Clinical trial NCT02567409
Conditions: Metastatic Bladder Urothelial Carcinoma Metastatic Renal Pelvis and Ureter Urothelial Carcinoma Metastatic Ureter Urothelial Carcinoma Stage IV Bladder Urothelial Carcinoma AJCC v7
Sponsor: National Cancer Institute (NCI)
Start date: 2017-01-31; Completion date: 2023-04-25
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well cisplatin and gemcitabine hydrochloride with or without berzosertib works in treating patients with urothelial cancer that has spread to other places in the body (metastatic). Drugs used in chemotherapy, such as cisplatin and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Berzosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if cisplatin and gemcitabine hydrochloride work better alone or with berzosertib in treating patients with urothelial cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine if the addition of berzosertib (M6620 \[VX-970\]) to cisplatin/gemcitabine hydrochloride (gemcitabine) improves progression-free survival (PFS) relative to cisplatin/gemcitabine alone.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative to cisplatin/gemcitabine alone.

II. To compare tumor response rate with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative to cisplatin/gemcitabine alone.

III. To compare safety with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative to cisplatin/gemcitabine alone.

IV. To assess the role of p53 status in predicting response to M6620 (VX-970)-based therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8, and cisplatin IV over 60 minutes on day 1. Patients also receive berzosertib IV over 60 minutes on days 2 and 9. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive gemcitabine hydrochloride and cisplatin as in Arm A.

After completion of study treatment, patients are followed up to 36 months.

Arms: arm 1: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and cisplatin IV over 60 minutes on day 1. Patients also receive berzosertib IV over 60 minutes on days 2 and 9. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive gemcitabine hydrochloride and cisplatin as in Arm A.
Interventions: intervention 1: Berzosertib intervention 2: Cisplatin intervention 3: Gemcitabine Hydrochloride
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
i 
SUMMARY OF CHANGES 
 
Date: 
 
August 25, 2020 
Document: 
NCI Protocol #9947, PhII-135: “A Randomized Phase 2 Trial of 
Cisplatin/Gemcitabine with or without M6620 (VX-970) in Metastatic 
Urothelial Carcinoma.” 
Note: 
The following is a Summary of Changes between the 6.4.19 and 8.25.20 
versions of protocol 
 
 
Section 
Description of Change (v. 6.4.19 and v. 8.25.20) 
Face Page 
Changed protocol version and headers to August 25, 2020.   
 
Updated participating sites to include CATCHUP / Creating Access to Targeted Cancer 
Therapy for Underserved Populations.   


1 
NCI Protocol #: 
9947 
 
Local Protocol #: 
PhII-135 
 
ClinicalTrials.gov Identifier:   NCT02567409 
 
TITLE:  A Randomized Phase 2 Trial of Cisplatin/Gemcitabine with or without M6620 (VX-
970) in Metastatic Urothelial Carcinoma 
 
 
Corresponding Organization: LAO-CA043 / City of Hope Comprehensive Cancer Center 
LAO 
 
 
California Cancer Consortium Data Coordinating Center 
 
 
City of Hope National Medical Center 
 
 
1500 E. Duarte Road, Duarte, California 91010 
 
 
Phone:  626-256-HOPE(4673), extension 65928 
 
 
Fax:      626-256-8654 
 
Email:  ccc@coh.org 
 
Principal Investigator: 
Sumanta Pal, MD 
 
1500 E. Duarte Road 
 
Duarte, California 91010 
 
Phone:  626-256-4673 
 
Fax:      (626) 301-8233 
 
Email:  spal@coh.org 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Opportunity Program 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
 


NCI Protocol #: 9947 
Version Date: August 25, 2020 
 
2 
 
 
 
Statisticians: 
Susan Groshen, PhD  
USC / Norris Comprehensive Cancer Center 
1441 Eastlake Ave. Rm 3419 
Los Angeles, CA  90033 
Telephone:  323-865 0375 
Fax:  323-865 0133 
E-mail:  groshen@usc.edu  
 
Paul Frankel, PhD 
City of Hope  
1500 E. Duarte Rd 
Duarte, CA 91010 
Telephone:  626-359-8111 x85265 
E-mail:  pfrankel@coh.org  
 
 
NCI-Supplied Agent:  M6620 (VX-970) (NSC 780162) 
 
Other Agent(s):   
Cisplatin (Platinol) (NSC# 119875) – commercial supply 
Gemcitabine (Gemzar) (NSC# 613327) – commercial supply 
 
IND #:   
 
IND Sponsor:  DCTD, NCI  
 
Protocol Type / Version # / Version Date: 
August 24, 2015  
 
Initial Protocol 
 
 
 
 
October 19, 2015  
 
Consensus Review 
 
 
 
 
November 9, 2015 
 
Follow Up Review 
 
 
 
 
December 9, 2015  
 
Amendment 
 
 
 
 
April 14, 2016  
 
 
Amendment (FDA) 
 
 
 
 
April 28, 2016  
 
 
Follow Up Review 
 
 
 
 
July 7, 2016 
 
 
 
CIRB Stipulations 
 
 
 
     
      August 22, 2016             Amendment 
 
 
 
 
      September 28, 2016          Amendment (RRA) 
 
 
 
 
      February 28, 2017             Amendment 
 
 
 
 
      March 9, 2018 
            Amendment 
 
 
 
 
      June 19, 2018 
            Amendment 
 
 
 
 
      June 4, 2019 
            Amendment (RA) 
 
 
 
 
      August 25, 2020             Amendment 


NCI Protocol #: 9947 
Version Date: August 25, 2020 
 
3 
SCHEMA 
 
 
 
* Using dosing established from an ongoing phase I trial (NCT02157792). Dosing of cisplatin 
and gemcitabine are 60 mg/m2 and 875 mg/m2 on day 1 and days 1/8, respectively, of a 21 day 
cycle.  Dosing reflects other RP2 studies employing a CG backbone (e.g., NCT01524991).  
M6620 (VX-970) at 90 mg/m2 will be administered on days 2 and 9 of a 21 day cycle.  


NCI Protocol #: 9947 
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TABLE OF CONTENTS 
 
 
SCHEMA 
......................................................................................................................3 
1. 
OBJECTIVES 6 
1.1 
Primary Objectives ...................................................................................................6 
1.2 
Secondary Objectives ...............................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Bladder Cancer .........................................................................................................6 
2.2 
CTEP IND Agent(s) .................................................................................................7 
2.3 
Commercially Available Agents ............................................................................14 
2.4 
Rationale for the combination of cisplatin/gemcitabine with M6620 (VX-
970) in advanced bladder cancer ............................................................................14 
3. 
PATIENT SELECTION ....................................................................................................15 
3.1 
Eligibility Criteria ..................................................................................................15 
3.2 
Exclusion Criteria ..................................................................................................16 
3.3 
Inclusion of Women and Minorities ......................................................................17 
4. 
REGISTRATION PROCEDURES ...................................................................................17 
4.1 
Investigator and Research Associate Registration with CTEP ..............................17 
4.2 
Site Registration .....................................................................................................18 
4.3 
Patient Registration ................................................................................................20 
4.4 
General Guidelines .................................................................................................22 
5. 
TREATMENT PLAN ........................................................................................................22 
5.1 
Agent Administration .............................................................................................22 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................24 
5.3 
Duration of Therapy ...............................................................................................25 
5.4 
Duration of Follow Up ...........................................................................................25 
5.5 
Criteria for Removal from Study ...........................................................................25 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................26 
6.1 
Dose-modifications for treatment-related hematological toxicity .........................26 
6.2 
Dose Modifications for Other Treatment Related Non-Hematological 
Toxicity Secondary to Gemcitabine or Cisplatin ...................................................27 
6.3 
Dose Modifications for M6620 (VX-970) .............................................................28 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................29 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............29 
7.2 
Adverse Event Characteristics ...............................................................................34 
7.3 
Expedited Adverse Event Reporting ......................................................................34 
7.4 
Routine Adverse Event Reporting .........................................................................36 
7.5 
Secondary Malignancy ...........................................................................................37 
7.6 
Second Malignancy ................................................................................................37 


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8. 
PHARMACEUTICAL INFORMATION ..........................................................................37 
8.1 
CTEP IND Agent(s) ...............................................................................................37 
8.2 
Commercial Agent(s) .............................................................................................40 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................43 
9.1 
Laboratory Studies .................................................................................................44 
9.2 
Exploratory Correlative Studies .............................................................................46 
10. 
STUDY CALENDAR .......................................................................................................50 
11. 
MEASUREMENT OF EFFECT........................................................................................52 
11.1 
Response Criteria ...................................................................................................52 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................57 
12.1 
Study Oversight .....................................................................................................57 
12.2 
Data Reporting .......................................................................................................58 
12.3 
CTEP Multicenter Guidelines ................................................................................60 
12.4 
Collaborative Agreements Language .....................................................................60 
13. 
STATISTICAL CONSIDERATIONS...............................................................................61 
13.1 
Study Design/Endpoints.........................................................................................61 
13.2 
Sample Size/Accrual Rate ......................................................................................62 
13.3 
Study Monitoring and Interim Analysis ................................................................62 
13.4 
Stratification Factors ..............................................................................................63 
13.5 
Analysis of Results ................................................................................................64 
13.6 
Reporting and Exclusions ......................................................................................65 
14. 
CCC POLICIES FOR MONITORING CONSORTIUM TRIALS ...................................65 
14.1 
Oversight ................................................................................................................66 
REFERENCES 
....................................................................................................................68 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................71 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT & WALLET  CARD ..72 
APPENDIX C 
COCKROFT-GAULT, MDRD AND CKD-EPI FORMULAS ................74 
APPENDIX D 
SPECIMEN COLLECTION FOR PHARMACOKINETIC STUDIES ....75 
APPENDIX E 
SUPPORTIVE CARE GUIDELINES FOR M6620 (VX-970) .................78 
 
 
 


NCI Protocol #: 9947 
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6 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To determine if the addition of M6620 (VX-970) to cisplatin/gemcitabine improves PFS 
relative to cisplatin/gemcitabine alone. 
 
1.2 
Secondary Objectives 
 
1.2.1 To compare OS with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative to 
cisplatin/gemcitabine alone 
 
1.2.2 To compare tumor response rate with the addition of M6620 (VX-970) to 
cisplatin/gemcitabine relative to cisplatin/gemcitabine alone  
 
1.2.3 To compare safety with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative 
to cisplatin/gemcitabine alone  
 
1.2.4 To assess the role of p53 status in predicting response to M6620 (VX-970)-based therapy 
 
 
2. BACKGROUND 
 
2.1 
Bladder Cancer 
 
Metastatic urothelial carcinoma (MUC) patients have a median overall survival of approximately 
15 months, and accounted for an estimated 15,580 deaths in the United States in 2014 (Abida et al 
, 2015). The use of platinating agents in treating urothelial carcinomas has been well-documented 
in the literature for over 30 years (Yagoda et al 1976). Previously, the combination methotrexate, 
vinblastine (Adriamycin) and cisplatin (MVAC) was the standard first-line treatment for MUC. 
More recently, combination gemcitabine and cisplatin (GC) has become a standard first-line 
treatment for MUC, because it appears to have similar efficacy as MVAC and may be less 
myelosuppressive (Roberts et al 2006). Some efforts have been made to build on GC through the 
addition of targeted agents (e.g., cetuximab or bevacizumab) (Grivas et al 2012; Hahn et al 2011), 
but prospective evaluations have shown little benefit with those novel combinations. For patients 
“unfit” for cisplatin, there are data to support carboplatin-based regimens as a first-line approach. 
In all others, cisplatin with gemcitabine remains a mainstay of treatment (Roberts et al 2006).   
 
ATR and DNA Damage response 
The DNA-damage response (DDR) is a multicomplex network of signaling pathways involved in 
surveillance and repair of DNA damage and transient cell cycle arrest to ensure genomic stability 
and cell viability (Fokas et al., 2014; Weber and Ryan, 2015; Zeman and Cimprich, 2014).  
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., 


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cytotoxic chemotherapy, ultraviolet light, ionizing radiation (IR), or hypoxia (Fokas et al., 2014; 
Pitts et al., 2014; Yan et al., 2014).  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 (Zeman and Cimprich, 2014).  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 (Fokas et al., 2014; Pitts et al., 
2014).  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 1,2.  The 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 (Fokas et al., 
2014).  Upon detecting DSBs, ATM activates CHK2, which controls p53-dependent G1-phase 
arrest.  Unlike normal cells, cancer cells are often deficient in ATM 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 (Reaper et al., 2011; Fokas 
et al., 2014).  Therefore, in tumor cells with defective ATM signaling, 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 which 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 (Fokas et al., 2014; Weber and Ryan, 2015).  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.   
 
