin resulting in precipitate formation and loss of potency. 
 
Agent Ordering: Commercial supplies. Pharmacies or clinics shall obtain supplies 
from normal commercial supply chain or wholesaler.  
 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
Summary of Required Specimens 
All Groups: Phase 1 and Expansion Cohort 
 
Study 
Required Sample 
Collection 
Timepoints 
Handling and Shipping/ 
Protocol Section 
Germline 
mutation 
testing by 
BROCA 
20 mL 
whole blood 
After consent 
and before 
Cycle 1 Day 2 
Collect in EDTA (purple top) 
tubes. Samples should be 
refrigerated and shipped with 
cold packs on the day of 
collection. See Section 9.2.3. 
 
 
Expansion Cohort 
Study 
Required Sample 
Collection 
Timepoints 
Handling and Shipping/ 
Protocol Section 
 
Multiplex 
Quantitative IFA 
Assay and Mass 
Spectometry Asaay 
Tumor tissue 
Pretreatment: 
Before C1D1 
On-Treatment: 
C1D2 
C2D2 
Tissue cores will be transferred 
into a 1.5 mL pre-chilled 
cryovial and then flash frozen 
in liquid nitrogen per DCTD 
SOP340507 (see Appendix D). 
Immediately snap-freeze the 
biopsy. Biopsies are stored in 
liquid nitrogen until shipped. 
See Section 9.2.2. 
 
 

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Expansion Cohort: 
Study 
Required Sample 
Collection 
Timepoints 
Handling and Shipping/ 
Protocol Section 
Tumor 
BROCA 
Testing 
Tumor tissue 
Pre-treatment 
biopsy 
Tissue cores will be transferred 
into a 1.5 mL pre-chilled 
cryovial and then flash frozen 
in liquid nitrogen per DCTD 
SOP340507 (see Appendix D). 
Immediately snap-freeze the 
biopsy. Biopsies are stored in 
liquid nitrogen until shipped. 
See Section 9.2.3. 
 
 
9.1 Integrated Biomarker Studies 
 
9.1.1 Multiplex Quantitative IFA Assay (Integrated biomarker, expansion cohort only) 
 
9.1.1.1 
Hypothesis and Rationale 
Hypothesis: We hypothesize that i) exposure to carboplatin + gemcitabine will 
activate the ATR/CHK1 pathway as manifested by increased ATR 
autophosphorylation as well as increased H2AX phosphorylation in samples 
harvested 1 day after carboplatin + gemcitabine compared to pretreatment biopsies 
and ii) treatment with M6620 (VX-970) will diminish the increase in ATR 
autophosphorylation but will increase the DNA damage as manifested by H2AX and 
NBS1 phosphorylation. 
 
Rationale: The purpose of this multiplex assay is to provide proof of mechanism for 
i) the activation of ATR by the carboplatin/gemcitabine combination at the doses 
administered in ovarian cancer in the clinical setting and ii) diminished ATR 
activation accompanied by enhanced DNA damage in tumors exposed to M6620 
(VX-970) 24 hours after carboplatin + gemcitabine. A pretreatment biopsy is needed 
to assess the baseline level of pATR and H2AX. A second biopsy is required either 
at 24 hours after the gemcitabine infusion to assess the level of pATR and H2AX after the 
cytotoxic chemotherapy or 4-6 hours after the infusion of M6620 (VX-970) in order to 
assess the effects of M6620 (VX-970). Ideally, all three samples would be taken from the 
same patient during the first cycle, in order to assess the effect of M6620 (VX-970). 
However, obtaining two invasive tumor biopsies within 4-6 hours is not feasible. Therefore, 
patients will undergo one post treatment biopsy in cycle 1 and one post treatment biopsy in 
cycle 2. 
 
9.1.1.2       Assay Validity and Appropriateness for Study 
All participating sites will ship the tumor specimens to Mayo Clinic for storage. One 

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core from each time point will be stored in the Mayo Biospecimen Repository for 
repeat analysis if necessary and use for further biomarkers if they become available. 
 
In batches, one core from each of the tumor specimens will be shipped to Dr. Ralph 
Parchment’s laboratory for evaluation of these markers. His laboratory is fully 
equipped to carry out these investigations and has previously developed this assay 
and is serving as a central resource laboratory for the tumor specimen correlates for 
some of the ongoing NCI approved ETCTN M6620 (VX-970) clinical trials. 
 
9.1.1.3       Performance Site 
The pATR and Rad51 IFA assays will be performed in the laboratory of Dr. Parchment at PADIS, 
Frederick National Laboratory for Cancer Research (FNLCR) under the guidance of Dr. Deborah 
Wilsker. ɣH2AX, pNBS1 IFA with βCATN segmentation assay will be performed in the NCLN 
PD Assay Laboratory at MD Anderson under the guidance of Dr. Kate Ferry-Galow. 
 
9.1.1.4       Justification of the Number of Patients and Specimens 
The purpose of the assay is to provide proof of mechanism that the carboplatin/ 
gemcitabine therapy is indeed activating the pathway of interest and M6620 (VX-
970) is decreasing that activation. This will be tested by obtaining information 
regarding the levels of DNA damage markers after exposure to cytotoxic therapy or 
after cytotoxic therapy and M6620 (VX-970). The number of samples will allow for 
analysis only in an exploratory fashion. 
 
 
9.1.1.5 
Description of Biological Samples Required for Assay 
Tumor biopsies will be collected and processed using validated SOPs that will ensure 
specimen quality and patient confidentiality pursuant to informed consent provisions. 
The tissue cores will be transferred into 1.5-mL pre-chilled cryovials and then flash 
frozen in liquid nitrogen per DCTD SOP340507 
(http://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507 Biopsy  
Frozen.pdf). Detailed instructions on biopsy collection and handling as well as 
sample shipping manifests are included in SOP340507 (Appendix D). Samples will 
be first submitted to Dr. Ralph Parchment’s laboratory at PADIS, Frederick National 
Laboratory for Cancer Research (FNLCR), then routed to IFA assay performance 
sites as described in Section 9.1.1.3.   The frozen biopsy specimens are transferred to 
PADIS on dry ice, where the core biopsy samples are stored at -80°C, or colder and 
subsequently processed for analysis as directed by the Principal Investigator 
according to SOP340522 
(http://dctd.cancer.gov/ResearchResources/biomarkers/docs/gH2AXIFA_Biopsy/SOP 
340522 Biopsy Section.pdf and Appendix E). Biopsy samples will be analyzed for 
γH2AX, Rad51, pNbs1, and pATR as described above; any additional cores will be 
returned to Mayo. 
 
9.1.2   Multiplexed Mass Spectometry Based Phospho-signaling Assay (Exploratory biomarker, 
expansion cohort only) 
 
9.1.2.1 
Hypothesis and Rationale 
Hypothesis: We hypothesize that i) exposure to carboplatin + gemcitabine will 
activate the ATR/CHK1 pathway as manifested by increased ATR 
autophosphorylation as well as increased H2AX phosphorylation in samples 

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harvested 1 day after carboplatin + gemcitabine compared to pretreatment biopsies 
and ii) treatment with M6620 (VX-970) will diminish the increase in ATR 
autophosphorylation but will increase the DNA damage as manifested by 
phosphorylation of  substrates of ATM, for example phospho-RAD50. 
Rationale: The purpose of this multiplex mass spectrometry based assay is to provide 
proof of mechanism for i) the activation of ATR by the carboplatin/gemcitabine 
combination at the doses administered in ovarian cancer in the clinical setting and ii) 
diminished ATR activation accompanied by enhanced DNA damage in tumors 
exposed to M6620 (VX-970) 24 hours after carboplatin + gemcitabine. A 
pretreatment biopsy is needed to assess the baseline level of phospho-Ser1989-ATR 
(pATR) and other DNA damage reseponse proteins. A second biopsy is required 
either at 24 hours after the gemcitabine infusion to assess the level of pATR and after 
the cytotoxic chemotherapy or 4-6 hours after the infusion of M6620 (VX-970) in 
order to assess the effects of M6620 (VX-970) and ATR activation. Ideally, all three 
samples would be taken from the same patient during the first cycle, in order to 
assess the effect of M6620 (VX-970). However, obtaining two invasive tumor 
biopsies within 4-6 hours is not feasible. Therefore, patients will undergo one post 
treatment biopsy in cycle 1 and one post treatment biopsy in cycle 2. 
 
