Conditions: Neoplasms
Keywords: Pharmacodynamic DNA Damage Repair BRCA Null Apoptosis Combination Therapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 53
Healthy volunteers: no

Brief summary:
Background:

The drug cisplatin treats certain cancers when given with other chemotherapy drugs. Researchers think combining cisplatin with 2 other drugs could block proteins that support cancer cell growth. The other drugs are ABT-888 (veliparib) and M6620 (VX-970). They want to test if this drug combination slows the growth of cancer and is safe.

Objectives:

To test the safety and tolerability of VX-970 and veliparib combined with cisplatin in people with advanced refractory solid tumors. To determine the maximum tolerated dose of these drugs.

Eligibility:

People ages 18 and older with:

* Solid tumors that have progressed after treatment or for which no treatment exists
* Normal organ and marrow function

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Computed tomography (CT) scan or magnetic resonance imaging (MRI)
* Blood and urine tests

Participants will get the study drugs in 3-week cycles:

* Cisplatin in a vein on 1 or 2 days
* VX-970 in a vein on 2 days
* Veliparib by mouth twice a day on 6 days

In each cycle, participants will have 5 physical exams and blood tests 5 times.

In some cycles, participants will have CT scans or MRIs.

In cycle 1, participants may have 2 tumor biopsies. A small piece of tissue is removed by needle.

Participants will keep a study diary. They will write when they take the drugs and if they have side effects.

Participants will stay in the study as long as they tolerate the drugs and their tumors are not getting worse.

Participants will have a phone call about a month after their last dose.

Detailed description:
Background:

* Ataxia-telangiectasia-related (ATR) protein kinase is central to the deoxyribonucleic acid (DNA) damage response and homologous recombination, activating a series of phosphorylation cascades, culminating in cell cycle arrest to allow time for deoxyribonucleic acid (DNA) repair. ATR additionally facilitates homologous recombination repair through modulation of the p53-replication protein A (p53-RPA) complex bound to single-stranded deoxyribonucleic acid (ssDNA) during the DNA repair process.
* Poly (ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in base-excision repair of single strand breaks formed either due to direct genotoxic stress or during the processing of double strand breaks. PARP also plays a role in alternative end joining, which may contribute to combination activity. PARP-1 binding to sites of DNA damage results in activation of its catalytic activity and generation of chains of poly (ADP-ribosyl)ated polymers, which serve as docking sites for recruitment of DNA repair proteins.
* Veliparib (ABT-888) is a potent PARP 1/2 inhibitor with clinical evidence of potentiation of antitumor activity in combination with cisplatin in breast cancer gene (BRCA) mutation carriers and patients with sporadic triple-negative breast cancer.
* M6620 (VX-970) is a potent ATR inhibitor, with half maximal inhibitory concentration (IC(50) of 20 nanomolar and antitumor activity across a broad range of cell lines in combination with DNA damaging agents. Preclinical studies show M6620 (VX-970) synergizes with cisplatin to induce DNA damage and antitumor activity. The addition of PARP inhibitor veliparib with ATR inhibitor M6620 (VX-970) allows for impairment of DNA repair, the induction of a BRCA null phenotype, and potentiation of the antitumor activity of cisplatin.

Primary Objective:

-To establish the safety, tolerability, and the maximum tolerated dose (MTD) of the combination of M6620 (VX-970) and veliparib in combination with cisplatin in patients with advanced refractory solid tumors

Secondary Objectives:

* To assess the effect of the combination of M6620 (VX-970), veliparib, and cisplatin on markers of DNA damage and apoptosis
* To assess antitumor activity of the combination

Exploratory Objective:

-To investigate tumor genomic alterations potentially associated with acquired resistance to the combination of M6620 (VX-970), veliparib, and cisplatin

Eligibility:

* Patients must have histologically confirmed solid tumors for which all standard therapy known to prolong survival has failed in the metastatic setting, or for which standard therapies do not exist
* Patients must have had no major surgery, radiation, or chemotherapy within 3 weeks prior to entering the study
* Patients must have adequate organ function

Study Design:

* Initially, M6620 (VX-970) will be administered intravenously on Days 2 and 9 of each 21-day cycle. Veliparib will be administered orally twice a day (every (q)12 hours +/- 1 hour) for Days 1-3 and 8-10 of each 21-day cycle. Cisplatin will be administered at 40 mg/m\^2 intravenously on Day 1 (and Day 8 from dose level 3 (DL3) onwards) of each 21-day cycle.
* As of Amendment I (12/7/2017), patients who have been on study for at least 6 cycles may have cisplatin administration held or discontinued at the discretion of the Principal Investigator (PI), Dr. Chen, in recognition of the cumulative neurotoxicity seen with cisplatin treatment. If cisplatin is not administered during a cycle M6620 (VX-970) will be administered on Days 1 and 8 of that cycle.
* The escalation portion of the trial will follow a standard 3+3 design, whereby patients will be dose escalated in cohorts of 3 until dose-limiting toxicity is observed
* Once the maximum tolerated dose (MTD) is established, up to 15 additional patients will be enrolled to an expansion phase at the MTD. Mandatory tumor biopsies will be obtained in the expansion phase to assess pharmacodynamic (PD) endpoints

Arms:
arm 1: M6620 will be administered intravenous (IV) on Days 2 and 9 of each 21-day cycle; Veliparib will be administered orally twice a day (BID) Days 1-3 and 8-10 of each cycle; Cisplatin will be administered at 40 mg/m\^2 IV Day 1 (and Day 8 from dose level 3 onwards) of each cycle

Interventions: intervention 1: Veliparib + VX-970 + Cisplatin
Intervention descriptions: intervention 1: Ataxia-telangiectasia-related (ATR) protein kinase is central to the deoxyribonucleic acid (DNA) damage response and homologous recombination, activating a series of phosphorylation cascades, culminating in cell cycle arrest to allow time for DNA repair. Poly (ADP-ribose) polymerase (PARP) plays a pivotal role in base-excision repair of single strand breaks formed either due to direct genotoxic stress or during the processing of double strand breaks. Preclinical studies show ATR inhibitor M6620 (VX-970) synergizes with cisplatin to induce DNA damage and antitumor activity. The addition of PARP inhibitor veliparib with VX-970 allows for impairment of DNA repair, induction of a breast cancer gene (BRCA) null phenotype, and potentiation of the antitumor activity of cisplatin.

Protocol document:
Prot_SAP_000.pdf: 




CTEP# P9771 
Clinical Center # l 6-C-0087 
Statistician: 
CTEP Drug Monitor: 
Study Sponsor: 
NCI Supplied Agents: 
IND Number: 
NCTNumber: 
Version Date: 
DCTD, NCI 
CTEP 
M6620 (VX-970) (NSC 780162) 
Veliparib (ABT-888) (NSC 737664) 
NCT02723864 
Januaiy 11, 2021 
Roles: A obtains information by intervening or interacting with living individuals for research purposes; 
Bobtains identifiable private information about living individuals; cobtains the voluntary infonned 
consent of individuals to be subjects; Dmakes decisions about subject eligibility; Estudies, interprets, or 
analyzes identifiable private information or data/specimens for research purposes 
3 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
4 
 
PRÉCIS 
Background: 
• Ataxia-telangiectasia-related (ATR) protein kinase is central to the DNA damage response and 
homologous recombination, activating a series of phosphorylation cascades, culminating in cell 
cycle arrest to allow time for DNA repair.  ATR additionally facilitates homologous 
recombination repair through modulation of the p53-replication protein A (p53-RPA) complex 
bound to ssDNA during the DNA repair process.   
• Poly (ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in base-excision repair of single 
strand breaks formed either due to direct genotoxic stress or during the processing of double 
strand breaks.  PARP also plays a role in alternative end joining, which may contribute to 
combination activity.  PARP-1 binding to sites of DNA damage results in activation of its 
catalytic activity and generation of chains of poly (ADP-ribosyl)ated polymers, which serve as 
docking sites for recruitment of DNA repair proteins. 
• Veliparib (ABT-888) is a potent PARP 1/2 inhibitor with clinical evidence of potentiation of 
antitumor activity in combination with cisplatin in BRCA mutation carriers and patients with 
sporadic triple-negative breast cancer. 
• M6620 (VX-970) is a potent ATR inhibitor, with IC50 of 20 nM and antitumor activity across a 
broad range of cell lines in combination with DNA damaging agents.  Preclinical studies show 
M6620 (VX-970) synergizes with cisplatin to induce DNA damage and antitumor activity.  The 
addition of PARP inhibitor veliparib with ATR inhibitor M6620 (VX-970) allows for 
impairment of DNA repair, the induction of a “BRCA null” phenotype, and potentiation of the 
antitumor activity of cisplatin. 
 