2.2 
CTEP IND Agent(s) 
 
2.2.1 M6620 (VX-970) 
 
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) (Fokas et al., 
2012; Investigator’s Brochure 2015).  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) (Fokas et al., 2012).  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 


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8 
kinases (Ki>15 nM), and >25-fold higher for FLT4 (Ki=8 nM) than its Ki for ATR (Investigator’s 
Brochure, 2015).  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) (Fokas et al., 2012).  
 
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 (Fokas et al., 2012; Hall et al., 2014; Investigator’s 
Brochure, 2015).  In the presence of DNA damage, primarily DSBs, histone H2AX is 
phosphorylated at serine 139 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.) (Kuo and Yang, 
2008).  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 (White et 
al., 2012).  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 (Hall et al., 2014; 
Investigator’s Brochure, 2015).  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) 
(Investigator’s Brochure, 2015).  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.   
 
M6620 (VX-970)-mediated radiosensitivity of pancreatic ductal adenocarcinoma cells was 
associated with inhibition of HR repair (Fokas et al., 2012).  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-mediated homologous recombination (HR) repair of DNA double strand breaks 
(DSBs) and for survival.   
 
 
Nonclinical studies 
 
In vitro antitumor activity 


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9 
 
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) (Investigator’s Brochure, 2015).  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) (Investigator’s Brochure, 2015).  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 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 (Investigator’s Brochure, 2015).  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 3 and (Investigator’s Brochure, 2015).  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 (Hall et al., 2014).  The 
greatest antitumor synergistic effect was demonstrated by 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 (Investigator’s 
Brochure, 2015). 
 
In addition, significant radiosensitization effects by 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 (Fokas et al., 2012).  In addition, 
M6620 (VX-970) profoundly sensitized pancreatic tumor cells to gemcitabine-based 
chemoradiation. 
 
Impact of defective ATM 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 (Hall et al., 2014; Investigator’s Brochure, 2015).  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 


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10 
resulting in cytotoxicity in ATM-null primary skin fibroblasts, but no cytotoxicity was observed 
against wild-type fibroblasts (Investigator’s Brochure, 2015).  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 (Hall et al., 2014).  Although not 
significant, there was a trend of causality between response and p53 status (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 (Hall et al., 2014; Investigator’s 
Brochure, 2015).  M6620 (VX-970) potentiated antitumor effects of cisplatin, gemcitabine, 
irinotecan, and IR in a dose-dependent as well as dosing 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 (Fokas 
et al., 2012).  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 the dosing-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 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/mg2) will be sufficient to achieve this exposure.   
 


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11 
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 450 (CYP) 
3A4 isoform being the principle 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 (Investigator’s Brochure, 2015).  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 
(Investigator’s Brochure, 2015).  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. 
 
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.   
 


NCI Protocol #: 9947 
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12 
 
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) (Investigator’s Brochure, 2015).  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 (Investigator’s Brochure, 
2015).  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. 
 
Clinical Pharmacokinetics   
 
Clinical PK have been evaluated both in whole blood and plasma (Investigator’s Brochure, 2015).  
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 M6620 (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 dose up to 480 mg/m2. 
 
Clinical Efficacy 
 
Preliminary efficacy data (cut off February 27, 2015) are available for 38 patients treated with 
M6620 (VX-970) in combination with gemcitabine or cisplatin (study 001) and for 11 patients 
treated with single-agent M6620 (VX-970) (study 002) (Investigator’s Brochure, 2015).  Of 29 
evaluable patients (receiving M6620 (VX-970) + gemcitabine, 16 patients had stable disease (SD) 
(5/6, 4/9, and 7/13 patients with NSCLC, CRC, or other cancers, respectively) and 1 patient with 
EBV+ nasopharyngeal cancer demonstrated a 51% tumor reduction corresponding to a partial 
response (PR).  Four of seven evaluable patients receiving M6620 (VX-970) + cisplatin 
demonstrated SD.  Among 10 evaluable patients treated with M6620 (VX-970) monotherapy, there 
were 3 SD and 1 PR.  The CRC patient who achieved a PR (80% reduction of the lesion) on 
monotherapy continues on treatment after completing 11 cycles.  
 
Clinical Safety 
 
Preliminary safety data for 38 patients receiving M6620 (VX-970) in combination with 


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13 
gemcitabine or cisplatin (Study 001) and 11 patients receiving M6620 (VX-970) alone (Study 002) 
can be found in Investigator’s Brochure (2015).  No dose-limiting toxicities (DLTs) were observed 
during either 7-14-day or 21-days lead-in period of M6620 (VX-970) monotherapy in Study 001.  
There were no deaths attributable to treatment with M6620 (VX-970) alone.  There were no grade 
3+ AEs; serious AEs (SAEs) were experienced by 2 patients (palpitation, pyrexia, and dyspnea).  
In the combination phase evaluating M6620 (VX-970) + gemcitabine, M6620 (VX-970) was 
administered at 18-140 mg/m2 IV and gemcitabine at 500-875 mg/m2 IV.  Of 27 patients included 
in the DLT analysis, 4 patients (14.8%) experienced 7 DLTs (2 alanine aminotransferase [ALT], 
2 aspartate aminotransferase [AST], 1 alkaline phosphatase, 1 thrombocytopenia, 1 fatigue). A 
total of 16 patients (2 during the M6620 (VX-970) lead-in phase and 14 during the combination 
treatment) experienced serious SAEs; 9 of them were assessed as related to treatment.  The most 
common AEs regardless causality were nausea (65%), vomiting (55%), and fatigue (48%).  In the 
sub-study evaluating M6620 (VX-970) + cisplatin, six patients received M6620 (VX-970) (90-
140 mg/m2) with cisplatin 40 mg/m2.  There were no DLTs and two SAEs (1 patient with 
metastases to CNS treated during the lead-in period and 1 patient with dyspnea), none of which 
were related to treatment.  The most common AEs, regardless of causality, were nausea and 
fatigue, both observed in 4/6 patients (67%).  
 
In the single-agent M6620 (VX-970) study (Study 002), M6620 (VX-970) was administered IV at 
doses ranging from 60-480 mg/m2.  There were no DLTs among 11 patients evaluated for toxicities 
(cut-off February 10, 2015).  One SAE of grade 3 fatigue was classified as possibly related to 
M6620 (VX-970).  The most common AE was fatigue (5/11 patients [46%]); nausea, urinary 
infection, headache, and flushing were observed in 3 patients (28%).   
 
As of April 17, 2015, acute hypersensitivity, reported in 2/66 patients (3.0%) during administering 
M6620 (VX-970), has been identified as an adverse drug reaction for VX 970. 
 
Safety Summary and Guidance for Investigators (Investigator’s Brochure, 2015) 
 
• 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 or port into a large-caliber peripheral vein.  The intravenous infusion 
site should be monitored closely for the development of erythema, induration, purulence, 
tenderness, or warmth. 
 
• Because the drug-interaction profile of M6620 (VX-970) has not been fully characterized, 
caution should be used when co-administering medications with VX 970.  Because M6620 
(VX-970) is primarily metabolized by CYP3A4, concomitant administration with strong 
inhibitors or inducers of CYP3A4 should be avoided. 
 
• Preclinical studies suggested that M6620 (VX-970) causes testicular changes with signs of 
reversibility after the drug discontinuation.  Developmental and reproductive toxicity 
studies have not been conducted yet.  Therefore, patients should take stringent measures to 


NCI Protocol #: 9947 
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14 
avoid fathering or bearing children while on study drug and for 6 months after 
discontinuation of M6620 (VX-970).   
 
2.3 
Commercially Available Agents 
 
The current protocol will use the combination of cisplatin and gemcitabine as a standard of care 
regimen, and patients will be treated with these drugs alone or in combination with M6620 (VX-
970) (as subsequently discussed).  Cisplatin is a platinating agent which works through the 
formation of monoadducts with cellular DNA.  Cisplatin reacts preferentially with the N7 position 
of guanine.  Interstrand cross links formed by a multiple monoadducts ultimately result in 
cumulative DNA damage and cellular death.  Cisplatin is principally renally excreted.  In contrast 
to cisplatin, gemcitabine is an antimetabolite. Gemcitabine requires a nuclear transporter for 
intracellular accumulation.  Once in the cell, gemcitabine is phosphorylated to 2,2-
difluorodeoxycytidine-phosphate, and this moiety inhibits ribonucleotide reductase.  As a 
consequence, pools of deoxynucleotide triphosphates occur and subsequent cell death is 
encountered.  The combination of cisplatin and gemcitabine was established as a standard in 
advanced bladder cancer through a randomized, phase III study comparing the regimen to the 
aforementioned 4 drug regimen, MVAC (Robert et al Ann Oncol 2006)  In total, the study included 
405 patients, with 203 randomized to cisplatin/gemcitabine and 202 randomized to MVAC.  
Overall survival was similar in both arms, with a median survival of 14.0 months with 
cisplatin/gemcitabine and 15.2 months in the MVAC arm (P=0.66).  Median PFS was 7.7 months 
with cisplatin/gemcitabine and 8.3 months with MVAC.  Several prognostic factors were noted in 
this study which correlated with overall survival.  These included performance status (>70), TNM 
stage (M0 v M1), low/normal alkaline phosphatase expression, number of sites of disease < 3, and 
the absence of visceral metastases.  Ultimately, the toxicity profile of cisplatin/gemcitabine 
appeared to be more favorable, particularly from the standpoint of a lesser incidence of neutropenic 
fever and sepsis. Thus, most modern trials of first-line therapy for advanced urothelial cancer 
utilized cisplatin/gemcitabine as a base.   
 
2.4 
Rationale for the combination of cisplatin/gemcitabine with M6620 (VX-970) in 
advanced bladder cancer  
 
It is hypothesized that M6620 (VX-970) may improve 
the efficacy of cisplatin and gemcitabine.  As previously 
described (see Section 2.1), cisplatin/gemcitabine 
represents a standard first-line regimen for metastatic 
urothelial carcinoma.   
 
Data supplied by Vertex Pharmaceuticals suggests that 
M6620 (VX-970) appears to have in vivo synergy with 
cisplatin; Figure 1a outlines the activity of M6620 (VX-
970) with cisplatin in a cisplatin-resistant xenograft, 
while Figure 1b reflects the synergy of cisplatin with 
M6620 (VX-970) in a non-small cell lung cancer PDX 
model.  In the context of bladder cancer, inhibition of 
Chk1 (a downstream mediator of ATR) may augment the 
 
 
Figure 2. Synergy of M6620 (VX-970) in combination with 
multiple DNA damaging agents in a panel of 10 bladder cancer 
cell lines. Figure legend:  The blue line indicates no interaction 
between the specified agent and M6620 (VX-970) (additivity). 
The orange line indicates synergy (Sum of AUC synergy of 7.5).  
Figure legend:  The blue line indicates no interaction between 
the specified agent and M6620 (VX-970) (additivity). The 
orange line indicates synergy (Sum of AUC synergy of 7.5).  
 


NCI Protocol #: 9947 
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15 
activity of gemcitabine in the TCC-sup urothelial cancer cell line. (Wang et al 2014)  Notably, this 
synergy is optimal when M6620 (VX-970) is 
administered 24 hours after cisplatin or gemcitabine in 
cellular models (Vertex Pharmaceuticals; data on file.) 
 
Furthermore, Vertex Pharmaceuticals evaluated the 
activity of M6620 (VX-970) in combination with 
carboplatin, cisplatin, and gemcitabine in a panel of 10 
bladder cancer cell lines.  Synergy or antagonism was 
calculated using the sum of AUC difference for each 
combination in each cell line.  Synergy (AUC of greater 
than 7.5) was seen when M6620 (VX-970) was 
combined with carboplatin (in 5/10 lines), cisplatin (in 
7/10 lines), and gemcitabine (in 3/10 lines). In the rest 
of the cell lines tested, additivity was observed. These 
results are summarized in Figure 2. (data on file, Vertex 
Pharmaceuticals) 
 
Collectively, these data provide rationale to investigate 
cisplatin and gemcitabine in combination with M6620 
(VX-970) in metastatic urothelial carcinoma.  
This protocol proposes a randomized, phase II study comparing cisplatin and gemcitabine with 
M6620 (VX-970) to cisplatin and gemcitabine alone.  A phase I trial is evaluating the M6620 (VX-
970) monotherapy (NCT02157792).  Integrated in this phase I experience is a dose escalation 
portion for the combination of M6620 (VX-970) with gemcitabine, and a further dose escalation 
of the combination of cisplatin, gemcitabine and M6620 (VX-970).  It has been hypothesized that 
M6620 (VX-970) may optimally synergize with cytotoxic therapy if delivered in a latent fashion 
– therefore, this current study will evaluate M6620 (VX-970) one day following cytotoxic 
treatment (i.e., on days 2 and 9 on a conventional 21 day cycle of cisplatin with gemcitabine). 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed metastatic urothelial 
carcinoma.  Urothelial cancer derived from the bladder, ureter or upper tract is permitted.  
 