9.1.2.2 Assay Validity and Appropriateness for Study  
All participating sites will ship 
the tumor specimens to Mayo Clinic for storage. One core from each time point will be stored in 
the Mayo Biospecimen Repository for repeat analysis if necessary and use for further biomarkers 
if they become available. 
 
In batches, one core from each of the tumor specimens will be shipped to Dr. 
Paulovich’s laboratory for evaluation of these markers. Her laboratory is fully 
equipped to carry out these investigations and has previously developed this assay 
(https://doi.org/10.1667/RR14963.1 ). 
 
9.1.2.3  
Performance Site 
The assay will be performed in the laboratory of Dr. Paulovich at the Fred 
Hutchinson Cancer Research Center. This laboratory has extensive experience with 
developing, validating and implementing assays assessing drug response. 
 
9.1.2.4  
Justification of the Number of Patients and Specimens 
The purpose of the assay is to provide proof of mechanism that the carboplatin/ 
gemcitabine therapy is indeed activating the pathway of interest and M6620 (VX-
970) is decreasing that activation. This will be tested by obtaining information 
regarding the levels of DNA damage markers after exposure to cytotoxic therapy or 
after cytotoxic therapy and M6620 (VX-970). Because this is an expansion cohort, 
the number of samples will allow for analysis only in an exploratory fashion.   
 
9.1.2.5 
Description of Biological Samples Required for Assay 
Tumor biopsies will be collected and processed using validated SOPs that will ensure 
specimen quality and patient confidentiality pursuant to informed consent provisions. 
The tissue cores will be transferred into 1.5-mL pre-chilled cryovials and then flash 
frozen in liquid nitrogen per DCTD SOP340507 
(http://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507_Biopsy_ 
Frozen.pdf). Detailed instructions on biopsy collection and handling as well as 
sample shipping manifests are included in SOP340507 (Appendix D). Once we are 

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assured that the integrated biomarker has been successfully assayed, samples will be 
submitted to Dr. Paulovich’s' laboratory for evaluation of phosphorylation of DNA 
damage markers.  The frozen biopsy specimens are transferred and shipped on dry 
ice, where the core biopsy samples are stored at -80°C, or colder and subsequently 
processed for analysis as directed by the Principal Investigator according to 
SOP340522 
(http://dctd.cancer.gov/ResearchResources/biomarkers/docs/gH2AXIFA_Biopsy/SOP 
340522_Biopsy_Section.pdf and Appendix E).  
 
9.1.3  
Germline mutation testing by BROCA (exploratory biomarker) 
 
9.1.3.1 
Hypothesis and Rationale 
Hypothesis: Ovarian cancers in patients with germline BRCA1 or BRCA2 mutations 
will have a higher response rate to carboplatin/gemcitabine/M6620 (VX-970) than 
ovarian cancers in patients without germline BRCA1 or BRCA2 mutations. 
Rationale: Preclinical studies have shown that ovarian cancer cell lines are sensitized 
by ATR inhibitors to platinum compounds and gemcitabine independent of whether 
the cell lines have HR defects or not. However, those cell lines with HR defects such 
as BRCA1 loss are particularly sensitive to the combination [32]. This germline 
mutation testing will allow us to determine whether the correlation between 
inactivating mutations of HR genes and cancer hypersensitivity to this combination is 
also observed in the clinic. 
 
 
9.1.3.2 
Assay Validity and Appropriateness for Study 
BRCA1 and BRCA2 are part of the BROCA panel (see below), which is being run at 
the University of Washington in a CLIA-certified laboratory. This assay involves the 
targeted capture of select DNA repair genes (including BRCA1 and BRCA2) followed 
by massively parallel sequencing to achieve substantial read depth. 
 
9.1.3.3  
Performance Site 
This BROCA analysis will be performed at the University of Washington in collaboration with Dr. 
Elizabeth Swisher. 
9.1.3.4 
Data Supporting the Degree of Biomarker “Fit for Purpose” 
Sequencing is performed in the University of Washington CLIA-certified Department 
of Laboratory Medicine sequencing laboratory. This panel has been used by 
Elizabeth Swisher and Mary Claire King to determine the frequency of mutations in 
BRCA1, BRCA2, and a number of additional genes encoding DNA repair proteins in 
patients with ovarian cancer [36]. 
 
9.1.3.5  
Justification of the Number of Patients and Specimens 
One sample of DNA from peripheral blood cells is needed for this analysis of 
germline DNA. The Swisher laboratory prefers to have 1 microgram of total DNA 
for these assays. 
This assay will be performed on both the control and experimental treatment groups. 
This will allow us to i) determine whether the two treatment groups of the 
randomized trial are evenly balanced for patients with germline deleterious mutations 

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in HR genes and ii) assess, in an exploratory manner, the relationship between 
germline HR gene mutations and response to the carboplatin/gemcitabine regimen in 
this setting. 
 
9.1.3.6  
Description of Biological Samples Required for Assay 
Assuming a normal leukocyte count, 6 cc of peripheral blood is sufficient for 
isolation of leukocyte DNA for this analysis. 
 
9.1.4 Tumor BROCA testing (Exploratory biomarker, expansion cohort) 
 
9.1.4.1  
Hypothesis and Rationale 
Hypothesis: Ovarian cancers with germline or somatic mutations in HR pathway 
genes will have a better response to the carboplatin/gemcitabine/M6620 (VX-970) 
combination. 
Rationale: Preclinical studies have shown that ovarian cancer cell lines are sensitized 
by ATR inhibitors to platinum compounds and gemcitabine independent of whether 
the cell lines have HR defects or not. However, those cell lines with HR defects such 
as BRCA1 loss are particularly sensitive to the combination [32]. This tumor sample 
mutation testing will allow us to determine which tumors have deleterious germline 
or somatic mutations in HR repair pathway genes and then assess whether these 
deleterious HR pathway mutations are associated with an improved outcome in either 
the control or experimental treatment group. 
 
9.1.4.2  
Assay Validity and Appropriateness for Study 
The BROCA assay performed in the Swisher laboratory at the University of 
Washington involves custom capture and massively parallel sequencing of 
approximately 40 genes encoding proteins known to be involved in HR, non- 
homologous end-joining, alternative end-joining and the Fanconi Anemia pathway. 
This sequencing is performed at the University of Washington in a CLIA-certified 
laboratory. The assay has been validated as described in ref. 35 and references 
therein. 
 
9.1.4.3 
Performance Site 
 
This BROCA analysis will be performed at the University of Washington in 
collaboration with Dr. Elizabeth Swisher. 
 
9.1.4.4  
Data Supporting the Degree of Biomarker “Fit for Purpose” 
Sequencing is performed in the University of Washington CLIA-certified Department 
of Laboratory Medicine sequencing laboratory. This panel has been used by 
Elizabeth Swisher and Mary Claire King to determine the frequency of mutations in 
BRCA1, BRCA2, and a number of additional genes encoding DNA repair proteins in 
patients with ovarian cancer [36]. More recently, this same methodology has been 
utilized to show that patients with somatic vs. germline mutations in these genes have 
similar disease-free survival after platinum-based chemotherapy [34]. Preliminary 
studies using samples from the Mayo Clinic Biospecimens Repository for Ovarian 
Cancer Research have demonstrated that 16.8% of HGSOCs seen at Mayo have 
deleterious germline mutations in HR genes (10% in BRCA1 or BRCA2 and 6.8% in 

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other HR genes); and an additional 9.9% have somatic mutations in these same genes 
(5.9% in BRCA1 or BRCA2 and 4.0% in other HR genes). 
 