Primary Objective: 
• To establish the safety, tolerability, and the maximum tolerated dose (MTD) of the combination 
of M6620 (VX-970) and veliparib in combination with cisplatin in patients with advanced 
refractory solid tumors 
 
Secondary Objectives: 
• To assess the effect of the combination of M6620 (VX-970), veliparib, and cisplatin on markers 
of DNA damage and apoptosis 
• To assess antitumor activity of the combination 
 
Exploratory Objective: 
• To investigate tumor genomic alterations potentially associated with acquired resistance 
to the combination of M6620 (VX-970), veliparib, and cisplatin 
 
Eligibility: 
• Patients must have histologically confirmed solid tumors for which standard therapy known to 
prolong survival has failed in the metastatic setting, or for which standard therapies do not exist 
• Patients must have had no major surgery, radiation, or chemotherapy within 3 weeks prior to 
entering the study 
• Patients must have adequate organ function 
 
Study Design: 
• Initially, M6620 (VX-970) will be administered intravenously on Days 2 and 9 of each 21-day 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
5 
 
cycle.  Veliparib will be administered orally twice a day (q12 hours ± 1 hour) for Days 1-3 and 
8-10 of each 21-day cycle.  Cisplatin will be administered at 40 mg/m2 intravenously on Day 1 
(and Day 8 from DL3 onwards) of each 21-day cycle. 
• As of Amendment I (12/7/2017), patients who have been on study for at least 6 cycles may 
have cisplatin administration held or discontinued at the discretion of the PI, Dr. 
 in 
recognition of the cumulative neurotoxicity seen with cisplatin treatment.  If cisplatin is not 
administered during a cycle, M6620 (VX-970) will be administered on Days 1 and 8 of that 
cycle. 
• The escalation portion of the trial will follow a standard 3+3 design, whereby patients will be 
dose escalated in cohorts of 3 until dose-limiting toxicity is observed 
• Once the MTD is established, up to 15 additional patients will be enrolled to an expansion phase 
at the MTD.  Mandatory tumor biopsies will be obtained in the expansion phase to assess PD 
endpoints   


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
6 
 
 
SCHEMA 
 
 
 
 
 
 
 
D1-3                       D8-10                                                D1-3                     D8-10 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cisplatinb 
M6620 (VX-970)c 
Tumor  
biopsies† 
Velipariba 
Cycle 1 (duration 21 days) 
Cycle 2 (duration 21 days) 
D2 
D1                               D9 
Week 1 
a Veliparib po q12 hours ± 1 hour on days 1-3, 8-10 of each cycle.  Veliparib should be administered before 
cisplatin and M6620 (VX-970). 
b Cisplatin IV day 1 only each cycle for dose levels up to DL 3; days 1 and 8 for dose level 3 and higher; as 
of Amendment I (12/7/2017), patients who have been on study for at least 6 cycles may have cisplatin 
administration held or discontinued at the discretion of the PI, Dr. 
 
c M6620 (VX-970) IV days 2 and 9 of each cycle (or days 1 and 8 if cisplatin administration has been held or 
discontinued) 
† Tumor biopsies to evaluate pharmacodynamic markers of DNA damage (optional during the escalation 
phase and mandatory during the expansion phase) after administration of cisplatin on C1D1 and on C1D9, 2-
5 hours after the day 9 dose of M6620 (VX-970).  One optional biopsy may also be performed, either at 
“restaging follow-up” on day 1 (± 2 days) of the cycle following any restaging at which a 10-19% increase in 
tumor volume is observed (according to RECIST criteria) for patients on study 4 or more cycles, or at the 
time of disease progression.  (For example, a restaging follow-up biopsy would be performed on cycle 6 day 
1 for a 10-19% tumor volume increase detected at the restaging following cycle 4).  
‡ Circulating tumor cells (optional) will be collected at baseline (prior to administration of study agents), 
prior to administration of M6620 (VX-970) on cycle 1 day 2, 8 hours (± 30 minutes) after the start of M6620 
(VX-970) administration on cycle 1 day 2,  on cycle 1 day 8 prior to veliparib/cisplatin administration, on 
cycle 1 day 9 prior to M6620 (VX-970) administration, on cycle 2 day 1 prior to veliparib/cisplatin 
administration, on cycle 2 day 2 prior to M6620 (VX-970) administration and again 10 hours (± 2 hours) after 
the start of M6620 (VX-970) administration (or, at NCI only, at 7:00pm ± 30 minutes; the time elapsed 
between M6620 (VX-970) administration and blood collection on cycle 2 day 2 will be recorded), and on the 
first day of every subsequent cycle prior to veliparib/cisplatin administration. 
D1 
Week 2  
Week 3  
CTCs‡ 
Baseline   D2 
D8 D9 
C2 D1 D2 
C3D1 
Week 1 
Week 2  
Week 3  
D1                         (D8) 
D9 
D2 
D9 
(D8) 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
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Dosing Schema: 
 
Dose 
Level 
Veliparib 
(PO q12 hours ± 1 hour) 
M6620 (VX-970) 
 (IV Days 1/2 and 8/9) 
Cisplatin 
(IV Day 1 or Days 1 
and 8) 
-2 
20 mg days 1-3, 8-10 
40 mg/m2 
40 mg/m2 day 1 
-1 
40 mg days 1-3, 8-10 
60 mg/m2 
40 mg/m2 day 1 
1 
100 mg days 1-3, 8-10 
90 mg/m2 
40 mg/m2 day 1 
2 
100 mg days 1-3, 8-10 
140 mg/m2 
40 mg/m2 day 1 
3 
100 mg days 1-3, 8-10 
120 mg/m2 
40 mg/m2 days 1, 8 
4 
100 mg days 1-3, 8-10 
210 mg/m2 
40 mg/m2 days 1, 8 
5 
150 mg days 1-3, 8-10 
210 mg/m2 
40 mg/m2 days 1, 8 
6 
200 mg days 1-3, 8-10 
210 mg/m2 
40 mg/m2 days 1, 8 
7 
300 mg days 1-3, 8-10 
210 mg/m2 
40 mg/m2 days 1, 8 
8 
400 mg days 1-3, 8-10 
210 mg/m2 
40 mg/m2 days 1, 8 
 
As of Amendment L (dated 4/22/2019), the MTD for this combination has been established as 
DL6. 
 