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 must have access to archival tumor tissue for proposed correlative studies.  These 
may be derived from TURBT, cystectomy, or biopsy.  If archival tissue is not available for 
proposed correlatives, patients may be enrolled at the discretion of the study PI (SKP).  


NCI Protocol #: 9947 
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16 
 
3.1.4 No prior cytotoxic chemotherapy for metastatic disease. Prior immunotherapy is permitted.  
 
3.1.5 At least 12 months have elapsed since platinum-based peri-operative treatment. 
 
3.1.6 Age ≥18 years.   
 
Because no dosing or adverse event data are currently available on the use of M6620 (VX-
970) in combination with cisplatin and gemcitabine in patients <18 years of age, children 
are excluded from this study, but will be eligible for future pediatric trials. 
 
3.1.7 Karnofsky ≥70% (ECOG performance status 0-1, see Appendix A). 
 
3.1.8 Life expectancy of greater than 3 months  
 
3.1.9 Patients must have normal organ and marrow function as defined below: 
 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
within institutional upper limit of normal 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
creatinine clearance 
≥50 mL/min by either measured (using the Cockcroft-
Gault, MDRD or CKD-EPI formula) or calculated 
clearance (i.e. GFR)(See Appendix C for formulas) 
 
3.1.10 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 
and men must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study participation.  Should 
a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.  Men 
treated or enrolled on this protocol must also agree to use adequate contraception prior to 
the study, for the duration of study participation, and 6 months after completion of M6620 
(VX-970) administration. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Radiotherapy within 4 weeks of protocol therapy.  
 
3.2.2 Patients who are receiving any other investigational agents. 
 


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17 
3.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to M6620 (VX-970), cisplatin, or gemcitabine. 
 
3.2.4 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 medications 
need to be prescribed or if the patient is considering a new over-the-counter medicine or 
herbal product. 
 
3.2.5 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.6 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 may also 
apply to other agents used in this study. 
 
3.2.7 Patients with ≥ Grade 2 neuropathy.  
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-defined 
clinical research unless a clear and compelling rationale and justification establishes to the 
satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate with 
respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of childbearing 
potential should not be routinely excluded from participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 


NCI Protocol #: 9947 
Version Date: August 25, 2020 
 
18 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
 
Documentation Required 
IVR 
NPIVR AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR 
Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 


NCI Protocol #: 9947 
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19 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the CTSU 
Regulatory Support System (RSS) uses extensive data to make a determination of whether a site 
has fulfilled all regulatory criteria including but not limited to the following: 
• An active Federal Wide 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 NCI protocol # 9947 protocol page 
located on the CTSU Web site.  Permission to view and download this protocol is restricted 
and is based on person and site roster data housed in the CTSU RSS.  To participate, 
Investigators and Associates must be associated with the Corresponding or Participating 
protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen. 
• Either enter the protocol # in the search field at the top of the protocol tree, or  
• Click on the By Lead Organization folder to expand, then select by LAO-CA043, 
and protocol #9947. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements For 9947 Site Registration: 
 


NCI Protocol #: 9947 
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20 
• 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) 
• Local informed consent document  
 
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. 
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
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 to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 


NCI Protocol #: 9947 
Version Date: August 25, 2020 
 
21 
4.3.1 OPEN / IWRS 
 
Patient enrollment and randomization will be facilitated using the Oncology Patient 
Enrollment Network (OPEN).  OPEN is a web-based registration system available to users 
on a 24/7 basis.  It is integrated with the CTSU Enterprise System for regulatory and roster 
data interchange and with the Theradex Interactive Web Response System (IWRS) for 
retrieval of patient registration/randomization assignment.  Patient enrollment data entered 
by Registrars in OPEN / IWRS will automatically transfer to the NCI’s clinical data 
management system, Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is available 
and secured for the patient before completing an enrollment. 
 
• Site staff with the appropriate roles will reserve slots using IWRS (https://open.ctsu.org/).  
• City of Hope Cancer Center will receive notification via the IWRS when a slot has been 
reserved. An email will be sent from the City of Hope Cancer Center to the site requesting 
further information such as: the patient initials, tumor type and potential start date. The 
spot will show as ‘pending approval’ in the system until the site sends a REGISTRATION 
FORM/ELIGIBILITY CHECKLIST (see CTSU website) accompanied with the signed 
consent, baseline labs, pathology report, CT/x-ray reports to the City of Hope Cancer 
Center at ccc@coh.org for review and confirmation of eligibility.  
• Once the Registration has been reviewed, the City of Hope Cancer Center will either 
approve or disapprove the request depending on confirmation of patient eligibility. If 
approved, the City of Hope Cancer Centre will update the spot to ‘reserved’ in IWRS.  
• The site can now enroll the patient into the study in OPEN  
* At the time of registration the treatment arm will be randomly assigned  
 
The OPEN system will provide the site with a printable confirmation of registration and 
the randomly assigned treatment information.  Please print this confirmation for your 
records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding or 
Participating Organization roster with the role of Registrar.  Registrars must hold a 
minimum of an AP registration type.  If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL.  (Note: A 
DTL is NOT required for this study.) 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 


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22 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes. Site 
staff should use the registration forms provided on the CTSU web site as a tool to 
verify eligibility. 
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is 
available 
on 
the 
Theradex 
website:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks 
are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Eligible patients will be randomized on either on Arm A or Arm B in OPEN;  in order for 
randomization to be completed, the following information will be required: (1) KPS and (2) 
visceral metastases (present or absent). 
 
Arm A – Cisplatin/Gemcitabine with M6620 (VX-970) 
 
Arm B – Cisplatin and Gemcitabine  
 


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23 
Please note that the dosing for the combination of cisplatin/gemcitabine with M6620 (VX-970) 
will utilized the recommended phase 2 dose (RP2D) from an ongoing phase I trial combining these 
agents (NCT02157792). The preferred dosing of cisplatin and gemcitabine are 60 mg/m2 and 875 
mg/m2 on day 1 and days 1/8, respectively, of a 21 day cycle.  This dosing regimen reflects other 
randomized, phase II studies employing a CG backbone (e.g., NCT01524991).  M6620 (VX-970) 
at 90 mg/m2 will be administered on days 2 and 9 of the 21 day cycle intravenously, as follows:  
 
 
Arm A – Cisplatin/Gemcitabine with M6620 (VX-970) Dosing Table 
Agent 
Route 
Dose 
Administration Frequency * 
(± 3 days) 
Cycle 
Length 
# 
Cycles 
M6620 (VX-
970) 
IV 
90 mg/m2 
(in D5W to a 
final 
concentration 
between 0.075 
mg/ml to 1 
mg/ml) 
Over 1 hour 
Day 2, 9 
21 days 
1-6 
Gemcitabine 
IV 
875 mg/m2  
(per institutional 
guidelines) 
Over 30 
minutes 
according to 
institutional 
guidelines 
Day 1, 8 
Cisplatin 
IV 
60 mg/m2  
(per institutional 
guidelines) 
As per 
institutional 
guidelines 
Day 1 
 
 
Arm B – Cisplatin/Gemcitabine Dosing Table 
Agent 
Route 
Dose 
Administration Frequency * 
(± 3 days) 
Cycle 
Length 
# 
Cycles 
Gemcitabine 
IV 
1000 mg/m2  
(per institutional 
guidelines) 
Over 30 
minutes 
according to 
institutional 
guidelines 
Day 1, 8 
21 days 
1-6 
Cisplatin 
IV 
70 mg/m2  
(per institutional 
guidelines) 
As per 
institutional 
guidelines 
Day 1 
 
Note: * Infusions may be given ±3 days for reasons such as observed holidays, inclement weather, 
scheduling conflicts, etc. It should be clearly documented in patient’s chart and case report forms. 
 
 


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24 
5.1.1 M6620 (VX-970) 
 
Prophylactic or supportive care regimens will be administered in accordance with those 
established in NCT02157792. See Appendix E. 
 
M6620 (VX-970) should not come in contact with 0.9% Sodium Chloride due to 
incompatibility.  5% dextrose in water solution must be used for IV line priming and 
flushing.  Infuse using an infusion set containing low-sorption, or non-PVC, DEHP-free 
tubing and an in-line 0.2 micron filter. 
 
5.1.2 Cisplatin 
 
The antiemetic regimen is at the discretion of the treating physician and according to 
institutional standards.  Hydration before and after cisplatin should be rendered as per 
institutional standards (including use of mannitol and addition of sodium, potassium or 
other electrolytes to intravenous fluids).   
 
5.1.3 Gemcitabine 
 
No pre-medications are required for gemcitabine therapy.  
 
 
5.1.4 Growth factor support  
 
Prophylactic use of filgrastim or pegfilgrastim on day 9 of each cycle is encouraged but 
not mandated.  If patients develop neutropenia or other neutropenic complications and 
remain on protocol-based treatment, then filgrastim or pegfilgrastim use beginning on day 
9 of each cycle is mandated. Dosing of these agents should follow institutional policies.  
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
M6620 (VX-970) is metabolized by cytochrome P450 (CYP) 3A4 isoenzyme (CYP3A4); 
exposure to M6620 (VX-970) may be affected by concomitantly administered drugs that are strong 
inhibitors or inducers of CYP3A4.  Because of the potential for drug interactions through 
CYP3A4, the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential for drug interactions.  The study team should 
check a frequently-updated medical reference for a list of drugs to avoid or minimize use of.  
Appendix B (Patient Drug Information Handout and Wallet Card) should be provided to patients. 
 
M6620 (VX-970) is a moderate inhibitor of P-gp and BCRP. Use caution when administered with 
substrates of P-gp and BCRP. 
 
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.   
 


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25 
To minimize the possibility of phlebitis, M6620 (VX-970) should be administered through a large-
bore catheter or port into a large-caliber peripheral vein.  The intravenous infusion site should be 
monitored closely for the development of erythema, induration, purulence, tenderness, or warmth. 
 
In the event of infusion reaction, the investigator may use dexamethasone 8 mg (or equivalent) 
intravenous 30 minutes prior to infusion and/or diphenhydramine 25 mg intravenous or oral 30 
minutes prior to infusion.   
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 6 cycles or 
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, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
• 
Pregnancy 
 
5.4 
Duration of Follow Up 
 
Patients will be followed for up to 36 months after removal from protocol therapy or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
For patients who have not progressed at the time that they are removed from treatment will be 
followed for progression;  for those who begin another treatment prior to progression, the  type of 
treatment will be recorded, as well as the time to 1st progression. 
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria apply: 
• 
Follow-up for 36 months after removal from protocol therapy 
• 
Withdrawal of consent for further follow-up 
• 
Death  
 
The reason for protocol therapy termination and study removal and the dates the patient was 
removed must be documented in the Case Report Form.   
 


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26 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose-modifications for treatment-related hematological toxicity 
 
Dose modifications for Day 1 Treatment (Cycle 2 through Cycle 6) 
 
The following dose modifications will be based on blood counts within 3 days prior to Day 
1 of each cycle of therapy. 
 
ANC 
 
Platelets 
Cisplatin dose 
Lowest 
gemcitabine 
dose in prior 
cycle 
Day 1 dose 
of 
gemcitabine 
≥1.5K/
mm3 
And ≥ 100 
K/mm3 
Continue dose of 
cisplatin from prior 
cycle (eg, if no prior 
dose reductions, 
continue at 60 
mg/m2) 
1000 mg/m2 
1000 mg/m2 
≥ 
1.5K/m
m3 
And ≥ 100 
K/mm3 
875 mg/m2 
875 mg/m2 
≥ 
1.5K/m
m3 
And ≥ 100 
K/mm3 
600 mg/m2 
600 mg/m2 
<1.5K/
mm3 
Or 
<100 
K/mm3 
*Hold and recheck in 
1 week 
Any 
*Hold and 
recheck 
in 1 week 
*Once ANC ≥ 1500 and platelets ≥ 100,000, resume therapy with gemcitabine 
reduced by 1 dose level. If gemcitabine has already been reduced by 1 dose level, 
discuss further dose reduction with principal investigator. Granulocyte colony 
stimulating factors may be used at the discretion of the treating physician; however, 
growth factors should be not used during cycle #1 or in lieu of recommended dose 
reductions. Treatment with M6620 (VX-970) will also be HELD until patients meet 
criteria to resume dosing with gemcitabine and cisplatin.   
 
 
 


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27 
Dose modifications for Day 8 Treatment (any cycle) 
 
The following dose modifications of gemcitabine will be based on blood counts within 3 
days prior to day 8 of each cycle of therapy. 
 