9.1.4.5 
Justification of the Number of Patients and Specimens 
One sample of tumor DNA is needed for this analysis. To test the hypothesis that 
tumor genotype correlates with response to the carboplatin/gemcitabine/M6620 (VX-
970) combination, we will need a tumor DNA specimen from each patient in the 
expansion cohort.  
 
9.1.4.6  
Description of Biological Samples Required for Assay 
Tumor biopsy samples that are formaldehyde fixed and paraffin embedded, snap 
frozen or embedded in OTC medium are sufficient for extraction of DNA. We prefer 
FFPE samples for this analysis because of the possibility of performing laser capture 
microdissection to isolate DNA from tumor cells if the percentage of tumor in the 
biopsy is small. 
 
 
 
9.1.5 Prioritization of Tissue-Based Integrated Biomarkers 
Tumor biopsies are being obtained from patients enrolled in the expansion cohort, in an 
attempt to confirm the mechanism of action of M6620 (VX-970) when combined with 
carboplatin and gemcitabine. Accordingly, when tissue obtained at biopsy is limiting, the 
highest priority will be the Multiplex Quantitative IFA Assay (Section 9.1.1), the second 
highest will be the Multiplexed Mass Spectometry Based Phospho-signaling Assay (Section 
9.1.2) and the third highest will be tumor sequencing for DNA repair genes (Section 9.1.4). 
 
9.2 
Laboratory Correlative Studies 
 
9.2.1 
Multiplex Quantitative IFA Assay (Integrated biomarker, expansion cohort) 
 
9.2.1.1 
Collection of Specimens 
In all patients enrolled in the expansion cohort, three tumor biopsies will be 
obtained. All patients will undergo a pretreatment biopsy which will be obtained 
after registration and before day 1 of therapy. Patients will then be randomized to the 
timing of the next two biopsies. Group A:  Cycle 1, day 2, 18-24 hours after 
carboplatin/gemcitabine and Cycle 2, day 2 4-6 hours after M6620 inhibitor. Group 
B: Cycle 1, day 2 4-6 hours after M6620 and Cycle 2, day 2, 18-24 hours after 
gemcitabine/carboplatin infusion.  Biopsies should be obtained by interventional 
radiology using four (4) passes of an 18 gauge needle under ultrasound or CT 
guidance. 
 
9.2.1.2 
Handling of Specimens 
Tissue cores will be transferred into a 1.5 mL pre-chilled cryovial and then flash 
frozen in liquid nitrogen per DCTD SOP340507 (see Appendix D). The preferred 
method of collection is for the interventional radiologist to eject the biopsy directly 
into the pre-chilled tube. Immediately snap-freeze the biopsy by placing the tube into 
liquid nitrogen or dry ice/ethanol bath. Biopsies are to be stored in liquid nitrogen 
until shipped. 

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9.2.1.3 
Shipping of Specimens 
All samples should be shipped via overnight express courier in insulated containers 
with enough dry ice to maintain samples at -80 C for at least 72 hours. All 
specimens are to be shipped on Monday, Tuesday, or Wednesday to: 
 
Mayo Clinic Attn: 
Jill Wagner 
Gonda 19-205B 
221 4th Avenue SW 
Rochester, MN 55905 
 
Wagner.Jill@mayo.edu 
 
Once monthly, one core from each time point will be sent to NCI from Mayo 
Clinic per directions below: 
 
FedEx return shipment labels will be provided to Mayo Clinic, which will be sending all 
frozen shipments for the study to PADIS, Frederick National Laboratory for Cancer Research 
(FNLCR) Specimen Central Receiving. All samples should be shipped via overnight express 
courier in insulated containers with enough dry ice to maintain samples at -80 C for at 
least 72 hours. All specimens are to be shipped on Monday, Tuesday, or Wednesday. 
 
Just prior to shipping, place specimen tubes into an 81-place freezer box and then in a 
shipping container with sufficient dry ice to maintain the samples at -80 C for at 
least 72 hours. All weekly processing specimens are recommended to ship out via 
FedEx on the following Monday afternoon for delivery by 10 a.m. overnight (FedEx 
First Overnight). PADIS, Frederick National Laboratory for Cancer Research (FNLCR) 
Specimen Central Receiving (NCI PD Support@mail.nih.gov) a shipment notification. 
Further details attached in Appendix D) 
 
9.2.1.4 
Site Performing Correlative Study. 
The pATR and RAD51 IFA assays will be performed at PADIS, Frederick National Laboratory 
for Cancer Research (FNLCR). The ɣH2AX, pNBS1 IFA with βCATN segmentation assay will be 
performed at the NCLN PD Assay Laboratory at MD Anderson.. 
 
9.2.2   Multiplexed Mass Spectometry Based Phospho-signaling Assay  
9.2.2.1 
Collection of Specimens:  
In all patients enrolled in the expansion cohort, three tumor biopsies will be 
obtained. All patients will undergo a pretreatment biopsy, which will be obtained 
after registration and before Day 1 of therapy. Patients will then be randomized to 
the timing of the next two biopsies. Group A:  Cycle 1, Day 2, 18-24 hours after 
carboplatin/gemcitabine and Cycle 2, Day 2 4-6 hours after M6620 inhibitor. Group 
B: Cycle 1, Day 2 4-6 hours after M6620 and Cycle 2, Day 2, 18-24 hours after 
gemcitabine/carboplatin infusion. Biopsies should be obtained by interventional 
radiology using two passes of an 18 gauge needle under ultrasound or CT guidance. 
 
9.2.2.2 
Handling of Specimens 

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Tissue cores will be transferred into a 1.5 mL pre-chilled cryovials and then flash 
frozen in liquid nitrogen per DCTD SOP340507 (see Appendix D). The preferred 
method of collection is for the interventional radiologist to eject the biopsy directly 
into the pre-chilled tube. Immediately snap-freeze the biopsy by placing the tube into 
liquid nitrogen or dry ice/ethanol bath. Biopsies are to be stored in liquid nitrogen 
until shipped. 
 
9.2.2.3 
Shipping of Specimens 
All samples should be shipped via overnight express courier in insulated containers 
with enough dry ice to maintain samples at -80 C for at least 72 hours. All 
specimens are to be shipped on Monday, Tuesday, or Wednesday to: 
 
Mayo Clinic Attn: 
Jill Wagner 
Gonda 19-205B 
221 4th Avenue SW 
Rochester, MN 55905 
Wagner.Jill@mayo.edu 
Once the trial has completed accrual, one core from each timepoint will be sent to 
the Fred Hutchinson Cancer Center from Mayo Clinic per directions below: 
 
Just prior to shipping, place specimen tubes into an 81-place freezer box and then in a 
shipping container with sufficient dry ice to maintain the samples at -80 C for at 
least 72 hours. All weekly processing specimens are recommended to ship out via 
FedEx on the following Monday afternoon for delivery by 10 a.m. overnight (FedEx 
First Overnight). Emailtlorentz@fredhutch.org. 
 
ATTN: Travis Lorentzen 
1100 Fairview Ave North 
Paulovich Lab, Room E2-423 
Seattle, WA 98109 
(206) 667-5107 
 
9.2.2.1 
Site Performing Correlative Study. 
The Multiplex Mass Spectometry Assay will be performed at the Fred Hutchinson 
Cancer Research Center in Seattle, WA. 
The additional tissue core will be stored at the Mayo Clinic Biospecimens Repository. 
 