 
 
 
 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
8 
 
TABLE OF CONTENTS 
PRÉCIS ............................................................................................................................................4 
SCHEMA .........................................................................................................................................6 
1 
OBJECTIVES ....................................................................................................................10 
2 
BACKGROUND ...............................................................................................................10 
2.1 
Rationale for combining cisplatin with ATR and PARP inhibitors .......................10 
2.2 
M6620 (VX-970) ...................................................................................................13 
2.3 
Veliparib (ABT-888) .............................................................................................17 
2.4 
Cisplatin .................................................................................................................19 
2.5 
Correlative Studies Background ............................................................................22 
3 
PATIENT SELECTION ....................................................................................................24 
3.1 
Eligibility Criteria ..................................................................................................24 
3.2 
Exclusion Criteria ..................................................................................................25 
3.3 
Inclusion of Women and Minorities ......................................................................26 
3.4 
Screening Evaluation .............................................................................................26 
4 
REGISTRATION PROCEDURES ...................................................................................26 
4.1 
NCI Clinical Center Patient Registration Process .................................................26 
4.2 
Participating Site Patient Registration ...................................................................27 
4.3 
Investigator and Research Associate Registration with CTEP ..............................27 
5 
TREATMENT PLAN ........................................................................................................28 
5.1 
Agent Administration .............................................................................................29 
5.2 
Intra-patient Dose Escalation .................................................................................31 
5.3 
Definition of Dose-Limiting Toxicity ....................................................................31 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................33 
5.5 
Duration of Therapy ...............................................................................................35 
5.6 
Duration of Follow Up ...........................................................................................36 
5.7 
Criteria for Removal from Study ...........................................................................36 
6 
DOSING DELAYS/DOSE MODIFICATIONS................................................................36 
6.1 
Dose Modifications ................................................................................................36 
6.2 
Agent-specific Dose Modifications: Veliparib ......................................................37 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................40 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
ABT-888 (Veliparib, NSC 737664) .......................................................................40 
7.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
M6620 (VX-970) (NSC 780162) ...........................................................................43 
7.3 
Adverse Event Characteristics ...............................................................................46 
7.4 
Expedited Adverse Event Reporting ......................................................................46 
7.5 
NIH-IRB and Clinical Director Reporting Requirements .....................................51 
7.6 
Secondary Malignancy ...........................................................................................52 
7.7 
Second Malignancy ................................................................................................52 
8 
PHARMACEUTICAL INFORMATION ..........................................................................53 
8.1 
M6620 (VX-970) (NSC 780162) ...........................................................................53 


CTEP # P9771 
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8.2 
Veliparib (NSC 737664) ........................................................................................55 
8.3 
Cisplatin .................................................................................................................56 
8.4 
Useful Links and Contacts: ....................................................................................57 
8.5 
Agent Ordering ......................................................................................................58 
8.6 
Agent Accountability .............................................................................................58 
9 
CORRELATIVE/SPECIAL STUDIES .............................................................................59 
9.1 
Pharmacodynamic Assays .....................................................................................59 
9.2 
Genomic Analyses .................................................................................................64 
9.3 
Human Data Sharing Plan ......................................................................................65 
10 
STUDY CALENDAR .......................................................................................................66 
11 
MEASUREMENT OF EFFECT........................................................................................68 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................68 
11.2 
Response Criteria ...................................................................................................72 
11.3 
Duration of Response .............................................................................................74 
12 
DATA REPORTING/REGULATORY REQUIREMENTS .............................................74 
12.1 
Study Oversight .....................................................................................................74 
12.2 
Data Reporting .......................................................................................................75 
12.3 
CTEP Multicenter Guidelines ................................................................................76 
12.4 
Collaborative Agreements Language .....................................................................76 
12.5 
Genomic Data Sharing Plan ...................................................................................78 
13 
STATISTICAL CONSIDERATIONS...............................................................................78 
13.1 
Study Design/Endpoints.........................................................................................78 
13.2 
Sample Size/Accrual Rate ......................................................................................78 
13.3 
Secondary Endpoints .............................................................................................78 
14 
HUMAN SUBJECTS PROTECTIONS ............................................................................78 
14.1 
Justification for Subject Selection .........................................................................78 
14.2 
Evaluation of Benefits and Risks/Discomforts ......................................................79 
14.3 
Consent and Assent Process and Documentation ..................................................79 
14.4 
Procedure for Protecting Against or Minimizing Any Potential Risks ..................81 
14.5 
Patient Advocate ....................................................................................................81 
REFERENCES ..............................................................................................................................82 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................84 
APPENDIX B:  PATIENT DRUG INTERACTIONS HANDOUT AND WALLET 
CARD ................................................................................................................................85 
APPENDIX C: PATIENT STUDY CALENDAR AND DIARY .................................................87 
APPENDIX D: PD SAMPLE COLLECTION WORKSHEETS AT THE NCI ...........................91 
APPENDIX E: INFORMED CONSENT FORM TEMPLATE ....................................................95 
APPENDIX F: CTEP MULTICENTER GUIDELINES .............................................................108 
APPENDIX G: PROCEDURE FOR SAMPLES FOR PHARMACODYNAMIC 
STUDIES .........................................................................................................................110 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
10 
 
1 OBJECTIVES 
Primary Objective: 
• To establish the safety, tolerability, and the maximum tolerated dose (MTD) of the 
combination of M6620 (VX-970), an ATR inhibitor and veliparib, an oral PARP 1/2 
inhibitor, in combination with cisplatin in patients with advanced refractory solid tumors. 
 
Secondary Objectives: 
• To assess the effect of the combination of M6620 (VX-970), veliparib, and cisplatin on 
markers of DNA damage and apoptosis 
• To assess the antitumor activity of the combination 
 
Exploratory Objective: 
• To investigate tumor genomic alterations potentially associated with acquired resistance to 
the combination of M6620 (VX-970), veliparib, and cisplatin 
 
 
2 
BACKGROUND 
2.1 
Rationale for combining cisplatin with ATR and PARP inhibitors 
Platinum compounds act through the formation of covalent bonds with DNA purine bases, 
forming intrastrand and interstrand cross-links with DNA, stalling replication forks and halting 
transcription [1].  Poly (ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in base-excision 
repair (BER) and the DNA damage response [2].  Once DNA damage is detected, surveillance 
protein complexes such as Mre11-Rad50-Nbs1 and Rad9/Rad1/Hus1 recruit repair proteins and 
halt cell cycle progression, allowing time for DNA repair.  Ataxia-telangiectasia mutated (ATM) 
protein kinase and ataxia-telangiectasia-related (ATR) protein kinase, two members of the 
phosphatidyl inositol 3-kinase-like kinase (PIKK) family, are central to the DNA damage repair 
process.  Depending on the type of genotoxic stress, either ATM or ATR is preferentially 
activated [3].  ATM is primarily activated in response to double-stranded DNA breaks (DSBs), 
while ATR is activated by a broader spectrum of genotoxic stimuli and primarily activated in 
response to single-strand DNA breaks (SSBs) arising through the processing of DSBs or the 
stalling of DNA replication forks after treatment with platinum compounds.  Both kinases initiate 
a cascade of phosphorylation events, culminating in cell cycle arrest to allow time for repair of 
DNA.  ATR additionally facilitates homologous recombination (HR) repair through modulation of 
the p53-replication protein A (p53-RPA) complex bound to ssDNA during the process of DNA 
repair [4].  SSBs are additionally repaired by PARP-1 through BER.  Binding of PARP-1 to sites 
of DNA damage results in activation of its catalytic activity and generation of chains of poly 
(ADP-ribosyl)ated polymers, which serve as docking sites for recruitment of DNA repair proteins 
[5, 6].  The accumulation of lethal DSBs during replication as a result of platinum compounds, in 
the setting of inhibition of both PARP and ATR, allows for chemopotentiation and a means to 
overcome treatment resistance. 
 




CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
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Figure 2.  Synergy of PARP inhibition + M6620 (VX-970) + cisplatin in H23 lung carcinoma 
(left panel) vs. HFL1 human fetal lung non-cancerous (right panel) cell lines.  Data from MTS 
cell viability assays of the combination of PARP inhibition with rucaparib + M6620 (VX-970) + 
80 nM of cisplatin subjected to statistical Bliss analysis in order to quantitate synergy or 
antagonism demonstrates synergy in cancer cell lines, with minimal effect in non-cancerous cell 
lines [Confidential communication with Vertex, unpublished data]. 
 
Data from nonclinical studies conducted by Vertex showed that the combination of cisplatin, 
Veliparib, and M6620 (VX-970) at clinically relevant doses and schedule was well tolerated in 
MF1 nude mice (Figure 3); body weight changes did not exceed ± 5% and were similar to vehicle.   
 