ANC 
 
Platelets 
if Day 1 dose 
level of 
gemcitabine 
was: 
then Day 8 dose 
level of 
gemcitabine will 
be: 
≥ 
1.5K/mm3 
And 
≥ 100 K/mm3 
1000 mg/m2 
1000 mg/m2 
≥1.5K/mm3 And 
≥ 100,000 
875 mg/m2 
875 mg/m2 
≥ 
1.5K/mm3 
And 
≥ 100 K/mm3 
600 mg/m2 
600 mg/m2 
1.0K/mm3-
1.4 K/mm3 
And 
≥ 100 K/mm3 
1000 mg/m2 
875 mg/m2 
1.0K/mm3-
1.4 K/mm3 
And 
≥ 100 K/mm3 
875 mg/m2 
600 mg/m2 
<1.0 
K/mm3 
Or 
<100,000 K/mm3 Any 
Hold and recheck 
in 1 week* 
*Treatment held on Day 8 should not be made up at a later date; resume next cycle as 
scheduled with gemcitabine reduced by 1 dose level.  
 
There should be no dose re-escalation after a dose reduction.  
 
 
Febrile neutropenia 
 
If febrile neutropenia develops in a given cycle, hold gemcitabine, cisplatin, and M6620 
(VX-970) during febrile neutropenia.  
 
NOTE: Doses missed on Days 8 of therapy will not be made up.  
 
Resume gemcitabine and cisplatin at one dose lower than the dose administered in the last 
cycle. This dose should be used for all subsequent cycles. The dose of M6620 (VX-970) 
will be unchanged. Granulocyte colony stimulating factors may be used at the discretion 
of the treating physician. 
 
6.2 
Dose Modifications for Other Treatment Related Non-Hematological Toxicity 
Secondary to Gemcitabine or Cisplatin 
 
Dose reductions for non-hematologic toxicities attributable to gemcitabine or cisplatin 
(with the exception of alopecia or nausea/vomiting not optimally managed with 
antiemetics) are outlined in the table below. Only the drugs felt to be contributing to the 
toxicity per the Treating Physician should be dose reduced. Patients with treatment-related 
nausea that is grade ≥ 2 despite optimal use of antiemetics will be dose reduced by 1 level.  
 


NCI Protocol #: 9947 
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28 
If nonhematologic toxicity occurs mid-cycle, and is attributed to gemcitabine, the Day 8 
gemcitabine dose should be held and resumed with the subsequent cycle as scheduled. 
 
Dose reductions for nonhematologic toxicities 
Nonhematologic toxicity 
Gemcitabine/Cisplatin 
Grade 0-2 
No change 
Grade 3 
Hold until Grade ≤1 and 
resume treatment reduced by 1 
dose level 
Grade 4 
Hold until Grade ≤1 and 
resume treatment reduced by 1 
dose level 
 
 
Dose modifications for gemcitabine and cisplatin for Arm A 
Dose level 
Gemcitabine 
Cisplatin 
Dose level -1 
600 mg/m2 
50 mg/m2 
Dose level -2 
500 mg/m2 
40 mg/m2 
 
 
Dose modifications for gemcitabine and cisplatin for Arm B 
Dose level 
Gemcitabine 
Cisplatin 
Dose level -1 
875 mg/m2 
60 mg/m2 
Dose level -2 
600 mg/m2 
50 mg/m2 
 
Dose re-escalation after a dose reduction for non-hematologic toxicity should not occur 
without discussion with the Study Investigator. 
 
If toxicity is specifically attributable to cisplatin and warrants discontinuation of cisplatin, 
patients may be considered for continuation on treatment with gemcitabine and M6620 
(VX-970) but this must be discussed with the Study Investigator. 
 
Treatment may be delayed for up to 7 days.  If more than 7 days, this must be discussed 
with the Study Investigator.   
 
6.3 
Dose Modifications for M6620 (VX-970) 
 
Dose reductions for toxicities attributable to M6620 (VX-970) (with the exception of 
alopecia or nausea/vomiting not optimally managed with antiemetics) are outlined in the 
table below. Only the drugs felt to be contributing to the toxicity per the Treating Physician 
should be dose reduced. Patients with treatment-related nausea that is grade ≥ 2 despite 
optimal use of antiemetics will be dose reduced by 1 level. 
  
 
 
 


NCI Protocol #: 9947 
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29 
 
 
Dose modifications for M6620 (VX-970) are as follows (acknowledging a starting dose of 
90 mg/m2):  
 
Dose reductions for nonhematologic toxicities 
Nonhematologic toxicity 
M6620 (VX-970) 
Grade 0-2 
No change 
Grade 3 
Hold until Grade ≤1 and 
resume treatment reduced by 1 
dose level 
Grade 4 
Hold until Grade ≤1 and 
resume treatment reduced by 1 
dose level 
 
Dose modifications for M6620 (VX-970) 
Dose level 
M6620 (VX-970) 
Dose level -1 
72 mg/m2 
Dose level -2 
60 mg/m2 
 
 
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(s) (CAEPRs) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text.  The SPEER is a list of events that are protocol-specific 
exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm for further clarification.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the SPEER.  
Report ONLY AEs higher than this grade expeditiously.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
 
7.1.1 CAEPRs for CTEP IND Agent 
 


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30 
7.1.1.1 
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. 
 
Version 1.4, April 30, 20191 
Adverse Events with Possible Relationship to M6620 (VX-970) 
(CTCAE 5.0 Term) 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 Anemia (Gr 3) 
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
 Diarrhea (Gr 2) 
Nausea 
 Nausea (Gr 2) 
Vomiting 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
  
Fatigue 
 Fatigue (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
Urinary tract infection 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS   
Infusion related reaction 
 Infusion related reaction (Gr 2) 
INVESTIGATIONS 
  


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31 
Adverse Events with Possible Relationship to M6620 (VX-970) 
(CTCAE 5.0 Term) 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Alanine aminotransferase increased 
 Alanine aminotransferase increased 
(Gr 2) 
Aspartate aminotransferase increased 
 Aspartate aminotransferase increased 
(Gr 2) 
Blood bilirubin increased 
  
Creatinine increased 
  
Lymphocyte count decreased 
 Lymphocyte count decreased (Gr 2) 
Neutrophil count decreased 
  
Platelet count decreased 
  
White blood cell decreased 
  
METABOLISM AND NUTRITION DISORDERS 
  
Hyperglycemia 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED 
(INCL CYSTS AND POLYPS) 
  
Tumor pain 
  
NERVOUS SYSTEM DISORDERS 
  
Dizziness 
  
Headache 
 Headache (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Pruritus 
  
Rash maculo-papular 
  
VASCULAR DISORDERS 
  
Flushing 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
 
Adverse events reported on M6620 (VX-970, NSC 780162) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that M6620 (VX-970, 
NSC 780162) caused the adverse event: 
 
CARDIAC DISORDERS - Palpitations 
GASTROINTESTINAL DISORDERS - Abdominal pain; Ascites; Colonic obstruction; 
Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; 
Fever 
IMMUNE SYSTEM DISORDERS - Allergic reaction 


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32 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (lower respiratory 
tract infection); Otitis externa; Sepsis; Soft tissue infection 
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  
 
>10%: Cardiovascular: Peripheral edema (20%), edema (13%) Central nervous system: 
Pain (10% to 48%), fever (30% to 41%), somnolence (5% to 11%) Dermatologic: Rash 
(24% to 30%), alopecia (15% to 18%), pruritus (13%) Gastrointestinal: 
Nausea/vomiting (64% to 71%; grades 3/4: 1% to 13%), constipation (10% to 31%), 
diarrhea (19% to 30%), stomatitis (10% to 14%) Hematologic: Anemia (65% to 73%; 
grade 4: 1% to 3%), leukopenia (62% to 71%; grade 4: ≤1%), neutropenia (61% to 
63%; grade 4: 6% to 7%), thrombocytopenia (24% to 47%; grade 4: ≤1%), hemorrhage 
(4% to 17%; grades 3/4: <1% to 2%); myelosuppression is the dose-limiting toxicity 
Hepatic: Transaminases increased (67% to 78%; grades 3/4: 1% to 12%), alkaline 
phosphatase increased (55% to 77%; grades 3/4: 2% to 16%), bilirubin increased (13% 
to 26%; grades 3/4: <1% to 6%) Renal: Proteinuria (10% to 45%; grades 3/4: <1%), 
hematuria (13% to 35%; grades 3/4: <1%), BUN increased (8% to 16%; grades 3/4: 
0%) Respiratory: Dyspnea (6% to 23%) Miscellaneous: Flu-like syndrome (19%), 
infection (8% to 16%; grades 3/4: <1% to 2%)  
 
1% to 10%: Local: Injection site reactions (4%) Neuromuscular & skeletal: Paresthesia 
(2% to 10%) Renal: Creatinine increased (2% to 8%) Respiratory: Bronchospasm 
(<2%) 
 
<1% (Limited to important or life-threatening; reported with single-agent use or with 
combination therapy, all reported rarely): Adult respiratory distress syndrome, 
anaphylactoid reaction, anorexia, arrhythmias, bullous skin eruptions, cellulitis, 


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33 
cerebrovascular accident, CHF, chills, cough, desquamation, diaphoresis, gangrene, 
GGT increased, headache, hemolytic uremic syndrome (HUS), hepatotoxic reaction 
(rare), 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 
 
Please refer the reader to the package insert(s) for the comprehensive list of adverse 
events 
 
7.1.2.2 
Cisplatin  
 
Renal: A dose-related cumulative renal tubular injury can occur.  Adequate hydration 
and diuresis usually minimize the risk.  Salt-wasting nephropathy and/or orthostatic 
hypotension with hyporeninemic hypoaldosteronism can occur in up to 10% of 
patients. 
 
Neurologic:  A dose-related ototoxicity, manifested by high-frequency hearing loss and 
tinnitus, occurs in about 30% of patients.  Paresthesias, decreased vibratory, position, 
and touch sensations are less common, particularly at cumulative doses < 400 mg/m2. 
 
Hematologic:  Mild leukopenia and thrombocytopenia occur in 25-30% of patients but 
is rarely dose limiting. Anemia is less common.  A potentially fatal hemolytic uremic 
syndrome has been reported. 
 
Gastrointestinal:  Severe, dose-limiting nausea and vomiting occur in almost 100% of 
patients unless adequate antiemetic prophylaxis is given. Even with successful 
prophylaxis of acute nausea, a delayed (72-96 hour) reaction may occur, requiring 
additional therapy.  Anorexia and taste changes may also occur. 
 
Hypersensitivity:  Allergic reactions are reported in up to 20% of patients. Symptoms 
include: rash, facial edema, wheezing, hypotension, and tachycardia. Severe 
anaphylaxis is rare. 
 
Extravasation: 
Extravasation can occur with cisplatin administration.  
Treatment should be per institutional policy on extravasation. 
 
Other:  Raynaud’s phenomena and digital ischemia has been described. 
 
Rare complications are alopecia, seizures, loss of taste, allergic reactions and loss of 
muscle or nerve function.  Tetany may occur due to hypomagnesinemia and/or 
hypocalcemia. Other electrolyte disturbances may occur. 
  
At high doses patients have experienced optic neuritis, papilledema, cerebral blindness, 
blurred vision and altered color perception.  Patients have experienced cardiac 
abnormalities, elevated SGOT and rash. Subsequent courses should not be given until 
serum creatinine returns to normal, if elevated.  Audiometric analyses should be 


NCI Protocol #: 9947 
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34 
monitored and courses withheld until auditory acuity is within normal limits.  The 
occurrence of acute leukemia has been reported rarely in patients treated with 
anthracycline/alkylator combination chemotherapy.  Cisplatin can cause fetal harm 
when administered to a pregnant woman.  In mice, cisplatin is teratogenic and 
embryogenic. No information is available on the excretion of this drug in human milk.  
Because many drugs are excreted in human milk and because of the potential for 
serious adverse reactions in nursing infants, it is recommended that nursing be 
discontinued. 
 
Please refer to the approved package labeling for complete toxicity information. 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized until March 31, 2018 for AE reporting.  CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• 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). 
 


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35 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for other 
e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” 
under the system organ class (SOC) “General disorders and administration site conditions.”  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR 
Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse 
Events, whether or not they are considered related to the investigational 
agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 


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36 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to 
the NCI via electronic submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found 
in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 
24 hours of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted 
electronically within 10 calendar days of learning of the AE. 
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 
 
N/A 
 
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. 