9.2.3 BROCA Analysis of germline DNA 
9.2.3.1 
Collection of Specimens 
All patients enrolled in the study will undergo a blood draw after signed consent. 
Two 10mL EDTA (purple top) whole blood specimens will be collected prior to 
treatment. This should be done on a Monday through Wednesday and can be drawn 
any time after consent has been signed or on day 1 or 2 of cycle 1. 
 
9.2.3.2 
Handling of Specimens 
If possible, these specimens should be refrigerated and shipped with cold packs on the 

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same day (if necessary, tubes can be stored for up to 5 days before shipping if 
properly refrigerated). 
 
9.2.3.3 
Shipping of Specimens 
All samples should be shipped via overnight express courier in insulated containers 
with enough cold packs to maintain samples around 4 C for at least 72 hours. All 
specimens are to be shipped on Monday, Tuesday, or Wednesday to: 
 
Mayo Clinic 
Biospecimen Accessioning and Processing Shared Resource 
Attn: BAP Supervisor 
2915 Valleyhigh Drive NW 
2915 Building Dock 200 
Rochester, MN 55901 
 
Shipment of samples must comply with appropriate regulations as specified by the 
carrier. At a minimum, all samples must be packaged within two containers with 
absorbent material between containers to control any spill or leakage. The outer 
container must be puncture-resistant. A biohazard sticker must be affixed to both the 
inner and outer containers. 
 
9.2.3.4 
Site Performing Correlative Study 
The BROCA analysis will be performed batchwise in the laboratory of Dr. Elizabeth 
Swisher at the University of Washington. 
Elizabeth Swisher MD 
University of Washington 
1959 NE Pacific Street 
HSB, K154 
Seattle, WA 98195 
(206)616-4296 
swishere@u.washington.edu 
 
9.2.4 BROCA Analysis of Tumor Sample (Expansion Cohort) 
 
9.2.4.1  
Collection of Specimens 
 
All patients enrolled in the expansion cohort of the study will undergo a pretreatment 
biopsy, which will be obtained after registration and before Day 1 of therapy. 
Biopsies should be obtained by interventional radiology using two passes of an 18 
gauge needle under ultrasound or CT guidance (one core for this correlative and one 
core for the integrated multiplex immunofluorescence assay described in Section 
9.2.2). This tumor sample for BROCA analysis is only required at the time of the 
pretreatment biopsy. No additional tissue needed on the additional biopsies unless 
there was inadequate tissue collection on Day 1. 
 
In the Event of an Inadequate Pretreatment Biopsy in the Expansion Cohort 
If the pretreatment biopsy in the experimental treatment group is not sufficient to 
provide material for BROCA analysis, two unstained 5 micron slides are required for 
the genomic analysis from an archival tumor sample. An adjacent slide H&E slide 

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(or an electronic version of the image) is also required to confirm the presence of  
tumor. 
 
9.2.4.2 
Handling of Specimens 
 
Expansion Cohort 
Tissue cores will be cut in half, transferred into two 1.5 mL pre-chilled cryovials and 
then flash frozen in liquid nitrogen by placing the tube into liquid nitrogen or dry 
ice/ethanol bath. 
 
Expansion Cohort with Inadequate Pretreatment Biopsy Specimen 
Slides should be labeled with the clinical trial ID number and clinical trial patient ID 
number. Slides will not be returned to the original institution. 
 
9.2.4.3 
Shipping of Specimens 
All biopsy samples should be shipped via overnight express courier in insulated 
containers with enough dry ice maintain samples at -80 C for at least 72 hours. All 
specimens are to be shipped on Monday, Tuesday, or Wednesday to: 
 
Mayo Clinic Attn: 
Jill Wagner 
Gonda 19-205B 
221 4th Avenue SW 
Rochester, MN 55905 
Wagner.Jill@mayo.edu 
 
Slides with archival tissue specimens should also be sent to the address above. If 
electronic images of immediately adjacent slides are provided to confirm tumor 
content, those should be sent by e-mail to the study PI. 
 
9.2.4.4Site Performing Correlative Study 
 
BROCA analysis will be performed batchwise in the laboratory of Dr. Elizabeth 
Swisher at the University of Washington. 
University of Washington 
Elizabeth Swisher MD 
1959 NE Pacific Street 
HSB, K154 
Seattle, WA 98195 
(206)616-4296 
swishere@u.washington.edu 
 
 
 

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10. 
STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy. In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. The study calendar pertains to all 
patients in the study. 
Please see the superscripts for notes as some evaluations pertain to specific groups only (for 
example the tumor biopsy and BROCA panel). 
 
Pre-Study 
(< 21 days 
prior to 
registration) 
Pre-Study 
(< 7 days 
prior to 
registration) 
After 
registration 
and 
prior to C1D1 
Cycle 1 
Prior to 
subsequent 
cycles 
(+/- 4 days) 
Off 
Treatment
h 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
X 
X 
Concurrent meds 
X -------------------------------------------------------------------------------------------- X 
Physical exam 
X 
X 
Vital Signs 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
CBC w/diff, plts 
X 
Xg 
Xg 
X 
CA-125 
X 
X 
X 
X 
Serum Chemistrya 
X 
X 
X 
X 
Adverse event evaluation 
X -------------------------------------------------------------------------------------------- X 
Tumor measurements 
X 
Tumor measurements are repeated every 2 cycles. Documentation (radiologic) must be 
provided for patients removed from study for progressive disease. 
Radiologic evaluation 
X Radiologic measurements should be performed every 2 cycles during the first year 
and every 3 months thereafter until progression. 
B-HCG 
Xb 
Tumor biopsy f,R 
Xc 
Xd 
Xd 
 
 
 
BROCA panel f,R 
Xf 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium.     Labs should be drawn on days 1 (or –1) and days 7 or 8 
b: 
Serum pregnancy test for women of childbearing potential only. 
c: 
Pretreatment tumor biopsy in the expansion cohort only (gemcitabine, carboplatin and M6620 (VX-970))  
d: 
Expansion Cohort only: Cycle 1 Day 2 and Cycle 2 Day 2 tumor biopsies (randomized to either 18-24 hours after gemcitabine 
infusion or 4-6 hours after M6620 (VX-970) infusion on day 2 of cycle 1 and  day 2 of cycle 2)  
 
 
e: 
All women enrolled in the study will undergo a blood draw to asses for BRCA mutation status. This can be done any time after signed 
consent and up to day 2 of cycle 1. 
f: Tumor biopsies and BROCA panel do not apply to the phase 1 dose escalation, they are performed only in expansion cohort, only 
g: CBC with differential to be performed on days -1 or 1 and days 7 or 8 of every cycle  

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11. 
MEASUREMENT OF EFFECT 
 
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) 
guidelines (version 1.1)36. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the short axis measurements in the case of lymph 
nodes are used in the RECIST guideline. 
 
 
11.1 Schedule of Evaluations 
For the purposes of this study, patients should be reevaluated every 6 weeks. In addition 
to a baseline scan, confirmatory scans should also be obtained at least 4 weeks following 
initial documentation of objective response. 
 
11.2 Definitions of Measurable and Non-Measurable Disease 
 
11.2.1 Measurable Disease 
 
11.2.1.1 A non-nodal lesion is considered measurable if its longest diameter can be accurately 
measured as ≥2.0 cm with chest x-ray, or as ≥ 1.0 cm with CT or MRI scan.  
11.2.1.2 A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in 
diameter as assessed using calipers (e.g. skin nodules) or imaging. In the case of 
skin lesions, documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended. 
 
11.2.1.3 A malignant lymph node is considered measurable if its short axis is >1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). 
 
NOTE: Tumor lesions in a previously irradiated area are not considered measurable 
disease. 
 
11.2.2 Non-Measurable Disease 
 
11.2.2.1 
All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥1.0 to <1.5 cm). Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable as well. 
 