 
Figure 3. Tolerability of cisplatin, Veliparib, and M6620 (VX-970) combination in MF1 nude 
mice administered on days 1 and 8 and assessed for 2 cycles.  Doses/routes of administration: 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
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cisplatin 3 mg/kg IP; Veliparib 50 mg/kg PO; M6620 (VX-970) 30, 60, and 90 mg/kg PO.  Drugs 
were administered on days 1 and 8 [Confidential communication with Vertex, unpublished data]. 
 
2.2 
M6620 (VX-970) 
ATR plays a central role in the DNA damage response; therefore, inhibition of ATR is expected to 
enhance the effects of DNA damage, either as a result of exposure to genotoxic chemotherapy 
agents or secondary to inherent errors in replication.  In vitro studies show that M6620 (VX-970) 
sensitized a panel of human cancer cell lines and primary human tumor cells to the cytotoxic 
effects of various DNA-damaging agents whereas normal cells (lung and skin fibroblasts and 
mammary epithelial cells) treated with the same DNA-damaging agents tolerated ATR inhibition 
with a reversible increase in growth [8]. 
 
Mechanism of Action 
 
M6620 (VX-970) is a potent, ATP-competitive, inhibitor of ATR (Ki < 300 pM; measured Ki 
values over the range of 0.1 to 0.3 nM).  It showed > 100-fold selectivity against closely-related 
DNA damage repair proteins, ATM, and DNA-dependent protein kinase.  Minimal inhibitory 
activity was observed against a large panel of unrelated protein kinases, with > 500-fold 
selectivity for ATR. 
 
Preclinical Studies 
In vitro studies of M6620 (VX-970) in HCT116 colorectal carcinoma cells, show synergism of 
M6620 (VX-970) with various DNA-damaging agents, with the most dramatic response in 
combination with cisplatin, where a 20-fold reduction in the IC50 for cisplatin was observed.  Cell 
viability assays were assessed by MTS assay at 96 hours (Figure 3 left panel) [Investigator's 
Brochure].  The effects of M6620 (VX-970) in combination with a range of DNA-damaging 
agents were also tested against a panel of lung, pancreatic, and 9 primary lung tumors in 
combination with cisplatin, using CellTiter-GloTM assays, demonstrating enhanced synergy, with 
concurrent dose-dependent decreases in pCHK1 confirming downstream target effect, and dose-
dependent increases in pH2AX demonstrating downstream DNA-damage effect (data not shown). 
 
M6620 (VX-970) and cisplatin were also assessed in a panel of primary human non-small cell 
lung cancer (NSCLC) xenografts in SCID mice with enhancement of antitumor activity in 7 of 9 
xenografts (Figure 4 right panel). 
 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
14 
 
 
 
Figure 4.  In vitro (left panel) and in vivo (right panel) synergy of cisplatin and M6620 (VX-
970).  Left panel shows MTS cell viability assays of cisplatin + M6620 (VX-970), with dose-
dependent increased potency with the addition of ATR inhibition with M6620 (VX-970).  Right 
panel shows M6620 (VX-970) improves tumor responses to cisplatin in a PDX NSCLC model in 
SCID mice, as reflected in reduction in tumor volumes.  M6620 (VX-970) was dosed at 60 mg/kg 
PO daily x 4, cisplatin was dosed at 1 mg/kg IP q weekly [14].  
 
Nonclinical Pharmacokinetics 
M6620 (VX-970) partitions between blood and plasma, and varies with dose and species.  
Therefore, whole blood is recommended for the determination of drug exposure.  The volume of 
distribution in rats, mice, dogs, and monkeys (21, 20, 10, and 6 L/kg, respectively) for M6620 
(VX-970) was high and exceeded the volume of total body water.  Tissue exposure, including 
tumor, was high with maximum concentrations reached after 3 hours for all tissues except for 
kidney and thymus, which peaked at 6 hours.  In rats, no accumulation or retention was observed 
in tissues and the elimination half-lives were similar across all tissues and whole blood.  Whole 
blood half-lives in rats and dogs were 11.6 and 9.8 hours, respectively.  M6620 (VX-970) had 
high plasma protein binding and the free fraction in human was 2.1%.  A low potential for drug-
drug interactions was predicted, based on minimal inhibition or induction of (CYP) 450 isozymes 
by M6620 (VX-970), however strong inducers or inhibitors or CYP3A4 may alter M6620 (VX-
970) kinetics and blood levels.  M6620 (VX-970) was primarily eliminated by oxidative 
metabolism, 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 values of M6620 (VX-970) following IV administration 
were determined to be 26 and 13 mL/min/kg in the rat and dog, respectively.  The impact of drug-
efflux pumps on the cellular activity of M6620 (VX-970) activity was tested in MDR-1 and MRP-
1 expressing cancer cells and matched drug sensitive cells, with no decrease in M6620 (VX-970) 
activity in cancer cells expressing drug efflux pumps [Investigator Brochure]. 
 
Preclinical Safety Pharmacology Studies and Toxicology Studies 
In vitro and in vivo safety pharmacology studies designed to evaluate effects of M6620 (VX-970) 
against multiple protein targets and the cardiovascular system did not demonstrate any 
toxicologically significant effects at exposures or concentrations that significantly exceed the 


CTEP # P9771 
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15 
 
targeted maximum circulating concentration of M6620 (VX-970) in humans.  M6620 (VX-970) 
was administered by both oral and IV routes to rats and dogs for up to 28 days.  The rat severely 
toxic dose in 10% of rats (STD10) was considered to be an IV dose of 30 mg/kg/day, and the dog 
highest non-severely toxic dose was considered to be an IV dose of 20 mg/kg/day.  Target organs 
of toxicity in the rat included the testes and peripheral blood cell populations (red cell mass, 
eosinophils, and platelets), and M6620 (VX-970) produced mild irritation at the infusion site.  
Target organs in the dog included the liver, testes, and peripheral blood cell populations (red cell 
mass and eosinophils).  M6620 (VX-970) had no cardiovascular toxicities, was not genotoxic in a 
non-GLP 2-strain 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-visible spectrum and has tissue distribution in rats 
[Investigator’s Brochure]. 
 
Clinical Pharmacokinetic Studies 
Preliminary clinical PK data available from the Phase I first-in-human study of M6620 (VX-970) 
[Study 001] show mean M6620 (VX-970) plasma concentration versus time profiles were similar 
in shape to those of the corresponding whole blood profiles.  Variability in the plasma matrix was 
generally reduced, however, and similar PK trends were detected between both matrices.  PK 
exposures tended to increase proportionally with increasing dose based upon Cmax (ranged from 
72.0 ng/mL in the 18 mg/m2 dose group to 817 ng/mL in the 140 mg/m2 dose group) and area 
under the concentration versus time curve extrapolated to infinity (AUC0-∞) (ranged from 351 
h*ng/mL in the 18 mg/m2 dose group to 6148 h*ng/mL in the 210 mg/m2 dose group).  The mean 
volume of distribution at steady-state (Vss) ranged from 1148 L to 1602 L and mean clearance 
ranged from 60.6 L/h to 98.2 L/h in the 140 mg/m2 and 18 mg/m2 dose groups, respectively, 
showing no apparent trends.  Similar to the whole blood matrix, the terminal elimination half-life 
was approximately 16 hours across all dose groups.  The administration of gemcitabine 24 hours 
prior to M6620 (VX-970) administration did not appear to affect the pharmacokinetics of M6620 
(VX-970) [Investigator’s Brochure].  
 
 
Clinical Experience 
As of February 2015 (data reporting cut-off date), preliminary safety and efficacy data are 
available for 38 subjects from Study 001 parts A and B (A: 7-14-day lead in with M6620 (VX-
970) then M6620 (VX-970) in combination with gemcitabine; B: 21-day lead in with M6620 
(VX-970) and then M6620 (VX-970) in combination with cisplatin) and for 11 subjects from 
Study 002A (single agent M6620 (VX-970)) [9].  Preliminary PK data are also available from 
study 002B (M6620 (VX-970) in combination with carboplatin) [Investigator’s Brochure].   
 