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37 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times during 
the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine AE 
reporting in Rave. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is 
not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to describe 
the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE reporting 
unless otherwise specified. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 
 VRT-0768079, MSC2527093A, VX-970NSC 780162 
 
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 


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38 
 
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 
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 


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39 
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. 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by the eligible participating Investigators (or 
their authorized designee) at each participating institution.  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  
If there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study.   
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application.  Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account and the maintenance of an 
“active” account status and a “current” password, and active person registration status.  
For questions about drug orders, transfers, returns, or accountability, call or email PMB 


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40 
anytime.  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 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.gov  
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP/  
CTEP Identity and Access Management (IAM) account:  
https://ctepcore.nci.nih.gov/iam/CTEP IAM account help:  
ctepreghelp@ctep.nci.nih.gov  
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 
 
Drug Name: Gemcitabine 
Other:  1” – Deoxy – 2, 2” – difluorocytidine monohydrochloride, Gemzar, NSC 
#613327 
 
Classification: 
Nucleoside analogue 
 
Action: Gemcitabine is metabolized intracellularly by nucleoside kinases to the active 
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of 


NCI Protocol #: 9947 
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41 
gemcitabine is attributed to a combination of 2 actions of the diphosphate and the 
triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, gemcitabine 
diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the 
reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of 
this enzyme by the diphosphate nucleoside causes a reduction in the concentrations of 
deoxynucleotides, including dCTP. Second, gemcitabine triphosphate competes with 
dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP 
(by the action of the diphosphate) enhances the incorporation of gemcitabine triphosphate 
into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, 
only 1 additional nucleotide is added to the growing DNA strands. After this addition, there 
is inhibition of further DNA synthesis. DNA polymerase epsilon is unable to remove the 
gemcitabine nucleotide and repair the growing DNA strands (masked chain termination). 
 
Availability: Commercially available and FDA approved for pancreatic cancer. Also, 
recently approved for locally unresectable or metastatic non-small cell lung cancer in 
combination with cisplatin. 
 
 
Storage: Unopened vials of Gemzar are stable until the expiration date indicated on the 
package when stored at controlled room temperature 20° to 25°C (68° to 77°F). When 
prepared as directed, Gemzar solutions are stable for 24 hours at controlled room 
temperature 20° to 25°C (68° to 77°F). Discard unused portion. Solutions of reconstituted 
Gemzar should not be refrigerated, as crystallization may occur. 
 
Reconstitution: 
The recommended diluent for reconstitution of Gemzar is 0.9% 
Sodium Chloride Injection without preservatives. Due to solubility considerations, the 
maximum concentration for Gemzar upon reconstitution is 40 mg/mL. Reconstitution at 
concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be 
avoided.  
 
To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200-mg vial or 25 mL 
of 0.9% Sodium Chloride Injection to the 1-g vial. Shake to dissolve. These dilutions each 
yield a gemcitabine concentration of 38 mg/mL which includes accounting for the 
displacement volume of the lyophilized powder (0.26 mL for the 200-mg vial or 1.3 mL 
for the 1-g vial). The total volume upon reconstitution will be 5.26 mL or 26.3 mL, 
respectively. Complete withdrawal of the vial contents will provide 200 mg or 1 g of 
gemcitabine, respectively. The appropriate amount of drug may be administered as 
prepared or further diluted with 0.9% Sodium Chloride Injection to concentrations as low 
as 0.1 mg/mL.  
 
Reconstituted Gemzar is a clear, colorless to light straw-colored solution. After 
reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies 
in the range of 2.7 to 3.3. The solution should be inspected visually for particulate matter 
and discoloration, prior to administration, whenever solution or container permit. If 
particulate matter or discoloration is found, do not administer. Gemzar should be 
administered by intravenous infusion at a dose of 1000 or 875 mg/m2 (depending on Arm) 
over 30 minutes. 


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42 
 
Administration: 
Gemzar should be administered by intravenous infusion over 30 
minutes. 
 
Product description and storage:  Gemcitabine will not be provided by the PMB and 
should be obtained from commercial sources. Gemcitabine is commercially available in 
vials containing either 200 mg or 1 g of gemcitabine HCl (expressed as free base) 
formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 
62.5 mg, respectively) as a sterile lyophilized powder. Hydrochloric acid and/or sodium 
hydroxide may have been added for pH adjustment. The recommended diluent for 
reconstitution of gemcitabine is 0.9% Sodium Chloride Injection without preservatives. 
Due to solubility considerations, the maximum concentration for gemcitabine upon 
reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may 
result in incomplete dissolution, and should be avoided. When prepared as directed, 
gemcitabine solutions are stable for 24 hours at controlled room temperature 20° to 25°C 
(68° to 77°F). Solutions of reconstituted gemcitabine should not be refrigerated, as 
crystallization may occur. Please refer to the commercial package insert for complete drug 
information.  
 
8.2.2 Cisplatin 
 
Drug Name: Cisplatin 
Other: Platinol (NSC-119875); Cis-diamminedichloroplatinum 
 
Classification: 
Aklylating agent 
 
Action: 
Cisplatin forms covalent bonds with nucleophilic sites on guanine present in all 
DNA. As cisplatin is a bifunctional agent, it is able to bind to 2 sites in a DNA strand. This 
results in the formation of inter- and intra- chain cross-linkings, which interferes with 
cellular transcription and replication. Regulatory mechanisms detect the abnormal DNA 
and so activate a chain of responses to try and correct it. This, ultimately, causes cell death 
(apoptosis). 
 
Availability: Cisplatin is commercially available. 
 
 
Storage: Cisplatin Injection is a sterile, multi-dose vial without preservatives. Store at 
15° to 25°C (59° to 77°F). Note: Do not refrigerate. Protect unopened container from light. 
The cisplatin remaining in the amber vial following initial entry is stable for 28 days 
protected from light or for 7 days under fluorescent room light. 
 
Reconstitution: The aqueous solution should be used intravenously only and should be 
administered by IV. Cisplatin is a cytotoxic chemotherapeutic agent. Appropriate 
precautions for hazardous drug handling should be taken during handling, preparation, 
administration and disposal of this agent. As with other potentially toxic compounds, 
caution should be exercised in handling the aqueous solution. Skin reactions associated 
with accidental exposure to cisplatin may occur. The use of gloves is recommended. If 


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43 
cisplatin contacts the skin or mucosa, immediately and thoroughly wash the skin with soap 
and water and flush the mucosa with water. 
 
Administration: Cisplatin will be administered IV according to institutional guidelines. 
 
Hydration 
Hydration for cisplatin can be administered at the discretion of the treating physician and 
according to institutional standards.  
 
Product description and storage:  Cisplatin will not be provided by the PMB and should 
be obtained from commercial sources.  Cis-diamminedichloroplatinum (Platinol or 
cisplatin) is a heavy metal complex and is water soluble. It is a white lyphilized powder 
with a molecular weight of 300.1.  Cisplatin is available as 50mg/50ml and 100mg/100ml 
multi-dose vials. Each ml also contains 9mg sodium chloride. Hydrochloric acid and/or 
sodium hydroxide is added to adjust the pH.   The intact vials may be stored at room 
temperature (15° - 25°C), protected from light, for the lot life indicated on the package.  
Do not refrigerate. The solution may be further diluted in a chloride-containing vehicle 
such as D5NS, NS, or D5-1/2NS (precipitate occurs in D5W) and stored at room 
temperature for up to 24 hours.  Cisplatin should be given immediately after preparation as 
slow intravenous infusion over 60 minutes.  Needles or intravenous sets containing 
aluminum parts that may come in contact with cisplatin (Platinol) should not be used for 
preparation or administration, as a black precipitate is formed within 30 minutes.  Please 
refer to the approved package labeling for complete prescribing and toxicity information. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
The proposed randomized phase II study offers ample opportunity to understand biomarkers of 
response to the combination of cisplatin/gemcitabine with M6620 (VX-970).  Alteration of p53 
will be investigated as a potential biomarker for response.  Cells deficient in p53 may potentially 
rely more heavily on ATR-mediated checkpoint signaling in the face of DNA damage (Reinhardt 
et al 2007).  Data from The Cancer Genome Atlas (TCGA) investigators suggest that p53 genomic 
alterations (either homozygous deletion or mutation) occur in roughly 52% of patients (TCGA 
Investigators 2014).  While previous prospective clinical studies have shown little predictive 
capability of p53 immunohistochemistry, there is preclinical data to suggest that inhibition of the 
ATR pathway may be more active in the setting of p53 mutation (Liu et al 2015).  The same studies 
identify even more potent inhibition in patients with mutations in both p53 and p21.   We therefore 
propose p53 mutation as a post-hoc stratification factor in our study, and we will retrospectively 
assess p21 as well.  ATM, a distinct mediator of double-stranded DNA break repair, and -H2AX, 
a surrogate for DNA damage, will also be explored as putative biomarkers of M6620 (VX-970) 
response (Wang et al Oncogene 2014).  We will develop patient-derived xenograft (PDX) models 
in collaboration with the UC Davis PDX Development and Trial Center (UM54CA233306, C-X 
Chong, PI).  To generate these models, fresh tissue will be collected prior to initiation of therapy 
and at the time of resistance.  In this manner, detailed studies can be performed to better understand 
in vivo the development of ATR-inhibitor resistance. 
Given evidence suggesting the role of ERCC2 mutation in modulating response to platinum-based 
therapies, this phenomenon will be assessed as well (Van Allen et al 2014).  


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44 
Finally, we will obtain limited pharmacokinetic samples in all patients to explore relationships 
between exposure to M6620 (VX-970) (and gemcitabine), and toxicity or efficacy. 
 
9.1 
Integrated Laboratory Studies 
 
9.1.1 Cytidine Deaminase (CDA) phenotype 
 
Cytidine Deaminase (CDA) phenotype will be correlated with gemcitabine PK parameters 
observed. 
 
9.1.1.1 
Collection of Specimens 
Blood samples to be obtained through a peripheral or central line blood draw. Samples should be 
drawn from the opposite arm if infusion is a peripheral infusion. Samples should NOT be drawn 
from the infusion line. 
 
A single serum tube will be collected prior to dosing (NO THU added !!!), (e.g. BD vacutainer 
367812 plastic 13x75 4.0 mL tube). 
 
9.1.1.2 
Handling of Specimens 
-Allow the blood to clot for 30 min at room temperature 
-Centrifuge at 1800 x g for 10 min 
-Freeze 2 serum aliquots at -80 C until shipment on dry-ice / analysis. 
 
9.1.1.3 
Shipping of Specimens 
See Pharmacokinetics section below. 
 
9.1.2 Pharmacokinetics 
 
Gemcitabine PK (D1 and D8, with baseline assessment) will be correlated with toxicity 
observed, and response. 
 
M6620 (VX-970) PK (D0, 2, 4, 9, 11) will be correlated with toxicity observed, and response 
performed, and possibly to add to the present knowledge base of M6620 (VX-970) PK by means 
of incorporation into a population pharmacokinetic model to be developed across studies. 
 
9.1.1.4 
Collection of Specimens 
 
Blood samples to be obtained through a peripheral or central line blood draw. Samples should be 
drawn from the opposite arm if infusion is a peripheral infusion. Samples should NOT be drawn 
from the infusion line. 
 
EDTA Vacutainer tubes shall be prepared by addition of THU solution to prevent ex vivo 
degradation of gemcitabine: 
 
Prepare a stock solution of tetrahydrouridine (THU) at 10 mg/mL (may be frozen for up to a 
year).  THU can be added to Vacutainer tubes up to several days in advance without causing 


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45 
significant loss of vacuum (no more than 7 days, and keep in fridge).  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 1 mL of blood to be drawn and transfer it to a Vacutainer tube 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. 
 
Pre-treatment of cycle 1 (all patients) 
EDTA anti-coagulated blood samples will be obtained at the following timepoints: 
 
At baseline, prior to infusion 
 
Day 1 and day 8 of cycle 1 (all patients) 
EDTA anti-coagulated blood samples will be obtained at the following timepoints: 
25 (±5) min after start of gemcitabine infusion = 5 min before end gemcitabine 
infusion 
 
Day 2 and day 9 of cycle 1 (ARM A patients only) 
EDTA anti-coagulated blood samples will be obtained at the following timepoints: 
55 min (±5 min) after start of M6620 (VX-970) infusion = 5 min before end M6620 
(VX-970) infusion 
 
Day 4 and day 11 of cycle 1 (ARM A patients only) 
EDTA anti-coagulated blood samples will be obtained at the following timepoints: 
47 h (±3 h) after end of M6620 (VX-970) infusion 
 
9.1.1.5 
Handling of Specimens 
 
Document exact start and stop times of each infusion and exact times of blood draws. 
 
Vacutainer tubes shall be inverted several times to mix blood with EDTA anticoagulant and 
placed on ice. Processing should begin within 20 minutes of collection. Samples should be 
centrifuged for 10 min at approximately 1000 x g in a refrigerated tabletop centrifuge so as to 
produce plasma. 
 
The resulting plasma should be aspirated from the tubes, placed into appropriately-labeled 
microcentrifuge tubes, and stored at -70 °C. 
 