Note: ‘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. In addition, lymph nodes that have a short axis <1.0 cm are 
h. 
Once therapy is discontinued (unacceptable adverse events, patient decision or disease progression) they will be followed for 3 years after 
removal from study or until death, whichever occurs first (see Section 5.4) 
R: Research funded 

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considered non-pathological (i.e., normal) and should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.3.1 Measurement Methods 
 
 All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
 The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
For patients having only lesions measuring at least 1 cm to less than 2 cm must use 
CT imaging for both pre- and post-treatment tumor assessments. 
 Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used at the same evaluation to assess the antitumor effect 
of a treatment. 
 
11.3.2 Acceptable Modalities for Measurable Disease 
 
 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 or less. If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness. 
 
 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. The lesions should be measured on the same pulse sequence. 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. 
 
 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 scans are 
preferable. 
 Physical Examination: For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is recommended. 
 
 
11.3.3 Measurement at Follow-up Evaluation 
 
 A subsequent scan must be obtained at least 4 weeks following initial 
documentation of an objective status of either complete response (CR) or partial 
response (PR). 
 
 In the case of stable disease (SD), follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 6 weeks (see 
Section 11.44). 
 
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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. 
 
 Cytologic and histologic techniques can be used to differentiate between PR and 
CR in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, 
where known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.4.1 Target Lesions & Target Lymph Nodes 
 
• Measurable lesions (as defined in Section 11.21) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” and 
recorded and measured at baseline. These lesions can be non-nodal or nodal (as 
defined in 11.21), where no more than 2 lesions are from the same organ and no 
more than 2 malignant nodal lesions are selected. 
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there 
often will be), there is no reason to perform additional studies beyond those 
specified in the protocol to discover new lesions. 
 
 Target lesions and target lymph nodes should be selected on the basis of their size, 
be representative of all involved sites of disease, but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case 
that, on occasion, the largest lesion (or malignant lymph node) does not lend itself 
to reproducible measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be selected. 
 
 Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the baseline sum of dimensions (BSD). The BSD will 
be used as reference to further characterize any objective tumor response in the 
measurable dimension of the disease. 
 
 Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph nodes 
will be calculated and reported as the post-baseline sum of dimensions (PBSD). 
If the radiologist is able to provide an actual measure for the target lesion (or 
target lymph node), that should be recorded, even if it is below 0.5 cm. If the 
target lesion (or target lymph node) is believed to be present and is faintly seen 
but too small to measure, a default value of 0.5 cm should be assigned. If it is the 
opinion of the radiologist that the target lesion or target lymph node has likely 
disappeared, the measurement should be recorded as 0 cm.The minimum sum of 
the dimensions (MSD) is the minimum of the BSD and the PBSD. 
 
11.4.2 Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
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lesions and lymph nodes should be followed in accord with 11.4.3.3. 
 
11.4.3 Response Criteria 
 
11.4.3.1 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest X- 
ray/physical examination must be measured on re-evaluation at evaluation times 
specified in Section 11.1. Specifically, a change in objective status to either a PR or 
CR cannot be done without re-measuring target lesions and target lymph nodes. 
 
Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response. In 
selected circumstances, certain non-target organs may be evaluated less frequently. 
For example, bone scans may need to be repeated only when complete response is 
identified in target disease or when progression in bone is suspected. 
 
 
11.4.3.2 
Evaluation of Target Lesions 
 
Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have reduction in short axis to <1.0 cm. 
 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph nodes at 
current evaluation) taking as reference the BSD (see Section 11.41). 
 
Progression (PD): At least one of the following must be true: 
 
a. At least one new malignant lesion, which also includes any lymph node that 
was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short 
axis during follow-up. 
 
b. At least a 20% increase in PBSD (sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes at current 
evaluation) taking as reference the MSD (Section 11.41). In addition, the 
PBSD must also demonstrate an absolute increase of at least 0.5 cm from the 
MSD. 
c. See Section 11.32 for details in regards to the requirements for PD via FDG- 
PET imaging. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD taking as reference the MSD. 
 
11.4.3.3 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all non-target lesions. 

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*See Section 11.431 
 
11.4.5 Symptomatic Deterioration 
Patients with global deterioration of health status that is not attributable to reversible 
drug side effects requiring discontinuation of treatment without objective evidence of 
disease progression at that time, and not either related to study treatment or other medical 
conditions, should be reported as PD due to “symptomatic deterioration.” Every effort 
should be made to document the objective progression even after discontinuation of 
treatment due to symptomatic deterioration. A patient is classified as having PD due to 
“symptomatic deterioration” if any of the following occur that are not either related to 
study treatment or other medical conditions: 
• Weight loss >10% of body weight. 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol 
Principal Investigator is responsible for monitoring the conduct and progress of the clinical 
trial, including the ongoing review of accrual, patient-specific clinical and laboratory data, 
and routine and serious adverse events; reporting of expedited adverse events; and 
accumulation of reported adverse events from other trials testing the same drug(s).  The 
Protocol Principal Investigator and statistician have access to the data at all times through 
the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  
In addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least 
monthly, or more frequently, conference calls with the Study Investigators and the CTEP 
Medical Officer(s) to review accrual, progress, and adverse events and unanticipated 
problems.  
 
For a Phase 1/2 trial, enrollment to the Phase 2 portion of the trial will not begin until a 
protocol amendment has been submitted which summarizes the Phase 1 results, the 
recommended Phase 2 dose, and the rationale for selecting it.  The amendment must be 
reviewed and approved by CTEP before enrollment to the Phase 2 portion can begin. 
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator 
and the Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol 
are responsible for timely submission of data via Medidata Rave and timely reporting of 
adverse events for that particular study.  This includes timely review of data collected on the 
electronic CRFs submitted via Medidata Rave. 
 

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All studies are also reviewed in accordance with the enrolling institution’s data safety 
monitoring plan. 
 
12.1 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 (check at https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, RAVE CRA (Lab Admin), SLA, or Site 
Investigator) (https://eapps-ctep.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. To the hold Rave CRA role or RAVE CRA (Lab 
Admin) role, the user must hold a minimum of an AP registration type.  To hold the Rave 
Investigator role, the individual must be registered as an NPIVR or IVR.  Associates can hold 
read-only roles in Rave.  
 
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. 
 
12.1.1 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) 799-7580 
or by email at CTMSSupport@theradex.com  for additional support with Rave and 
completion of CRFs. 
 
12.1.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 

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investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave. 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks. The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS. Metrics for timeliness will be followed and 
assessed on a quarterly basis. For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received. Queries will be issued by CTMS directly within Rave. The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve. Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP. Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) 
and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs). CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics- 
resources/interoperability-and-semantics/metadata-and-models). Customized eCRFs will 
be included when appropriate to meet 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). 
 
12.2 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” 

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(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. 
 
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 

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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/Primary Endpoint 
 
13.1.1 Phase 1 Dose Escalation 
 
The safety analysis will enroll in cohorts of 3 patients each where the study will be 
temporarily suspended after the enrollment of each cohort of 3 patients. For this 
protocol, dose-limiting toxicity (DLT) will be defined as an adverse event attributed 
(definitely, probably, or possibly) to the study treatment for cycle 1 only and meeting 
the following criteria: 
 
• DLT will be defined as grade 4 absolute neutrophil count for ≥ 5 days, grade 4 
anemia, platelet count < 25,000, or other non-hematologic events ≥ grade 3 as 
per NCI Common Terminology Criteria for Adverse Events Version 4.0 
(except fatigue, alopecia and anorexia). 
 
Maximum Tolerated Dose (MTD) Determination 
 
The MTD in this study will be defined as the highest safely tolerated dose, up to a 
maximum of dose level 4, where at most 1 out of six patients experience a DLT with 
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patients will be enrolled and observed for 6 weeks (i.e., 2 cycles) to assess toxicity 
before new patients are treated. If ≥ 2 of 3 patients at a dose level experience a DLT, 
then the MTD has been exceeded, and the previous dose must be considered as MTD 
for the randomized phase II portion, as long as 6 patients were treated at that dose 
level. If dose level 1 is found too toxic, we will consider adding additional lower dose 
levels to assess safety further. 
 