In Study 001A (M6620 (VX-970) from 18 to 140 mg/m2 IV, gemcitabine from 500 to 875 mg/m2 
IV), 5 of 6 subjects with NSCLC, 7 of 13 subjects with other types of cancers, and 4 of 9 subjects 
with colorectal cancer had stable disease as best overall response, and one subject with EBV+ 
nasopharyngeal cancer exhibited a partial response.  Several subjects had an overall response of 
stable disease for at least 4 cycles.  In Study 001B, 4 of 7 subjects had stable disease as best 
overall response; one subject with endometrial cancer had stable disease for 6 cycles (ongoing at 
time of report).  In Study 002A, 3 of 10 subjects with other types of cancers had stable disease as 
best overall response; one subject with colorectal cancer exhibited a partial response (80% 
reduction of tumor lesion diameter) and continues on treatment after 11 cycles.  


CTEP # P9771 
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During the lead-in phase of Study 001A (single dose M6620 (VX-970) ranging from 18 to 210 
mg/m2 IV), 2 subjects had SAEs of palpitations, pyrexia, and dyspnea; during the combination 
phase, 9 of 31 subjects had SAEs classified as related to study drug, 3 had SAEs of Grade 1 
pyrexia classified as possibly related or related to study drug, and 2 had SAEs of Grade 4 
thrombocytopenia classified as related to study drugs.  The most common AEs, regardless of 
causality, were nausea (20 subjects), vomiting (17 subjects), and fatigue (15 subjects).  
 
During Study 001B, one subject had an SAE of metastases to the central nervous system that led 
to study drug discontinuation; during the combination phase (M6620 (VX-970) at 90 or 140 
mg/m2 IV in combination with cisplatin 40 mg/m2 IV), 1 of 6 subjects had an SAE of metastases 
to central nervous system and one had dyspnea, which were not related to study drugs.  The most 
common AEs, regardless of causality, were nausea (4 subjects) and fatigue (4 subjects).  
 
In Study 002, 11 subjects received M6620 (VX-970) at doses ranging from 60 to 480 mg/m2 IV.  
Two subjects had SAEs of Grade 3 ascites, which were classified as not related to study drug, and 
Grade 3 fatigue, which was classified as possibly related to study drug.  Serious acute 
hypersensitivity has been identified as an adverse drug reaction for M6620 (VX-970).  As of 17 
April 2015, a serious acute hypersensitivity reaction occurred in 2 of 66 subjects and a third 
reaction occurred after the SAE data cut-off date of 17 April 2015, raising the estimated incidence 
of this ADR to between 4% and 5%.  
 
Preliminary clinical pharmacokinetic data are available from Studies 001 and 002.  PK exposures 
tended to increase proportionally with increasing dose based upon Cmax (ranged from 72.0 
ng/mL in the 18 mg/m2 dose group to 817 ng/mL in the 140 mg/m2 dose group) and AUC0-∞ 
(ranged from 351 h*ng/mL in the 18 mg/m2 dose group to 6148 h*ng/mL in the 210 mg/m2 dose 
group).  The mean volume of distribution at steady-state (Vss) ranged from 1148 L to 1602 L and 
mean clearance (CL) ranged from 60.6 L/h to 98.2 L/h in the 140 mg/m2 and 18 mg/m2 dose 
groups, respectively, showing no apparent trends.  The terminal elimination half-life was 
approximately 16 hours across all dose groups.  Overall, the Cmax were 1.36-fold greater and the 
AUC0-∞ was 1.43-fold greater in whole blood than plasma matrix, suggesting that plasma is an 
appropriate matrix to characterize the pharmacokinetics of M6620 (VX-970).  M6620 (VX-970) 
PK exposure parameters were similar when dosed alone versus after gemcitabine or carboplatin 
administration and indicated no apparent interactions between M6620 (VX-970) and these agents.   
 
Dose escalation for M6620 (VX-970) on this current study P9771 was informed by results from 
ongoing Study 002B, which has reached 480 mg/m2; no DLTs have been observed (Vertex 
communication).  
At the time of Amendment L, dated 4/22/2019, 36 patients have been enrolled onto this study 
and the MTD established as DL6 (200 mg veliparib q12 hours on days 1-3 and 8-10, 210 mg/m2 
M6620 on days 2 and 9, and 40 mg/m2 cisplatin on days 1 and 8 of 21-day cycles).  The DLTs on 
DL7 were a grade 4 thrombocytopenia and an infusion reaction to M6620 (VX970) that kept the 
patient from completing the cycle. 
 


CTEP # P9771 
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Potential Drug Interactions 
Because the drug interaction profile of M6620 (VX-970) has not been fully characterized, caution 
should be used when co-administering medications with M6620 (VX-970).  As M6620 (VX-970) 
is primarily metabolized by CYP3A4, concomitant administration with potent inhibitors or 
inducers of CYP3A4 should be avoided [Investigator’s Brochure]. 
2.3 
Veliparib (ABT-888) 
Poly (ADP-ribose) polymerases (PARPs) are a family of nuclear protein enzymes involved in the 
post-translational modification of proteins and synthesis of poly (ADP-ribose) required for 
recognition of DNA damage and repair.  PARP-1 and PARP-2 are the best characterized members 
of the PARP family, and play a key role in the DNA damage response and repair of SSBs through 
BER.  PARP inhibition has been shown to result in catalytic inhibition, trapping of PARP-1 on 
DNA repair intermediates at SSBs, and stalling of replication forks that require BRCA-dependent 
HR for resolution [10]. 
 
Mechanism of Action 
Veliparib is an orally available, potent small molecule inhibitor of PARP1/2 that has shown 
activity through sensitization of a broad range of tumor cells and xenografts to various DNA-
damaging agents [11].  Expression of PARP is higher in tumor cells compared to normal cells and 
increased PARP activity is one of the mechanisms by which tumor cells avoid apoptosis caused 
by DNA damaging agents [12].  PARP inhibition impairs the cell’s ability to repair DNA damage 
through exposure to chemotoxic agents, such as cisplatin, and further defects in compensatory 
DNA repair mechanisms further impairs the ability to withstand genotoxic stress and allows for 
potentiation of antitumor activity. 
 
Nonclinical Toxicology Studies 
In a variety of nonclinical models, veliparib increased the sensitivity of tumor cells to DNA-
damaging agents, including temozolomide, irinotecan, cyclophosphamide, cisplatin, carboplatin, 
and radiation at therapeutic doses that do not increase the toxicity of chemotherapeutic agents.  
 
Pharmacokinetic Studies 
A Phase 0 study of veliparib administered as a single dose, ranging from 10 to 50 mg, to 
13 subjects, showed that veliparib was rapidly absorbed, with peak plasma levels occurring 
between 0.5 and 1.5 hours post-dosing [13].  At a dose of 25 mg, the mean plasma concentration 
of veliparib (0.15 µg/mL) was higher than the plasma concentration associated with maximal 
efficacy in nonclinical models (0.070 µg/mL) for an average of 4.1 hours.  These results were 
consistent with the projected human pharmacokinetic profile based on nonclinical data. 


CTEP # P9771 
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In Phase 1 studies, the exposure of veliparib was approximately dose-proportional over the 10 
through 500 mg twice daily (BID) dosing range, with peak plasma concentrations at 
approximately 1 to 2 hours after dosing across dose levels.  The terminal half-life (t1/2) of veliparib 
was about 6 hours, with minimal accumulation following multiple BID dosing.  Food did not have 
a significant effect on veliparib bioavailability.  The administration of a high-fat meal had no 
significant effect on AUC and only caused a slight decrease in veliparib Cmax (17%) and a delay of 
approximately 1 hour in Tmax.  In clinical studies, the mean urinary recovery of unchanged 
veliparib was 72% and the total urinary recovery of veliparib (as parent compound and M8 
metabolite) was 86% [Investigator’s Brochure]. 
 