9.1.1.6 
Shipping of Specimens 
 
Preparing the shipment 
*Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH). 
*Please organize the samples by Patient and Time point in the box. 
*Do not store in plastic bags (they break on dry-ice and labels will detach). 
*A copy of each of the pharmacokinetic sample collection forms for the respective patients or a 
sample list should be included with each shipment. To prevent problems with illegible writing on 


NCI Protocol #: 9947 
Version Date: August 25, 2020 
 
46 
tubes, consider numbering them and numbering samples on the sample sheet. 
*Note the study number, PI, and the drugs used/to be measured. 
*A name, phone number and email address should be included with samples so that receipt can 
be acknowledged. 
*Please notify the lab by telephone (412-623-3248) or fax (412-623-1212) at least 24 hours prior 
to shipment. 
 
Shipping 
*All samples should be shipped via overnight express courier in insulated containers with 
enough dry ice to maintain the samples in a frozen state (if samples are to be shipped frozen). 
All specimens are to be shipped on either Monday, Tuesday or Wednesday to: 
 
Cancer Pharmacokinetics and Pharmacodynamics Facility 
University of Pittsburgh Cancer Institute 
Room G27 Hillman Research Laboratories 
5117 Centre Avenue 
Pittsburgh, PA 15213. 
 
Regulations 
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 (e.g. 
cardboard mailing tube, corrugated cardboard box). A biohazard sticker must be affixed to both 
the inner and outer containers. 
 
9.1.1.7 
Site Performing Correlative Study 
 
Cancer Pharmacokinetics and Pharmacodynamics Facility 
University of Pittsburgh Cancer Institute 
Room G27 Hillman Research Laboratories 
5117 Centre Avenue 
Pittsburgh, PA 15213 
 
 
9.2 
Exploratory Correlative Studies 
 
9.2.1 Understanding the role of p53, CDKN1a (p21) and ERCC2 mutation in predicting 
differential response to cisplatin/gemcitabine versus cisplatin/gemcitabine with M6620 
(VX-970) 
 
9.2.1.1 
Collection of Specimen:  Archival FFPE specimens from prior TURBT or cystectomy 
will be submitted to the California Cancer Consortium Biobank at UC Davis to be 
accessioned and stored prior to analysis. 
 


NCI Protocol #: 9947 
Version Date: August 25, 2020 
 
47 
9.2.1.2 
Handling of Specimens(s):  A total of 10 unstained slides (4 micrometer thickness) 
along with 2 reference H&E slide with representative tumor specimens should be 
submitted.  Tissue should be mounted on positively charged (+) slides, coverslips may 
be used on H&E stained slides only. 
 
All submissions must be accompanied by a completed CCC specimen submission form 
(available on the CTSU website) and a copy of the corresponding pathology report.  
Forms must be submitted to both the bank and the CCC data center. 
 
If no tissue is available, participating sites must submit a CCC specimen submission 
form stating the reason for the unavailability of tissue.  Forms must be submitted to 
both the bank and the CCC data center. 
 
9.2.1.3 
Shipping of Specimen(s):  
All FFPE tissue should be send at ambient temperature and slides should be packed 
appropriately to protect from breakage.  For summer shipments, please include a 
room temperature cool pack to insulate the specimen and protect paraffin from 
melting.  Specimens should be shipped to the following address: 
 
Dr. Philip Mack/Anthony Martinez 
UC Davis Comprehensive Cancer Center 
4501 X Street, Suite 1009 
Sacramento, CA 95817 
 
Phone: 916-734-0162 
Email: axmartinez@ucdavis.edu or pcmack@ucdavis.edu 
 
Please notify the bank at the time of shipping via email (axmartinez@ucdavis.edu) 
 
9.2.1.4 
Analysis of Specimens: Targeted sequencing will be performed using a BROCA-like 
sequencing platform developed at Yale, including a large panel of DDR and HRD 
genes.  The panel includes genes of interest in the current study, including p53, 
CDKN1a and ERCC2.   
 
9.2.1.5 
Site(s) Performing Correlative Study: Yale University Comprehensive Cancer Center  
 
 
9.2.2 Assessment of DNA damage and ATM pathway activation with cisplatin/gemcitabine +/- 
M6620 (VX-970) and generation of PDX models 
 
 
9.2.2.1 
Collection of Specimen(s): Patients treated at City of Hope and UC Davis will be 
offered biopsies prior to treatment initiation (to be performed from day -14 to day -1) 
and at the time of documented treatment progression (to be performed +/- 14 days from 
the documented date of progression).  Notably, these biopsies are not mandatory.  
 


NCI Protocol #: 9947 
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48 
9.2.2.2 
Handling of Specimens: At least 24 hours prior to the biopsy, the research coordinator 
is to notify the institutional research team involved in this protocol, of the scheduled 
sample collections. A laboratory technician should prepare cryomolds prior to the 
biopsy, by labeling them, using the provided alcohol-proof marker, with the following 
information:  
 
Clinical protocol number  
Specimen ID  
Biopsy time and Date  
 
The laboratory technician should arrive at the biopsy collection site at least 15 min 
ahead of the scheduled biopsy to allow sufficient time to set up laboratory supplies and 
ensure rapid transport of specimens to the laboratory after collection. He should also, 
immediately before the biopsy, fill the insulated bucket with dry ice and isopentane.  
 
Immediately after the biopsy is performed, the freshly collected specimen should be 
placed in the cryomold. A single drop of Tissue Tek™ OCT should be placed on the 
specimen, and the sterile tweezers should be used to gently hold one end of the freshly 
collected needle biopsy and to push the biopsy to the bottom of the cryomold cassette 
with forceps. Make sure biopsy is as flat as possible. The cryomold should then be 
filled with OCT, and the cryomold should be immediately placed in direct contact with 
the dry ice/isopentane cocktail until the bottom of the OCT freezes and turns white. 
Only the bottom of the cryomold should contact the dry ice/isopentane--none of the dry 
ice/isopentane should spill inside the cryomold itself and contact the specimen.  
 
This process can be repeated using separate cryomold cassettes for separate biopsy 
samples.  
 
Once frozen, place cryomolds on dry ice for transport. The used isopentane should be 
poured back into its bottle using funnel.  
 
The cryopreserved biopsy should be stored at -80°C until shipment. After completion 
of each biopsy, the following information should be recorded:  
 
Biopsy collection  
Date:  
Specimen ID:  
Time guide needle placement confirmed:  
Needle Type:  
Needle diameter: gauge; and length: cm  
Time biopsy needle introduced:  
Time biopsy snap-frozen on dry ice:  
Number of specimens:  
Time aspirate performed (for bone lesions):  
Time aspirate snap-frozen on dry ice:  


NCI Protocol #: 9947 
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49 
Date/time of biopsy specimen(s) (and aspirate specimens, if applicable) placed at -
80°C:  
Date/time of biopsy specimen(s) (and aspirate specimens, if applicable) shipped:  
Notes, including any deviations from the standard operating procedure: 
 
PDX models will be generated using previously published methods (Lin T-Y et al 
2014).  Assessment of ATM P1981 and -H2AX will be performed via IHC using 
previously published methods (Wang et al 2014).  Importantly, these exploratory 
studies are being done on tissue derived from PDX models, not on primary patient 
derived tissues (where the persistence of labile phospho-moieties would be low).   
 
Shipping of Specimens: Specimens will be stored at UC Davis; if additional centers are 
chosen to participate in these correlative studies, these specimens will be shipped to 
UC Davis.  Ideally, shipment should occur on the same day as the biopsy, unless the 
biopsy occurs on a Friday, in which case the specimen should be preserved at -80°C 
until shipment on the following Monday.  
 
9.2.2.3 
Site(s) Performing Correlative Study: City of Hope and UC Davis  
 


50 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans and x-rays must be done <4 weeks prior to the start of 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. 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15 
Wk 
16 
Wk 
17 
Wk 
18 
Off Studyc 
Cisplatin 
 
A 
 
 
A 
 
 
A 
 
 
A 
 
 
A 
 
 
A 
 
 
 
Gemcitabine  
 
B 
B 
 
B 
B 
 
B 
B 
 
B 
B 
 
B 
B 
 
B 
B 
 
 
M6620 (VX-970) 
 
C 
C 
 
C 
C 
 
C 
C 
 
C 
C 
 
C 
C 
 
C 
C 
 
 
Informed consent & history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X----------------------------------------------------------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signs 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Performance status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------------------------------------------------------X 
X 
Radiologic evaluationd 
X 
Radiologic measurements should be performed every 9 weeks during the first six months of treatment and every 12 weeks thereafter until 
the time of progression.  
X 
Biopsy (optional)e   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue submissionf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Drawsg  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A:     Arm A - Cisplatin to be initiated at 60 mg/m2 on day 1 of each 21 day cycle (dose modification as specified in Section 6).  Arm B – Cisplatin to be initiated at 70 mg/m2 on day 1 of each 21 
day cycle (dose modification as specified in Section 6). 
B:     Arm A - Gemcitabine to be initiated at 875 mg/m2 on days 1 and 8 of each 21 day cycle (dose modification as specified in Section 6).  Arm B – Gemcitabine to be initiated at 1000 mg/m2 on 
days 1 and 8 of each 21 day cycle (dose modification as specified in Section 6). 
C:     Arm A - For patients randomized to M6620 (VX-970) at 90 mg/m2, dosing on days 2 and 9 of each 21 day (dose modification as specified in Section 6).  Notably, M6620 (VX-970) is 
administered over 1 hour.    
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
Off-study evaluation.  Following completion of 6 cycles of chemotherapy, patients should be evaluated every 9 weeks with the noted off-study assessments (including radiologic evaluation). 
d:      Radiologic evaluation should include CT of the chest, abdomen and pelvis for all patients.  If there is clinical suspicion for bone metastases at the time of enrollment (at the discretion of the 


NCI Protocol #: 9947 
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51 
investigator), bone scan should be performed at baseline.  If bone metastases are detected, a bone scan should be conducted at the time of each radiologic evaluation. Window for scans is +/- 
7 days. 
e:      Optional biopsies will be offered to patients treated at UC Davis.  Please see specimen shipping and handling instructions in Section 9.  
f:      A total of 10 unstained slides and 2 H&E slides (4 micrometer thickness) derived from previous TURBT or cystectomy (and including tumor tissue) should be submitted.  See Section 9. 
g.      Please refer to Section 9.1.1 for a schedule of blood draws for PK analyses.  All patients will have blood drawn at baseline, and on Days 1 and 8 of Cycle 1, and patients on Arm A will have 
additional blood days on days 2, 4, 9 and 11.   


52 
11. MEASUREMENT OF EFFECT 
 
11.1 
Response Criteria  
 
For the purposes of this study, patients should be re-evaluated for response every 9 weeks for the 
first 6 months, and then every 12 weeks thereafter.  Response and progression will be evaluated in 
this study using the new international criteria proposed by the revised Response Evaluation Criteria 
in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in 
the case of malignant lymph nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with cisplatin/gemcitabine or cisplatin/gemcitabine with M6620 (VX-970).  
 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area may be considered 
measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 


NCI Protocol #: 9947 
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53 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 


NCI Protocol #: 9947 
Version Date: August 25, 2020 
 
54 
by color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have 
slice thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for 
body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT  PET-CT (or PET alone; e.g., 18FDG-PET) is not permitted in the current study as 
a means of radiologic assessment.   
 
Ultrasound  Ultrasound is not permitted in the current study as a means of radiologic 
assessment.   
 
Tumor markers  As there are no reliable tumor markers for bladder cancer, tumor markers 
are not permitted as a means of disease assessment.  
 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 
cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 


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55 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm (0.5 cm).  (Note:  the appearance 
of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 
cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
 
 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 


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56 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    In this randomized trial, confirmation will not be required for Best Overall Response. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 


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57 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival (PFS) 
 
PFS is defined as the duration of time from randomization to time of progression or death, 
whichever occurs first.  For patients who have not progressed at the time that they are removed 
from treatment  (for completion of 6 courses or reasons described in Section 5.3) will be followed 
for progression;  for those who begin another treatment prior to progression, the  type of treatment 
will be recorded, as well as the time to 1st progression. 
 
11.1.7 Overall Survival (OS) 
 
OS is defined as the duration of time from randomization to death from any cause.  Patients who 
have not died at the time of analysis, will be censored at the date of they were last documented to 
be alive.   
 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
See also Section 14 ‘CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS,’ 
Subsection 14.1 ‘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.   
 