A total of 6 patients treated at the MTD will be sufficient to identify common 
toxicities at the MTD. For instance, those toxicities with an incidence of at least 25% 
will be observed with a probability of at least 82% (1-(1-0.25)6). 
 
If 1 of 3 patients at a dose level experiences DLT, then 3 additional patients will be 
treated at the same dose level, expanding that dose cohort to 6 patients. Upon dose 
cohort expansion to 6 patients, if ≥ 2 out of 6 patients at a dose level experiences a 
DLT, then the MTD has been exceeded, and the previous dose must be considered as 
the MTD, as long as 6 patients were treated at that dose level. If only 1 of 6 patients 
experience a DLT at a given dose level, the next higher dose level will be assessed up 
to the maximum dose level, dose level 4. If 0 of 3 patients at a dose level experience 
a DLT, then 3 additional patients will be treated at the next higher dose level up to a 
maximum of dose level 3.  
 
From this phase, treatment data, adverse events, and the MTD will be reported 
descriptively. The maximum grade for each type of adverse event will be 
summarized using CTCAE version 5.0. The frequency and percentage of grade 3+ 
adverse events will be reported. 
 
Evaluable Patients 
 
If a patient fails to complete the first cycle for reasons other than toxicity, the patient 
will be regarded as inevaluable and will be replaced in the phase I portion of this 
study. 
 
13.1.2 Expansion Cohort 
The expansion cohort will enroll an additional 20 patients at the MTD, for 26 total patients 
treated at the MTD.   
Primary Endpoint of expansion cohort: 
The primary endpoint of the expansion cohort is to confirm the safety at the MTD of the 
addition of M6620 (VX-970) to carboplatin and gemcitabine in first or second recurrence 
of platinum sensitive high grade serous or endometrioid ovarian, primary peritoneal or 
fallopian tube carcinoma.  From this phase, adverse events will be reported descriptively. 
The maximum grade for each type of adverse event will be summarized using CTCAE 
version 5.0. The frequency and percentage of grade 3+ adverse events will be reported.  
We will ensure that the treatment combination is safe enough for future studies in this 
disease population by comparing the AE data from our trial to historical data in this 
disease.  If we feel the treatment combination is safe enough at the MTD to proceed to 
larger studies, we will make that recommendation in our summary of conclusions in future 
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13.4 
Analysis of Secondary Endpoints 
 
The following secondary endpoints will be assessed for patients treated at the 
MTD:  confirmed response rate, overall survival, duration of response, and 
progression free survival.   
 
13.4.1 The key secondary endpoint is to determine if the MTD for the 
combination of carboplatin, gemcitabine and M6620 (VX-970) 
improves the confirmed response rate in adult women with platinum 
sensitive recurrent high grade serous or high grade endometrioid 
ovarian, primary peritoneal or fallopian tube cancer.  Any confirmed 
response that occurs during the first 8 cycles of treatment will count as 
a success (24 weeks). Per RECIST 1.1, responses need to be 
confirmed (2 consecutive responses at least 4 weeks apart) to count as 
a response (see Section 11). All patients who meet the eligibility 
criteria, sign the consent form, and start treatment will be considered 
evaluable for this endpoint.  
 
 
 
 
 
 
 
 
 
 
   
 
     
13.4.2 Overall Survival 
Overall survival (OS) is defined as the time from registration to death from 
any cause. OS will be estimated using the Kaplan-Meier method.  All 
patients who meet the eligibility criteria, sign the consent form, and start 
treatment will be considered evaluable for this endpoint.  
 
             13.4.3  Duration of Response:  The duration of confirmed responses will be assessed 
using the Kaplan-Meier method, where the duration of confirmed response will be 
defined as the time from the first documented date of confirmed response (CR or 
PR) to the date at which progression is first documented. 
 
     
13.4.4 Progression Free Survival 
PFS is defined as the time from registration to the first of either disease 
progression or death from any cause, where disease progression will be 
determined based on RECIST 1.1 criteria. All patients who meet the 
eligibility criteria, sign the consent form, and start treatment will be 
considered evaluable for this endpoint. PFS will be estimated using the 
Kaplan-Meier method.   
 

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13.4.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.4.6 Exploratory Endpoints 
Due to the limited sample size in this study, the proposed translational studies 
are considered exploratory and hypothesis generating. We will correlate the 
DNA damage markers and mutation data with clinical endpoints (i.e. response, 
PFS, OS). Statistical and graphical techniques will be used to explore these 
relationships. For time-to-event endpoints, we will use Cox proportional 
hazards models, and for response data we will use Logistic regression models. 
In addition, we will use Fisher’s exact tests to test the association between 
categorical marker data and response. All patients who meet the eligibility 
criteria, sign the consent form, start treatment and have translational data will be 
considered evaluable for these endpoints.  
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time they start treatment. 
 
13.5.2 Evaluation of Response 
 
All patients who meet the eligibility criteria, sign the consent form, and start treatment 
will be considered evaluable for efficacy endpoints. This analysis will not be an intent-to-
treat analysis. All conclusions should be based on all eligible patients. 
Sub analyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.). However, 
these sub analyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported. The 95% confidence intervals will also be provided. 
 
 
 
 

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13.6 
Adverse Event Stopping Rule 
 
13.6.1 Monitoring 
The principal investigator and the study statistician will review the study periodically 
(every 4-6 months, or more frequently if clinically indicated) to identify accrual and any 
endpoint problems that might be developing. For toxicity monitoring for the phase 1 
portion of the study, the study team will review toxicity data after every 3 patients and 
after the occurrence of each DLT by conference calls, as well as during the Phase I DOG 
meetings on a bi-weekly basis. For the expansion cohort, the study team will review 
toxicity data every 4 months.   
 
13.6.2 Adverse Event Stopping Rule 
In this study, we will suspend accrual to allow for a full review of the data, if any of the 
following occur during the expansion cohort portion of the trial: 
(1) If at any time, 2 of the initial 10 patients (or 20% of all patients when 
accrual is greater than 10) have experienced any grade 4 adverse event 
(at least possibly related to the study medication). 
(2) If at any time, 1 of the initial 10 patients (or 10% of all patients when 
accrual is greater than 10) have experienced any grade 5 adverse event 
(at least possibly related to the study medication). Of course, we will 
also closely monitor each grade 5 event on a case-by-case basis, and 
may immediately suspend accrual after one grade 5 event if we feel it 
is best for patient safety. 
 
After consideration by the study team (ie, Study Chair and statisticians) and consultation with 
representatives at the Cancer Therapy Evaluation Program (CTEP) and the Central 
Institutional Review Board (CIRB), a decision will be made as to whether and how the study 
will proceed. 
 