Drug Interactions 
Veliparib is not a reversible or time-dependent inhibitor of the human cytochrome P450 (CYP) 
enzymes CYP1A2, 2C8, 2C9, 2D6, or 3A4/5 (half maximal inhibitory concentration, IC50 > 30 
µM).  It is not a reversible CYP3B6 inhibitor (IC50 > 30 µM), and causes minimal time-dependent 
inhibition of CYP2B6 at 50 µM.  Veliparib does not significantly induce activities of major CYPs 
CYP1A2, 2B6, 2C9, and 3A4.  Veliparib is not a potent inhibitor of the major human CYPs and 
does not significantly induce activities of major human CYP isoforms, suggesting a negligible 
potential for CYP-mediated drug-drug interactions at anticipated therapeutic concentrations. 
 
Veliparib is a substrate of P-gp and kidney transporters OCT2, MATE1, and MATE2K.  
Consequently, co-administration of veliparib with potent inhibitors of OCT2, MATE1, and 
MATE2K and/or P-gp may decrease veliparib renal clearance and increase its plasma exposure.  
Veliparib does not inhibit P-gp or BCRP at concentrations up to 1000 µM.  At therapeutic doses 
in combination, veliparib has a low potential for clinical pharmacokinetic drug-drug interactions 
with transporters: P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, 
and MATE2K).  Veliparib may inhibit OCT1 in the liver and MATE1 and MATE2K in the 
kidney at higher doses (e.g., 400 mg BID) [Investigator’s Brochure]. 
 
Summary of Clinical Studies 
 
As of March 24, 2014, approximately 1255 patients have been treated with veliparib in AbbVie-
sponsored clinical trials, with veliparib administered as either monotherapy or in combination 
therapy in patients with various solid tumors.  As of March 31, 2014, approximately 1687 adult 
patients and 44 pediatric patients have been treated with veliparib in CTEP-sponsored studies.  
Veliparib has been generally administered in doses up to 500 mg BID as monotherapy, and up to 
400 mg BID in combination with cytotoxic chemotherapies or radiation therapy [Investigator’s 
Brochure].  Recent published results of Phase I studies of veliparib in combination with cisplatin 
and vinorelbine in patients with advanced triple-negative breast cancer and/or BRCA mutation-
associated breast cancer show tolerability of veliparib at a dose of 300 mg BID when combined 
with cisplatin at 75 mg/m2 on day 1 and vinorelbine at 25 mg/m2 on days 1 and 8 of a 21-day 
cycle.  Responses were seen in 73% of patients who carried a BRCA mutation (6/11 partial 
responses, 2/11 complete responses) compared with 53% of patients without a known BRCA 
mutation (11/21 partial responses) and 33% of patients with unknown BRCA status (2/6 partial 
responses).  The majority of toxicities were hematologic [14]. 
 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
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Veliparib, when used in combination with cytotoxic chemotherapy, is expected to have unique 
toxicities reflected in amplification of the toxicities of the backbone regimen, and have included 
hematologic, gastrointestinal, and CNS toxicities, and possibly thromboembolic events in 
combination with temozolomide.  Secondary malignancies are a potential risk of veliparib based 
on its mechanism of action [Investigator’s Brochure]. 
 
2.4 
Cisplatin 
Cisplatin injection is currently FDA-approved in combination with other chemotherapeutic agents 
in patients with transitional cell bladder cancer no longer amenable to local treatments, metastatic 
ovarian tumors after surgery and/or radiotherapeutic procedures or as second-line in the refractory 
setting, and for metastatic testicular tumors who have already received appropriate surgical and/or 
radiotherapeutic procedures.   
 
Mechanism of Action: 
Cisplatin is a divalent inorganic, water-soluble, platinum-containing complex.  Following 
administration, cisplatin undergoes mono- and di-hydroxyl substitution of its cis-oriented 
chloride, allowing for interaction with negatively charged DNA bases, and the formation of 
interstrand and intrastrand crosslinks.  DNA adducts formed by cisplatin interfere with DNA 
replication and transcription, leading to DNA breaks. 
 
Pharmacokinetics: 
Cisplatin plasma concentrations decay mono-exponentially with a half-life of ~20-30 minutes 
following bolus administrations of 50 or 100 mg/m2, and after 2 hour or 7 hour infusions of 
cisplatin 100 mg/m2.  The total body clearance and volume of distribution at steady-state after 7 
hour infusion of cisplatin at 100 mg/m2 are ~ 15-16 L/h/m2 and 11-12 L/m2, respectively. 
 
Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is 
characteristic of normal drug-protein binding.  However, the platinum from cisplatin, but not 
cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and 
gamma globulin.  The unbound fraction, composed predominantly of parent drug, is cleared 
within minutes.  The ratios of cisplatin to total free (ultrafiltrable) platinum in the plasma vary 
considerably between patients and range from 0.5-1.1 after a dose of 100 mg/m2.  Three hours 
after a bolus injection and two hours after the end of a 3-hour infusion, 90% of the plasma 
platinum is protein bound.  The complexes between albumin and the platinum from cisplatin do 
not dissociate to a significant extent and are slowly eliminated with a minimum half-life of 5 days 
or more. 
 
Following cisplatin dose of 20-120 mg/m2, the concentrations of platinum are highest in liver, 
prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and 
lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum.  Platinum is present in tissues for 
as long as 180 days after the last administration.  Maximum red blood cell concentrations of 
platinum are reached within 90-150 minutes after a 100 mg/m2 dose of cisplatin and decline in a 
biphasic manner with a terminal half-life of 36-47 days.   
 


CTEP # P9771 
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Only a small portion of the drug is excreted by the kidneys during the first 6 hours after 
administration.  Over a dose range of 40-140 mg/m2 given as a bolus injection or as infusions 
varying in length from 1 hour to 24 hours, 10-40% of the administered platinum is excreted in the 
urine within 24 hours.  Over 5 days following administration of  
40-100 mg/m2 doses given as rapid, 2-3 hours, or 6-8 hour infusions, a mean of 35-51% of the 
dosed platinum is excreted in the urine, mostly covalently bound to protein and peptides.  Mean 
urinary recoveries of platinum of about 14-30% of the dose are found following 5-day 
administrations of 20, 30 or 40 mg/m2/day.  Only a small percentage of the administered platinum 
is excreted beyond 24 hours post-infusion and most of the platinum excreted in the urine in 24 
hours is excreted within the first few hours.  The parent compound is also excreted in the urine 
and accounts for 13-17% of the dose excreted within one hour after administration of 50 mg/m2.  
The mean renal clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 
following administration of 100 mg/m2 as 2 hour or 6-7 hour infusions, respectively.  The renal 
clearance of free (ultrafiltrable) platinum also exceeds the glomerular filtration rate indicating that 
cisplatin or other platinum-containing molecules are actively secreted by the kidneys.  The renal 
clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and 
individual variability in the extent of active secretion and possible tubular reabsorption.  There is a 
potential for accumulation of ultrafiltrable platinum plasma concentrations whenever cisplatin is 
administered on a daily basis but not when dosed on an intermittent basis.  No significant 
relationships exist between the renal clearance of either free platinum or cisplatin and creatinine 
clearance.  Although small amounts of platinum are present in the bile and large intestine after 
administration of cisplatin, the fecal excretion of platinum appears to be insignificant. 
 
Drug Interactions: 
Concomitant use of cisplatin and aminoglycosides (amikacin, gentamicin, streptomycin, 
tobramycin) has the potential to increase the risk of nephrotoxicity.  Concomitant use of 
anticonvulsant agents (carbamazepine, fosphenytoin, phenytoin, valproic acid) may result in 
subtherapeutic plasma concentrations of these agents, resulting in seizure activity.  In a 
randomized trial in advanced ovarian cancer, response duration was adversely affected when 
pyridoxine was used in combination with altretamine (hexamethylmelamine) and cisplatin. 
 