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 


NCI Protocol #: 9947 
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58 
stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the Protocol 
Statistician through IWRS and Medidata Rave. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
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, CRA (Lab Admin, SLA or Site Investigator) on 
either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA role 
or CRA Lab Admin role, the user must hold a minimum of an AP registration type.  To hold the 
Rave Site Investigator role, the individual must be registered as an NPIVR or IVR.  Associates can 
hold read-only roles in Rave.  If the study has a DTL, individuals requiring write access to Rave 
must also be assigned the appropriate Rave tasks on the DTL.  (Note: A DTL is NOT required for 
this study.) 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper right -corner 
of the iMedidata page.  Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed.  Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right 
pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail 
at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will 
be submitted to CTMS at least once every two weeks via Medidata Rave (or other modality 


NCI Protocol #: 9947 
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59 
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. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than 
once every 2 weeks.  The timeliness of data submissions and timeliness in resolving data 
queries will be tracked by CTMS.  Metrics for timeliness will be followed and assessed on 
a quarterly basis.  For the purpose of Institutional Performance Monitoring, data will be 
considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis 
as data is received.  Queries will be issued by CTMS directly within Rave.  The queries 
will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  
Monthly web-based reports are posted for review by the Drug Monitors in the IDB, CTEP.  
Onsite audits will be conducted by the CTMS to ensure compliance with regulatory 
requirements, GCP, and NCI policies and procedures with the overarching goal of ensuring 
the integrity of data generated from NCI-sponsored clinical trials, as described in the 
ETCTN 
Program 
Guidelines, 
which 
may 
be 
found 
on 
the 
CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of 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 


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60 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
12.3 
CTEP Multicenter Guidelines 
 
 
 
N/A 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a 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 


NCI Protocol #: 9947 
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61 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings.  Press releases and 
other media presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
13.1.1 Study Design: This study will employ a randomized, phase II design in which patients 
who have no prior cytotoxic chemotherapy for metastatic bladder cancer will be 
randomized 1:1 to receive either cisplatin/gemcitabine alone or cisplatin/gemcitabine with 
M6620 (VX-970).  Prior to randomization, patients will be stratified according the Bajorin 
risk category:  0=KPS≥80 and no visceral metastases; 1=KPS <80 or visceral metastases 
(but not both); 2=both KPS<80 and presence of visceral metastases.  Randomization will 
be done using a (stratified) permuted block design with randomly varying block sizes.  


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62 
 
A total of 90 patients will be enrolled and randomized; a single interim analysis will occur 
when 60% of the expected events have been observed; toxicity will be monitored monthly 
and reviewed formally twice a year. 
 
13.1.2 Primary Endpoint: Progression-free survival (PFS) as defined in Section 11.1.6. 
 
13.1.3 Secondary Endpoints: Response rate (RR) as defined in Section 11.1, overall survival 
(OS) as defined in Section 11.1.7, and toxicity graded according the CTCAE v4.  
 
13.2 
Sample Size/Accrual Rate 
 
The primary objective of the study is to determine if PFS is improved with the addition of M6620 
(VX-970) to the combination of cisplatin/gemcitabine as compared to cisplatin/gemcitabine alone.  
Based on a meta-analysis including multiple trials of cisplatin-based chemotherapy, we estimate a 
median PFS of 5.3 months with cisplatin/gemcitabine (Galsky et al Cancer 2013).  With 90 patients 
accrued and 80 evaluable for this primary endpoint, we will have 90% power to detect an 
improvement in median PFS from 5.3 months with cisplatin/gemcitabine alone to a median PFS 
of 10.1 months with cisplatin, gemcitabine and M6620 (VX-970) (i.e. a hazard ratio of 0.52).  This 
assumes a 1-sided α of 0.1, exponential failure, and uniform accrual over 2 years with 9 additional 
months of follow-up – with 66 events at the time of the final analysis.   
 
The number of patients required for this study will be a low of ≈71 (if the hypothesis that M6620 
(VX-970) is not active is true and the trial is stopped at the time of the interim analysis) to a 
maximum of 90 (if the trial continues to completion). 
 
13.3 
Study Monitoring and Interim Analysis 
 
13.3.1  Toxicity and Safety Monitoring  
 
The DCC (Data Coordinating Center) will review cumulative toxicities on a monthly 
basis.  Twice a year, the CCC (California Cancer Consortium) will prepare reports for the 
independent DSMC.   At these semi-annual reviews, the two arms will be compared in 
terms of toxicities (by any type of Grade 3+ toxicity).  Those toxicities resulting in a 2-
sided p-value of 0.10 or less will be flagged for examination.  While there are no formal 
rules for stopping because of toxicities, based on these reviews, the protocol may be 
modified or even closed, after discussion with CTEP. 
 
All deaths within 30 days of last treatment will be reviewed; all deaths due to treatment 
will be reviewed and compared across arms.  
 
13.3.2 Interim Analysis 
 
 
As described above, under the alternative hypothesis that the addition of M6620 (VX-970) 
nearly doubles the median PFS, we expect 66 events after 24 months of accrual and 9 
additional months of follow-up.  In this setting, we plan a single interim analysis after 40 


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63 
events have been observed – which should occur after about 19 months of accrual (if the 
hypothesis that M6620 (VX-970) is not active is true).   Accrual will not be paused to wait 
for 40 events.  At the time of the interim analysis, we will use two rules to guide our 
decision to continue or halt accrual. 
• Stopping for futility:  The two arms will be compared using the logrank test.  If overall 
the Cisplatin/Gemcitabine+M6620 (VX-970) PFS is not nominally superior to the 
Cisplatin/Gemcitabine arm and the corresponding one-sided p-value is less than or 
equal to 0.50, then consideration will be given to stopping for futility (Wieand S et al 
Statistics in Medicine 1994). 
• Stopping for success:  The two arms will be compared using the logrank test.  If overall 
the 
Cisplatin/Gemcitabine+M6620 
(VX-970) 
PFS 
is 
superior 
to 
the 
Cisplatin/Gemcitabine arm and the corresponding one-sided p-value is less than (but 
not equal to) 0.005, then consideration will be given to stopping for success, using the 
Haybittle-Peto approach (Peto R et al British Journal of Medicine 1976). 
  
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
0 
1 
0 
0 
1 
Asian 
2 
6 
0 
0 
8 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
1 
12 
0 
0 
13 
White 
14 
46 
2 
6 
68 
More Than One Race 
0 
0 
0 
0 
0 
Total 
17 
65 
2 
6 
90 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
13.4 
Stratification Factors 
 
Prior to randomization, patients will be stratified according to the Bajorin risk category:  
0=KPS≥80 and no visceral metastases; 1=KPS <80 or visceral metastases (but not both); 2=both 
KPS<80 and presence of visceral metastases.    


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64 
 
13.5 
Analysis of Results 
 
The outcome status (in terms of toxicity, number of course begun, amount of each of the planned 
drugs received (and percent of planned), reason off treatment, tumor response, and progression 
and survival status) of all randomized patients, will be reported. All eligible randomized patients 
will be included in the primary analysis of progression-free survival and response. All toxicities 
experienced by patients who begin treatment will be reported.   
 
Toxicity.  All observed toxicities will be summarized in terms of type (organ affected or laboratory 
determination such as absolute neutrophil count), severity (by the CTCAE v5.0), and time of onset 
(i.e. course of treatment).  Tables will be created to summarize these toxicities and side effects, 
overall by arm and by course.  Proportions and associated 95% confidence intervals will be 
calculated for each arm separately and if indicated, for the difference between the arms.  The two 
treatment arms will be compared using Fisher’s exact test when the presence of toxicities is 
dichotomized and by the Cochran-Armitage test for trend if all grades are considered. 
 
Clinical Outcome.  PFS will be measured from the day of randomization, until progression, death, 
or the start of another treatment.  In the primary analysis, patients who have not progressed, but 
who begin another treatment, will be censored at that time, for the measure of PFS; in the 
secondary analysis, all patients who begin another treatment prior to progression on this protocol, 
will be followed for the first progression on the subsequent treatment.   PFS for each arm will be 
summarized with a Kaplan-Meier plot and 95% confidence intervals (at 3, 6, 9, and 12 months); 
the one-sided 0.10-level logrank test will be used to compare the two arms. 
 
Overall survival, in which all patients will be followed until death (due to any cause) or for 36 
months, will be summarized in a manner similar to PFS.  The overall response rate will be 
calculated as the ratio of the number of eligible randomized patients who experienced a confirmed 
CR or PR (by RECIST v1.1) divided by the total number of randomized eligible patients who 
began treatment; 95% confidence intervals will be constructed.   Pearson chi-square test will be 
used to compare the two arms in terms of the overall response rate. 
 
Analysis of Potential Predictors of Response.  Archival tumor tissue will be analyzed for the 
presence of p53, p21, and ERCC2 mutations.  It is expected that the majority of patients will 
provide adequate specimens for analysis – conservatively we will assume that 75% (or 30/arm) of 
the evaluable patients will provide specimens.    For each gene, each tumor will be coded as 1 
(having a mutation) or 0 (having no mutation) for that gene.  For each treatment arm separately 
and for each of the 3 indicators (one each for the presence of p53, p21, and ERCC2 mutations), 
the hazard ratio will be used to quantify the overall association between that gene and PFS.   The 
Cox proportional hazards model (assuming that the assumption of proportional hazards is not 
unreasonable – which it should not be for PFS over the 1st year) will be used to estimate the 
interactions between the genes and PFS as well as the interaction between the treatment arm and 
each of the genes.   Although associations will be tested, it is possible that that resulting p-values 
are not less than 0.05 simply due to small numbers.  Based on the TCGA project (see the Figure 
below) we would expect about 50% of tumors to harbor p53 mutations, 14% to harbor p21 
mutations, and 12% to harbor ERCC2 mutations;  with 30 specimens per arm, that should yield 


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65 
about 15, 4, and 3-4 tumors with mutations, respectively.   Nonetheless, these analyses will guide 
the design of future studies.  To analyze the patterns further, the association between more frequent 
specific mutations for each gene and PFS (as well as objective response) will be quantified with 
an estimate of the hazard ratio and displayed with Kaplan-Meier plots.   
 
 
 
For patients treated at UC Davis, every attempt will be made to obtain fresh tumor biopsies prior 
to start of treatment as well as at the time of progression.  The primary purpose of these biopsies 
is to develop PDX models.   While the goal is to obtain as many models as possible, even one new 
model will be useful for future studies.  Practically speaking we expect that 4-6 patients will 
provide matched specimens.  Tissue from these biopsies will also be analyzed for changes in ATM 
activation and γH2AX.    
 
13.6 
Reporting and Exclusions 
 
13.6.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment on their 
respective arm.  
 
13.6.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death 
from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the exception of those who received 
no study medication) should be included in the main analysis of the response rate.  Patients 
in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result 
in exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 
will be protocol specific.   A secondary analysis will be undertaken which will include all 
patients who are evaluable for objective response (as defined in Section 11.1).  The 95% 
confidence intervals should also be provided.  
 
14. CCC POLICIES FOR MONITORING CONSORTIUM TRIALS 
 
This protocol is monitored at several levels, as described in more detail below.  To 


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66 
summarize:  The trial PI has access to the data at all times.  The CCC Data Coordinating Center 
reviews accrual and toxicities monthly.  An external, independent DSMC reviews the study 
progress twice yearly.  In addition, for Phase I trials or the Phase I portion of a trial, the PI will 
have monthly - and as needed - conference calls with study investigators to review accrual, 
progress, and any unforeseen issues.  Dose escalation/expansion/de-escalation decisions require 
sign-off by the PI (or his designee) and the study statistician (or designee).   During the Phase II 
trial or a Phase II portion of a trial, the PI will have quarterly - and as needed - conference calls 
with study investigators to review accrual, progress, and any unforeseen issues.  Decisions to 
proceed to the second stage of the Phase II trial will require sign-off by the study PI and the trial 
statistician. 
 
The protocol principal investigator (PI) is responsible for monitoring the conduct and progress of 
this Phase II trial, including the ongoing review of accrual, data and toxicities, as well as the 
accumulation of reported adverse events from other trials testing the same drug(s).  The 
participating clinicians and their designees are responsible for timely submission of adverse event 
reports (see Section 7) and case report forms.  The Data Coordinating Center for the CCC 
Consortium is responsible for providing the PI with access to the submitted case report form data 
in summary and detail in a timely fashion.   Although the PI is responsible for evaluating the 
cumulative reported adverse events and the impact that these have on the continued conduct of the 
trial, it is the Data Coordinating Center of the CCC that distributes all submitted SAE reports to 
the appropriate individuals, including the local protocol principal investigators, at each of the 
participating institutions.   
 
The Data Coordinating Center posts a summary (accrual, toxicities, and responses) of each CCC 
initiated trial on the CCC website.  In this way, each PI has access to up-to-date information on 
the status of his or her trial.  In consultation with the collaborating statistician, the PI is responsible 
for review of the toxicities and therapeutic endpoints referred to in the statistical plan. 
 
The Data Coordinating Committee meets monthly to review data management and data quality 
issues – completeness of data submissions as well as accuracy in terms of built-in, computerized 
logic checks.  Any issues identified and the corrective plans are presented to the Internal 
Committee and at the next CCC teleconference meeting for review and approval. 
 