 
 
 

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REFERENCES 
 
1. 
Siegel, R., et al., Cancer statistics, 2011: the impact of eliminating socioeconomic and 
racial disparities on premature cancer deaths. CA Cancer J Clin, 2011. 61(4): p. 212-36. 
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Herzog, T.J., The current treatment of recurrent ovarian cancer. Curr Oncol Rep, 2006. 
8(6): p. 448-54. 
3. 
Armstrong, D.K., Relapsed ovarian cancer: challenges and management strategies for a 
chronic disease. Oncologist, 2002. 7 Suppl 5: p. 20-8. 
4. 
Ferrandina, G., et al., Phase III trial of gemcitabine compared with pegylated liposomal 
doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol, 2008. 26(6): p. 
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5. 
Mutch, D.G., et al., Randomized phase III trial of gemcitabine compared with pegylated 
liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol, 
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6. 
Gordon, A.N., et al., Long-term survival advantage for women treated with pegylated 
liposomal doxorubicin compared with topotecan in a phase 3 randomized study of 
recurrent and refractory epithelial ovarian cancer. Gynecol Oncol, 2004. 95(1): p. 1-8. 
7. 
Lawrie, T.A., et al., Pegylated liposomal doxorubicin for relapsed epithelial ovarian 
cancer. Cochrane Database Syst Rev, 2013. 7: p. CD006910. 
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Parmar, M.K., et al., Paclitaxel plus platinum-based chemotherapy versus conventional 
platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO- 
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9. 
Pfisterer, J., et al., Gemcitabine plus carboplatin compared with carboplatin in patients 
with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, 
the NCIC CTG, and the EORTC GCG. J Clin Oncol, 2006. 24(29): p. 4699-707. 
10. 
Perren, T.J., et al., A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med, 
2011. 365(26): p. 2484-96. 
11. 
Burger, R.A., et al., Incorporation of bevacizumab in the primary treatment of ovarian 
cancer. N Engl J Med, 2011. 365(26): p. 2473-83. 
12. 
Pujade-Lauraine, E., et al., Bevacizumab combined with chemotherapy for platinum-resistant 
recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. 
J Clin Oncol, 2014. 32(13): p. 1302-8. 
13. 
Aghajanian, C., et al., OCEANS: a randomized, double-blind, placebo-controlled phase 
III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive 
recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol, 
2012. 30(17): p. 2039-45. 
14. 
Oza, A.M., et al., Standard chemotherapy with or without bevacizumab for women with 
newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 
randomised trial. Lancet Oncol, 2015. 16(8): p. 928-36. 
15. 
Fokas, E., et al., Targeting ATR in DNA damage response and cancer therapeutics. 
Cancer Treat Rev, 2014. 40(1): p. 109-17. 
16. 
Weber, A.M. and A.J. Ryan, ATM and ATR as therapeutic targets in cancer. Pharmacol 
Ther, 2015. 149: p. 124-38. 
17. 
Zeman, M.K. and K.A. Cimprich, Causes and consequences of replication stress. Nat 
Cell Biol, 2014. 16(1): p. 2-9. 
18. 
Pitts, T.M., et al., Targeting nuclear kinases in cancer: development of cell cycle kinase 
inhibitors. Pharmacol Ther, 2014. 142(2): p. 258-69. 
19. 
Yan, S., M. Sorrell, and Z. Berman, Functional interplay between ATM/ATR-mediated 
DNA damage response and DNA repair pathways in oxidative stress. Cell Mol Life Sci, 
2014. 71(20): p. 3951-67. 

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20. 
Dickson, M.A. and G.K. Schwartz, Development of cell-cycle inhibitors for cancer 
therapy. Curr Oncol, 2009. 16(2): p. 36-43. 
21. 
Reaper, P.M., et al., Selective killing of ATM- or p53-deficient cancer cells through 
inhibition of ATR. Nat Chem Biol, 2011. 7(7): p. 428-30. 
22. 
Fokas, E., et al., Targeting ATR in vivo using the novel inhibitor VE-822 results in 
selective sensitization of pancreatic tumors to radiation. Cell Death Dis, 2012. 3: p. e441. 
23. 
Brochure, I.s., M6620 (VX-970). Vertex Pharmaceuticals Inc. Boston, MA, 2015. Version 5. 
24. 
Kuo, L.J. and L.X. Yang, Gamma-H2AX - a novel biomarker for DNA double-strand 
breaks. In Vivo, 2008. 22(3): p. 305-9. 
25. 
White, D., et al., The ATM substrate KAP1 controls DNA repair in heterochromatin: 
regulation by HP1 proteins and serine 473/824 phosphorylation. Mol Cancer Res, 2012. 
10(3): p. 401-14. 
26. 
Hall, A.B., et al., Potentiation of tumor responses to DNA damaging therapy by the 
selective ATR inhibitor M6620 (VX-970). Oncotarget, 2014. 5(14): p. 5674-85. 
27. 
Hall, A.B., et al., Potentiation of tumor responses to DNA damaging therapy by the 
selective ATR inhibitor M6620 (VX-970). 2014. 2014. 
28. 
Plunkett, W., et al., Gemcitabine: preclinical pharmacology and mechanisms of action. 
Semin Oncol, 1996. 23(5 Suppl 10): p. 3-15. 
29. 
O'Connell, M.J. and K.A. Cimprich, G2 damage checkpoints: what is the turn-on? J Cell 
Sci, 2005. 118(Pt 1): p. 1-6. 
30. 
Karnitz, L.M., et al., Gemcitabine-induced activation of checkpoint signaling pathways 
that affect tumor cell survival. Mol Pharmacol, 2005. 68(6): p. 1636-44. 
31. 
Parsels, L.A., et al., Gemcitabine sensitization by checkpoint kinase 1 inhibition 
correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells. 
Mol Cancer Ther, 2009. 8(1): p. 45-54. 
32. 
Huntoon, C.J., et al., ATR inhibition broadly sensitizes ovarian cancer cells to 

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chemotherapy independent of BRCA status. Cancer Res, 2013. 73(12): p. 3683-91. 
33. 
Risch, H.A., et al., Prevalence and penetrance of germline BRCA1 and BRCA2 mutations 
in a population series of 649 women with ovarian cancer. Am J Hum Genet, 2001. 68(3): 
p. 700-10. 
34. 
Pennington, K.P., et al., Germline and somatic mutations in homologous recombination 
genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal 
carcinomas. Clin Cancer Res, 2014. 20(3): p. 764-75. 
35. 
Turner, N., A. Tutt, and A. Ashworth, Hallmarks of 'BRCAness' in sporadic cancers. Nat 
Rev Cancer, 2004. 4(10): p. 814-9. 
36. 
Walsh, T., et al., Mutations in 12 genes for inherited ovarian, fallopian tube, and 
peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U 
S A, 2011. 108(44): p. 18032-7. 
37. 
Shah, V.P., et al., Analytical methods validation: bioavailability, bioequivalence and 
pharmacokinetic studies. Conference report. Eur J Drug Metab Pharmacokinet, 1991. 
16(4): p. 249-55. 
38. 
Shah, V.P., et al., Bioanalytical method validation--a revisit with a decade of progress. 
Pharm Res, 2000. 17(12): p. 1551-7. 
39. 
Guidance for Industry: Bioanalytical Method Validation. U.S. Department of Health and 
Human Services Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER), Center for Veterinary Medicine (CVM). Draft Guidance, September 
2013., F.a.D. Administration, Editor. 

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

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APPENDIX B: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions with 
Other Drugs and Herbal Supplements  
 
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 
 
(Next page: Patient Drug Interaction Wallet Card) 
 
 
 
 
 

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APPENDIX C: BROCA GENE LIST 
 
University of Washington –Department of Laboratory Medicine 
BROCA-Cancer Risk Panel 
http://tests.labmed.washington.edu/BROCA#BROCA Gene List 
 
Gene 
Function/Path 
way 
Heterozygote 
Cancer risk* 
Associated 
syndrome 
References (PMID) 
AKT1 
AKT signaling Breast, Thyroid 
Cowden-like 
23246288 
APC 
WNT signaling Colon 
Familial 
adenomatous 
polyposis 
20301519 
ATM 
Double stranded 
break repair 
Breast, 
Pancreatic 
Ataxia 
telangiectasia 
(recessive) 
16832357,19781682,2258 
5167 
ATR 
Double stranded 
break repair 
Oropharyngeal 
Seckel 
(recessive) 
22341969 
NEW AXIN2 
Colon 
Oligodontia- 
colorectal 
cancer 
syndrome 
15042511 
BAP1 
BRCA1- 
associated 
protein complex 
Uveal 
Melanoma, 
Mesothelioma 
21874000,21874003 
BARD1 
BRCA1- 
associated 
protein complex 
Breast, Ovarian 
21344236 
BMPR1A 
TGF-beta 
signaling 
Colon 
Juvenile 
polyposis 
20301642 
BRCA1 
BRCA1- 
associated 
protein complex 
Breast, Ovarian 
Hereditary 
breast and 
ovarian cancer 
22006311,2270482,75459 
54 
BRCA2 
Fanconi/BRCA Breast, Ovarian 
Hereditary 
breast and 
ovarian cancer, 
Fanconi 
anaemia FA-D1 
(recessive) 
22006311,8524414 
BRIP1 
Fanconi/BRCA Breast, Ovarian 
Fanconi 
anaemia FA-J 
(recessive) 
22006311,17033622,2196 
4575 
CDH1 
Cell adhesion 
Breast, Gastric 
Hereditary 
20301318 