Adverse Reactions 
Nephrotoxicity 
Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-
limiting toxicity of cisplatin.  Renal toxicity has been noted in 28-36% of patients treated with a 
single dose of 50 mg/m2.  It is first noted during the second week after a dose and is manifested by 
elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance.  The 
severity of toxicity correlates directly with the amount of cisplatin administered in individual and 
cumulative doses.  Renal toxicity may be mitigated by the administration of hydration during and 
after cisplatin administration and avoiding administration of concurrent nephrotoxic drugs. 
 
Impairment of renal function has been associated with renal tubular damage, and may present with 
electrolyte disturbances such as hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, 
and hypophosphatemia.  Tetany has been reported in those patients with hypocalcemia and 
hypomagnesemia.  Hypomagnesemia may be a possible permanent adverse effect of cisplatin.  
Decreased serum sodium concentrations have been observed within 24-72 hours following 


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Clinical Center # 16-C-0087 
 
 
 
21 
 
cisplatin infusion.  Chronic salt wasting and hyponatremia may persist after discontinuation of 
cisplatin. 
 
Ototoxicity 
Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50 
mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4000-8000 
Hz).  Hearing loss may be unilateral or bilateral and tends to become more frequent and severe 
with repeated cisplatin doses.  Vestibular toxicity has also been reported.  Ototoxic effects may be 
related to peak plasma concentration of cisplatin.   
 
Ocular Toxicity 
Optic neuritis, papilledema, and cerebral blindness have been reported in patients receiving 
standard recommended doses of cisplatin.  Improvement and/or total recovery usually occur with 
discontinuation of therapy.  Blurred vision and altered color perception have been reported after 
the use of regimens with higher doses of cisplatin or greater dose frequencies than recommended.  
The altered color perception manifests as a loss of color discrimination, particularly in the blue-
yellow axis.  Findings on fundoscopic exam include irregular pigmentation of the macular area. 
 
Neurotoxicity 
Peripheral neuropathy is a dose-limiting toxicity.  The severity of neuropathy varies with dose 
intensity and the total cumulative dose administered.  Symptoms usually develop during 
treatment, and persist after discontinuation of treatment, and include numbness, tingling, 
impairment of reflexes, vibratory sense, proprioception, and sensory ataxia. 
 
Hematologic Toxicity 
Myelosuppression occurs in 25-30% of patients.  The nadir platelet count and leukocyte count 
occurs between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 
to 62).  Leukopenia and thrombocytopenia are more pronounced at higher doses (> 50 mg/m2).  
Anemia (defined as decrease of 2 g/dL) occurs at approximately the same frequency and timing as 
leukopenia and thrombocytopenia.  Fever and infection have been reported in patients with 
neutropenia. 
 
Gastrointestinal Toxicity 
Cisplatin is highly emetogenic; nausea and vomiting may begin within 1 to 4 hours after treatment 
and may last up to 24 hours.  Delayed nausea and vomiting (begins or persists 24 hours or more 
after chemotherapy) has occurred in patients despite adequate emetic control on the day of 
therapy.  In some cases, vomiting, nausea, and/or anorexia may persist for up to 1 week after 
treatment. 
 
Hepatotoxicity 
Transient elevations of liver enzymes and bilirubin have been reported to be associated with 
cisplatin administration at the recommended doses. 
 
Anaphylactic-Like Reactions 
Anaphylactic-like reactions have been reported in patients previously exposed to platinums.  The 
reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
22 
 
after drug administration.  Reactions may be controlled by intravenous epinephrine with 
corticosteroids and/or antihistamines as indicated.   
 
2.5 Correlative Studies Background 
2.5.1 Pharmacodynamic Assessment of Drug Response 
Evaluation of drug effect on DNA damage response in tumor and CTCs will be 
performed by immunofluorescence assays for measurement of DNA damage-repair 
markers, such as γH2AX, RAD51, pNbs1, and pATR. 
 
ATR phosphorylation in response to DNA damage will be used as a marker of direct 
target effect.  A quantitative immunofluorescence assay for pT1989-ATR will be used 
as a marker of ATR inhibitor activity.   
 
Downstream from the primary biomarker are three additional biomarkers of interest: 
• Histone H2AX is one of the H2A histones present in nucleosomes from 
normal tissues as well as cancer tissues.  H2AX is phosphorylated at its C-
terminus (serine 139) following DNA double-strand breaks.  Phosphorylated 
H2AX, referred to as γH2AX, can be selectively detected using antibodies by 
Western blots or immunofluorescence.  The levels of γH2AX are directly 
correlated to the amounts of double-strand breaks per cell, and can be used as 
a dosimeter and biomarker for DNA double-strand breaks. 
 
• Nbs1 is an adapter protein, linking Mre11 and Rad50 to form the MRN 
complex involved in recognition of DNA damage and initiation of the 
signaling cascade in response to DNA double-strand breaks. 
 
• Rad51 plays a central role in recognition of double-strand breaks and 
homologous recombination. 
 
A multiplexed immunofluorescence assay for γH2AX, phosphorylated Nbs1, and 
Rad51 has recently been validated and published by the Pharmacodynamic Assay 
Development and Implementation Section (PADIS) at the Frederick National 
Laboratory for Cancer Research (FNLCR) [15].  PADIS and the National Clinical 
Target Validation Laboratory (NCTVL) will carry out the testing of all 4 PD 
biomarkers on tumor tissue and CTCs collected from this study. 
2.5.2 Genomic Analysis 
Genomic sequencing of patient biopsies will be performed in the laboratory of Dr. 
Mickey Williams, Director of the Molecular Characterization (MoCha) Laboratory, 
located at FNLCR.  MoCha is registered under Clinical Laboratory Improvement 
Amendments (CLIA) for the performance of high-complexity molecular testing for 
clinical purposes.  MoCha will perform two types of analysis: (1) exploratory (non-
CLIA) whole exome sequencing (WES) analysis of tumor tissues, and (2) the CLIA-


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Clinical Center # 16-C-0087 
 
 
 
23 
 
certified Oncomine Comprehensive Assay v3 (OCAv3), a next generation sequencing 
(NGS) assay designed to find gene mutations within tumors (somatic mutations).  
 
2.5.2.1 WES 
To address the reality that even those patients who respond to this drug combination 
are likely to eventually progress, genomic (whole exome) information from 
consenting patients undergoing optional tumor biopsies at restaging follow-up or at 
the time of progression will be compared with C1D1 genomic information from those 
patients to investigate the development of acquired drug resistance. 
2.5.2.2 OCAv3 
OCAv3 is not designed to be used to find hereditary or germline mutations.  The assay 
was originally validated for the NCI-MATCH clinical trial (NCT02465060) and is 
considered an investigational device limited by Federal law to investigational use.  Its 
performance characteristics have been determined through extensive testing by the 
NCI-MATCH network laboratories.  It has not been cleared by the US Food and Drug 
Administration and such approval is not required for clinical implementation.  
 
OCAv3 can reliably identify the presence or absence of greater than 3,000 known 
mutations of interest (MOIs) in 161 unique genes, with results compared to the 
Human Reference Genome hg19.   The assay identifies greater than 3,000 annotated 
mutations of interest (MOIs) characterized into 5 mutation types: single nucleotide 
variants (SNV), small insertions/deletions (indels), large (> 3 bases) 
insertions/deletions (large indels), copy number variants (CNV), and gene fusions.  In 
the majority of cases, we do not know the medical significance of the genetic variants 
[16, 17]. 
 
This report generated from the assay is intended to provide background information to 
the oncology team and the patient about mutations detected within the patient’s tumor.  
It does not determine assignment of a patient to a clinical trial; however, as MoCha is 
a MATCH study-designated lab (see https://ecog-acrin.org/nci-match-eay131-
designated-labs), a CLIA OCAv3 report from MoCha indicating that a patient carries 
an eligible aMOI is sufficient for enrollment on the NCI MATCH (NCT02465060) 
and MPACT (NCT01827384) trials.  
 