14.1 
Oversight 
 
Oversight of the conduct of CCC trials occurs at several levels: 
 
1. 
The Data Coordinating Center for the CCC flags all trials that are approaching a decision 
in terms of toxicity (for both Phase I and Phase II trials) or responses (for Phase II trials).  
Decisions are made by the PI with input from the statistician and discussion with the 
principal investigator of the funding mechanism or his or her designee, and are 
communicated to the participating centers by the CCC Data Coordinating Center. At the 
monthly teleconferences, the accrual of each open protocol is reviewed. 
 


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67 
2. 
For CTEP sponsored Phase I trials, data are reported to the NCI-designated clinical trials 
monitoring service (CTMS) which will audit patients’ records on each protocol – at each 
CCC institution; this audit is initiated by CTEP.   
 
3. 
An independent CCC DSMC will review CCC trials every 6 months. This DSMC will 
consist of 6 voting members (3 medical oncologists or hematologists involved in Phase I/II 
cancer clinical trials but not participating in CCC studies, a patient representative and a 
statistician) and a non-voting CCC statistician.   
 
a. DSMC meetings will take place twice a year.  Additional meetings will be convened if 
necessary.  
 
b. This DSMC will review each CCC trial in terms of accrual, toxicity/safety, and 
adherence to trial design, audit results, and likelihood of successful completion.   
 
c. The DSMC will report to the CCC leadership. 
 
 
 


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68 
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Weber, A.M. and A.J. Ryan.  (2015).  ATM and ATR as therapeutic targets in cancer.  
Pharmacol Therap.  Epub (ahead of print). 
 
White, D., I.U. Rafalska-Metcalf, A.V. Ivanov, et al.  (2012).  The ATM substrate KAP1 
controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 
phosphorylation.  Mol Cancer Res.  10:401-414. 
 
Yagoda A, Watson RC, Gonzalez-Vitale JC, Grabstald H, Whitmore WF. Cis-
dichlorodiammineplatinum(II) in advanced bladder cancer. Cancer Treat Rep. 1976;60: 917–923. 
 
Yan, S., M. Sorrell, and Z. Berman.  (2014).  Functional interplay between ATM/ATR-mediated 
DNA damage response and DNA repair pathways in oxidative stress.  Cell Mol Life Sci.  
71:3951-3967. 


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70 
 
Zeman, M.K. and K.A. Cimprich.  (2014).  Causes and consequences of replication stress.  Nat 
Cell Biol.  16:2-9.   
 
 
 


NCI Protocol #: 9947 
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71 
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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72 
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.   


NCI Protocol #: 9947 
Version Date: August 25, 2020 
 
73 
 
PATIENT DRUG INTERACTION WALLET CARD  
 
 
 
 
 
 
EMERGENCY 
INFORMATION 
 
DRUG INTERACTIONS  
Show this card to all of your 
healthcare providers. Keep it 
with you in case you go to the 
emergency room. 
Tell your doctors before you start or 
stop any medicines. 
Check with your doctor or 
pharmacist if you need to use an 
over-the-counter medicine or herbal 
supplement! 
Carry this card with you at all times   
M6620 (VX-970) interacts with specific enzymes in your liver or other tissues 
like the gut and transport proteins that help move drugs in and out of cells 
and must be used very carefully with other medicines. 
Patient Name:       
Use caution and avoid the 
following drugs if possible:  
 
 
Your healthcare providers should be aware of any medicines that are strong 
inhibitors or inducers of CYP3A4, and substrates of P-gp and BCRP. 
• Strong inhibitors or inducers of CYP3A4 should be avoided. 
• Substrates of P-gp and BCRP should be used with caution. 
Diagnosis:       
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:       
Before prescribing new medicines, your health care provider should check a 
frequently-updated medical reference for a list of drugs to avoid or contact 
your study doctor. 
Study Drug(S):       
 
             Version Feb/2019 
 
For more information: 1-800-4-CANCER 
For more information: 1-800-4-CANCER 
For more information: 1-800-4-
CANCER 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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74 
 
APPENDIX C 
COCKROFT-GAULT, MDRD AND CKD-EPI FORMULAS 
 
 
 
Cockcroft-Gault Formula 
 
Calculated Creatinine Clearance = [140 – age (yrs)] x [actual weight (kg)] 
 
 
 
           72 x serum creatinine (mg/dl) 
 
 
 
 
Females = 0.85 x male value 
 
 
Modification of Diet in Renal Disease Formula (MDRD)  
 
eGFR = [186 x serum creatinine (mg/dl)]-1.154 x [age (yrs)]-0.203 x (0.742 if female) x (1.210 if 
black) 
 
 
Chronic Kidney Disease Epidemiology Collaboration Formula (CKD-EPI) 
 
eGFR = 141 x min(Scr/κ,1)α x max(Scr/κ,1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black] 
 
Where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is –0.329 for 
females and –0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the 
maximum of Scr/κ or 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX D 
SPECIMEN COLLECTION FOR PHARMACOKINETIC STUDIES 
FOR PHII-135 (NCI# 9947) 
 
Title: A Randomized Phase 2 Trial of Cisplatin/Gemcitabine with or without M6620 (VX-970) 
in Metastatic Urothelial Carcinoma 
 
Blood samples to be obtained through a peripheral or central line blood draw. Samples should be 
drawn from the opposite arm if infusion is a peripheral infusion. Samples should NOT be drawn 
from the infusion line. 
EDTA Vacutainer tubes shall be prepared by addition of THU solution to prevent ex vivo 
degradation of gemcitabine: 
 
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 1 mL of blood to be drawn and transfer it to a Vacutainer tube 
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. 
 
Day 1 and day 8 of cycle 1 (all patients) 
EDTA anti-coagulated blood samples will be obtained at the following timepoints: 
25 (±5) min after start of gemcitabine infusion = 5 min before end gemcitabine 
infusion 
 
Day 2 and day 9 of cycle 1 (ARM A patients only) 
EDTA anti-coagulated blood samples will be obtained at the following timepoints: 
55 min (±5 min) after start of M6620 (VX-970) infusion = 5 min before end M6620 
(VX-970) infusion 
 
Day 4 and day 11 of cycle 1 (ARM A patients only) 
EDTA anti-coagulated blood samples will be obtained at the following timepoints: 
47 h (±3 h) after end of M6620 (VX-970) infusion 
 
Handling of Specimens 
 
Document exact start and stop times of each infusion and exact times of blood draws. 
 
Vacutainer tubes shall be inverted several times to mix blood with EDTA anticoagulant and placed 
on ice. Processing should begin within 20 minutes of collection. Samples should be centrifuged 
for 10 minutes at approximately 1000 x g in a refrigerated tabletop centrifuge so as to produce 
plasma. 
 
The resulting plasma should be aspirated from the tubes, placed into appropriately-labeled 
microcentrifuge tubes, and stored at -70 °C. 


NCI Protocol #: 9947 
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76 
  
Pharmacokinetic Sample Collection Schedule 
 
Title: A Randomized Phase 2 Trial of Cisplatin/Gemcitabine with or without M6620 (VX-970) in Metastatic Urothelial 
Carcinoma (NCI 9947, PhII-135) 
 
Patient's Initials _______________   _____________________         Patient Accession #  ______ _____ 
                                          (first)                                        (last) 
 
Study Site _____________     Height ________ cm    Weight:  ____ . ____ kg    BSA ____ . ____ ____ m2 
 
Check one:  □ Arm A (Cisplatin/Gemcitabine with M6620 (VX-970))        □ Arm B (Cisplatin/Gemcitabine) 
 
Baseline Sample          Date/time   __________________ 
 
Day 1 Gemcitabine Dose   __________ mg/m2 IV infusion  
 
Day 1 Infusion Start Date/time   __________________         Infusion End time _______________________ 
 
Day 8 Gemcitabine Dose   __________ mg/m2 IV infusion  
 
Day 8 Infusion Start Date/time   __________________         Infusion End time _______________________ 
 
Day 2 M6620 (VX-970) Dose                              mg/m2 IV infusion  
 
Day 2 Infusion Start Date/time   __________________         Infusion End time _______________________ 
 
Day 9 M6620 (VX-970) Dose                              mg/m2 IV infusion  
 
Day 9 Infusion Start Date/time   __________________         Infusion End time _______________________ 
 
Sample 
 Name 
Planned Collection 
Time Relative to 
Gemcitabine Infusion  
All Patients 
Planned Collection 
Time Relative to 
M6620 (VX-970) 
Infusion  
Arm A Patients Only 
Sample Date 
(mm:dd:yy)  
Expected 
Time 
(hh:mm)  
Actual 
Time 
(hh:mm)  
Drawn 
By 
(initials)  
Comments 
P0 
Baseline (prior to 
infusion) 
  
  
  
  
  
  
P1 
Day 1 - 25 min (± 5 min) 
after start of 
Gemcitabine  
 
 
 
 
 
 
P2 
  
Day 2 - 55 min (± 5 min) 
after start of M6620 (VX-
970) 
  
  
  
  
  
P3 
  
Day 4 - 47 h (±3 h) after 
end of M6620 (VX-970) 
  
  
  
  
  


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77 
P4 
Day 8 - 25 min (± 5 min) 
after start of 
Gemcitabine  
  
  
  
  
  
  
P5 
  
Day 9 - 55 min (± 5 min) 
after start of M6620 (VX-
970) 
  
  
  
  
  
P6 
  
Day 11 - 47 h (±3 h) after 
end of M6620 (VX-970) 
  
  
  
  
  
Preparing the shipment 
*Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH). 
*Please organize the samples by Patient and time point in the box. 
*Do not store in plastic bags (they break on dry-ice and labels will detach). 
*A copy of each of the pharmacokinetic sample collection forms for the respective patients or a 
sample list should be included with each shipment. To prevent problems with illegible writing on 
tubes, consider numbering them and numbering samples on the sample sheet. 
*Note the study number, PI, and the drugs used/to be measured. 
*A name, phone number and email address should be included with samples so that receipt can be 
acknowledged. 
*Please notify the lab by telephone (412-623-3248) or fax (412-623-1212) at least 24 hours prior 
to shipment. 
 
Shipping 
*All samples should be shipped via overnight express courier in insulated containers with enough 
dry ice to maintain the samples in a frozen state (if samples are to be shipped frozen). 
All specimens are to be shipped on either Monday, Tuesday or Wednesday to: 
 
Cancer Pharmacokinetics and Pharmacodynamics Facility 
University of Pittsburgh Cancer Institute 
Room G27E Hillman Research Laboratories 
5117 Centre Avenue 
Pittsburgh, PA 15213 
 
Regulations 
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 (e.g. 
cardboard mailing tube, corrugated cardboard box). A biohazard sticker must be affixed to both 
the inner and outer containers. 
 
 


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78 
APPENDIX E 
SUPPORTIVE CARE GUIDELINES FOR M6620 (VX-970) 
 
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 phlebitis, or signs or symptoms of inflammation that may progress to 
phlebitis or that the patient cannot tolerate, standard measures should be employed to ameliorate 
these symptoms (including removal of the infusion catheter and resumption of infusion through a 
different vein). 
 
Based on the observation of acute hypersensitivity in 3 subjects at various doses of M6620 (VX-
970) and of pruritus in 2 subjects at 480 mg/m2 of M6620 (VX-970), pre-medication with a 
corticosteroid and an antihistamine may be considered for all subjects receiving M6620 (VX-970) 
(to prophylax against possible acute hypersensitivity), and is strongly recommended for subjects 
receiving doses of M6620 (VX-970) above 240 mg/m2 (to prophylax against pruritus). In addition, 
corticosteroids and antihistamine should be used for treatment of subjects that develop acute 
hypersensitivity or pruritus after M6620 (VX-970) infusion, and should be used prophylactically 
as pre-medication for all subjects who develop acute hypersensitivity or pruritus with M6620 (VX-
970) infusion and who continue to receive treatment with M6620 (VX-970). 
 
Corticosteroid and antihistamine combinations that may be used include: 100 mg to 200 mg 
hydrocortisone intravenously approximately 60 minutes (± 15 minutes) before M6620 (VX-970) 
infusion, and either 10 mg of chlorphenamine or 25 mg of diphenhydramine intravenously 
approximately 30 minutes (± 10 minutes) before M6620 (VX-970) infusion. Alternative 
antihistamine and steroid doses, timing, routes of administration, and agents may be considered, 
as long as not prohibited by protocol. In addition, treatment with an H2-blocker (e.g., ranitidine) 
may be considered for subjects not responsive to a regimen with an H1 blocker.  
 
If standard procedures to limit symptoms of injection site reaction, or pruritus or acute 
hypersensitivity are insufficient, then the infusion time may be extended beyond 60 minutes, but 
no more than 90 minutes.