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diffuse gastric 
cancer 
CDK4 
Cell cycle 
Melanoma 
19585149 
CDKN2A 
Cell cycle 
Pancreatic, 
Melanoma 
19585149 
CHEK1 
Double stranded 
break repair 
Unknown 
11479205 
CHEK2 
Double stranded 
break repair 
Breast 
11967536 
CTNNA1 
Beta-catenin, e- 
cadherin 
complex 
Gastric 
Hereditary 
diffuse gastric 
cancer 
23208944 
FAM175A/Abra 
xas 
Double stranded 
break repair 
Breast 
22357538 
NEW FH 
Renal 
Hereditary 
leiomyomatosis 
and renal cell 
cancer 
25018647,11865300,2500 
4247 
NEW FLCN 
Renal 
Birt-Hogg-Dube 
syndrome 
12204536,20301695 
GALNT12 
O-glycosylation Colon 
19617566,22461326 
GEN1 
Double stranded 
break repair 
Breast 
2052659 
GREM1 
BMP antagonist Colon 
Hereditary 
mixed polyposis 
syndrome 
22561515 
HOXB13 
transcription 
factor 
Prostate 
22236224 
MEN1 
Gene expression 
regulation 
Endocrine 
Multiple 
endocrine 
neoplasia type 1 
9215689 
MLH1 
Mismatch DNA 
repair 
Colon, Ovarian, 
Endometrial 
Lynch syndrome 20301390 
MRE11A 
Double stranded 
break repair 
Breast 
Ataxia- 
telangiectasia- 
like disorder 
(recessive) 
10612394,19383352 
MSH2 
(+EPCAM) 
Mismatch DNA 
repair 
Colon, Ovarian, 
Endometrial 
Lynch syndrome 20301390 
MSH6 
Mismatch DNA Colon, 
Lynch syndrome 20301390 

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repair 
Endometrial 
MUTYH 
DNA repair 
Colon 
(homozygotes) 
MUTYH- 
associated 
polyposis 
20301519,21952991 
NBN 
Double stranded 
break repair 
Breast 
Nijmegen 
breakage 
syndrome 
(recessive) 
15185344,9590180 
NEW NF1 
Optic Glioma, 
Peripheral Nerve 
Sheath, Breast 
Neurofibromato 
sis 
2114220,23165953,20301 
288 
PALB2 
Fanconi/BRCA Breast, 
Pancreatic 
Fanconi 
anaemia FA-N 
(recessive) 
17200668,17200671,2509 
9575 
NEW PALLD 
Pancreatic 
Familial 
pancreatic 
cancer 
17194196 
PIK3CA 
AKT signaling Breast, Thyroid 
Cowden-like 
22729224,23246288 
PMS2 
Mismatch DNA 
repair 
Colon, 
Endometrial 
Lynch syndrome 20301390 
POLD1 
DNA 
Polymerase 
Colon, 
Endometrial 
Familial 
polyposis, 
colorectal 
cancer 
23263490,23770608 
POLE 
DNA 
Polymerase 
Colon 
Familial 
polyposis, 
colorectal 
cancer 
23263490 
NEW POT1 
Brain, Melanoma 
Familial 
melanoma and 
brain cancer 
25482530,24686849 
NEW 
PRKAR1A 
Endocrine 
Carney complex 
(recessive) 
4010501 
PRSS1 
Digestion 
(Trypsin 1) 
Pancreatic 
Pancreatitis 
22379635 
NEW PTCH1 
Basal cell 
carcinoma, 
PNET 
Nevoid basal 
cell-carcinoma 
syndrome 
8681379,8658145,203013 
30 
PTEN 
PI3K/MAPK 
Signaling 
Breast 
Cowden 
syndrome 
20301661 
RAD51B 
Double stranded Unknown 
24139550 

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break repair 
RAD51C 
Fanconi/BRCA Ovarian, Breast 
Fanconi 
anaemia FA-O 
(recessive) 
22006311,22538716 
RAD51D 
Fanconi/BRCA Ovarian, Breast 
Fanconi 
anaemia 
(recessive) 
21822267,22415235 
NEW RB1 
Retinoblastoma, 
Sarcoma, 
Melanoma 
Hereditary 
retinoblastoma 
25621664,22355046,2030 
1625 
RET 
Receptor 
Tyrosine Kinase Endocrine 
Multiple 
endocrine 
neoplasia type 2 
20301434 
NEW RINT1 
Breast, Colon 
25050558 
NEW RPS20 
Colon 
24941021 
SDHB 
Succinate 
dehydrogenase 
complex 
Pheochromocyto 
ma, 
Paraganglioma 
Hereditary 
paraganglioma- 
pheochromoctyo 
ma 
11404820 
SDHC 
Succinate 
dehydrogenase 
complex 
Pheochromocyto 
ma, 
Paraganglioma 
Hereditary 
paraganglioma- 
pheochromoctyo 
ma 
11062460 
SDHD 
Succinate 
dehydrogenase 
complex 
Pheochromocyto 
ma, 
Paraganglioma 
Hereditary 
paraganglioma- 
pheochromoctyo 
ma 
10657297 
SLX4 
Fanconi/BRCA Unknown 
Fanconi 
anaemia 
(recessive) 
23840564 
SMAD4 
TGF-beta 
signaling 
Colon 
Juvenile 
polyposis 
20301642 
NEW 
SMARCA4 
Ovarian 
24658002 
STK11 
Cell Cycle/p53 
regulation 
Breast, 
Pancreatic 
Peutz-Jeghers 
syndrome 
20301443 
TP53 
Cell growth 
Breast, Ovarian 
Li-Fraumeni 
syndrome 
22006311,20301488 
VHL 
p53 regulation 
Kidney, 
Neuroendocrine 
von Hippel- 
Lindau 
syndrome 
20301636 

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XRCC2 
Double stranded 
break repair 
Breast 
Fanconi 
anaemia 
(recessive) 
22464251,22232082 
 
*Only the most commonly associated cancer types are listed. A more detailed description of 
cancer risk for some BROCA genes can be found at GeneReviews. 

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APPENDIX D: SOP340507 FOR TUMOR FROZEN NEEDLE BIOPSY SPECIMEN 
COLLECTION AND HANDLING 

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APPENDIX E: SOP340522 TUMOR FROZEN NEEDLE BIOPSY PREPARATION FOR 
THE ΓH2AX IFA 

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APPENDIX F: PREPARATION OF THU FOR PHARMACOKINETIC STUDIES 
 
Prepare a stock solution of tetrahydrouridine (THU) at 10 mg/mL (may be frozen). 
 
THU can be added to Vacutainer tubes up to several days in advance without causing significant 
loss of vacuum. Using a 3/10 cc insulin syringe or other similar sized syringe with a fine needle, 
draw up 10 μL of the THU solution for each mL of blood to be drawn and transfer it to a 
heparinized Vacutainer tube (cat # 366667) by piercing the stopper. Do not draw up THU 
solution for more than one tube at a time. You will not be able to control the volume of THU 
solution that leaves the needle, as it is sucked out by the vacuum. Because of the fine needle, 
you will not lose the vacuum (apart from the volume added) in the collection tube.