Mutations detected by the assay may be present only in the tumor, or in every cell of 
the body; this test also cannot tell whether a potential germline mutation causes or will 
cause a hereditary cancer syndrome.  If the patient’s personal and/or family history are 
suggestive of a hereditary cancer predisposition, it is recommended that the PI arrange 
for the patient to meet with a genetic counselor and, if warranted, undergo the 
appropriate genetic test.   
 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
24 
 
A Certificate of Confidentiality has been obtained from the NIH to help protect the 
privacy of all study participants.  Information on tumor gene variants will be stored in 
the patient’s medical records. 
 
3 PATIENT SELECTION 
3.1 
Eligibility Criteria 
3.1.1 Patients must have histologically confirmed solid tumors for which standard therapy 
known to prolong survival has failed in the metastatic setting or for which standard 
therapies do not exist. 
3.1.2 Tumor amenable to biopsy and willingness to undergo tumor biopsies before and after 
M6620 (VX-970) treatment during the expansion phase of the trial (biopsies optional 
during the escalation phase).  
3.1.3 Patients must have completed any chemotherapy, radiation therapy, surgery, or 
biologic therapy ≥3 weeks (or ≥ 5 half-lives, whichever is shorter) prior to entering 
the study.  Patients must be ≥ 2 weeks since any prior administration of a study drug 
in an exploratory IND/Phase 0 study and ≥ 1 week since any palliative radiation 
therapy.  Patients must have recovered to eligibility levels from prior toxicity or 
adverse events. 
3.1.4 Age ≥18 years of age.   
3.1.5 ECOG performance status ≤ 2 (see Appendix A). 
3.1.6 Life expectancy > 3 months. 
3.1.7 Patients must have normal organ and marrow function as defined below: 
− absolute neutrophil count  
≥1,500/mcL 
− hemoglobin  
 
 
 
 
≥ 10 g/dL 
− platelets  
 
 
 
 
 
≥100,000/mcL 
− total bilirubin 
 
 
 
 
≤1.5 X institutional upper limit of normal 
− AST(SGOT)/ALT(SGPT)  
≤1.5 X institutional upper limit of normal  
 
 
 
 
 
 
 
 
(OR ≤ 3X ULN in the setting of liver metastases) 
− creatinine 
 
 
 
 
 
≤1.5X institutional upper limit of normal 
 
OR 
 
− creatinine clearance  
 
 
≥ 60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal 
3.1.8 The effects of M6620 (VX-970) and veliparib on the developing human fetus are 
unknown.  For this reason and because cisplatin is known to be teratogenic, 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, for the duration of 
study participation, and for 6 months after completing study treatment.  Should a 
woman become pregnant or suspect she is pregnant while she or her partner is 


CTEP # P9771 
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participating in this study, she should inform her treating physician immediately.  Men 
treated or enrolled on this protocol must also agree to use adequate contraception prior 
to the study, for the duration of study participation, and for 6 months after completion 
of administration of study agents. 
3.1.9 HIV-positive subjects on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with M6620 (VX-970).  In addition, 
these subjects are at increased risk of lethal infections when treated with marrow-
suppressive therapy. 
3.1.10 Patients must be able to swallow whole tablets or capsules.  Nasogastric or G-tube 
administration is not allowed.  Any gastrointestinal disease which would impair 
ability to swallow, retain, or absorb drug is not allowed. 
3.1.11 Ability to understand and the willingness to sign a written informed consent form. 
3.1.12 During the expansion phase of the protocol, patients must have disease amenable to 
biopsy and be willing to undergo pre- and post-treatment biopsies. 
3.1.13 Patients must have ≥10.0 g/dL Hb and no blood transfusion in the past 28 days to 
receive Veliparib. 
3.2 
Exclusion Criteria 
3.2.1 Patients who are receiving any other investigational agents. 
3.2.2 Patients with known active brain metastases or carcinomatous meningitis are excluded 
from this clinical trial.  Patients whose brain metastatic disease status has remained 
stable for ≥ 4 weeks following treatment of brain metastases are eligible to participate 
at the discretion of the principal investigator. 
3.2.3 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
untreated infection, or psychiatric illness/social situations that would limit compliance 
with study requirements.   
3.2.4 Patients required to be on any of the concomitant medications listed in Appendix B 
are excluded.  
3.2.5 Pregnant women and women who are breastfeeding are excluded from this study 
because the effects of the study drugs on the developing fetus are unknown.   
3.2.6 Patients who have had prior platinum-based therapy who have > Grade 1 
neurotoxicity or ototoxicity at the time of enrollment will not be permitted on study. 
3.2.7 Patients with a seizure history will not be permitted on protocol due to association of 
veliparib with seizure activity in animal toxicology studies at higher doses.  Patients 
on anticonvulsant medications will not be permitted on study due to the potential to 
lower plasma levels of anticonvulsants and risk for seizure activity. 


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26 
 
3.2.8 Patients with treatment-related AML (t-AML)/MDS, or with features suggestive of 
AML/MDS, or who have had prior allogeneic bone marrow transplant or double 
umbilical cord blood transplantation, should not receive Veliparib due to reports of 
MDS and leukemia secondary to oncology therapy on CTEP-sponsored studies 
utilizing Veliparib. 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
3.4 
Screening Evaluation 
3.4.1 Histologic confirmation of primary tumor tissue or of known recurrence will be 
required from each participant to confirm diagnosis.  Pathology reports from outside 
institutions will be accepted. 
3.4.2 History and physical examination: Complete history and physical examination 
(including height, weight, vital signs, ECG, and performance score) will be conducted 
within 8 days prior to enrollment.   
3.4.3 Imaging Studies (Baseline): Every participant should have an evaluation of known 
sites of disease as part of the baseline evaluation.  All patients will be required to 
undergo a CT scan of the chest/abdomen/pelvis to evaluate sites of disease within 28 
days prior to enrollment.  MRI evaluation of site of disease may be performed in lieu 
of CT evaluation at the discretion of the principal investigator if it is the opinion of the 
investigator that this modality would provide a more accurate assessment of disease 
than a CT would, for a given site. 
3.4.4 Laboratory Evaluation: Baseline laboratory data are to be obtained within 8 days prior 
to enrollment: 
• Hematological Profile: CBC with differential. 
• Biochemical Profile: albumin, total bilirubin, BUN, calcium, creatinine, SGOT 
[AST], SGPT [ALT], magnesium, potassium, and sodium. 
• Coagulation Profile: PT, PTT, INR required within 1 week prior to all biopsies, and 
may also be performed as clinically indicated.   
• Serum or urine pregnancy test for female participants of childbearing potential. 
 
4 REGISTRATION PROCEDURES 
4.1 
NCI Clinical Center Patient Registration Process 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
and through the Theradex Interactive Web Response System (IWRS) within 24 hours after signing 
consent.  Access IWRS through https://iwrs.theradex.com under the “Patient” tab utilizing your 
CTEP-IAM Username and Password.  A registration Eligibility Checklist from the Web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 






CTEP # P9771 
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29 
 
o Day 15 (may be performed by patients’ home oncologist) 
• Cycle 2 and beyond 
o Day 1 prior to treatment 
o Week 2 prior to first IV treatment 
o Day 15 (optional and may be performed by patients’ home oncologist) 
 
CT scans will be performed at baseline (within 28 days prior to start of protocol therapy), and 
repeat-imaging scans will be performed every 2 cycles (every 3 cycles for patients on study for 
more than one year, 4 cycles for patients on study more than 3 years).  MRI evaluation of site of 
disease may be performed in lieu of CT evaluation at the discretion of the principal investigator if 
it is the opinion of the investigator that this modality would provide a more accurate assessment 
of disease than a CT would for a given site. 
 
ECG will be performed at baseline (within 8 days prior to start of protocol therapy), within 
approximately 1 hour after the end of M6620 (VX-970) infusion during cycle 1 only, and as 
clinically indicated. 
 
The starting dose will start at dose level 1 per dosing schema below.  Intra-patient dose escalation 
will be allowed.   
 
Once the MTD is established, additional patients will be enrolled to the expansion phase as 
described in Section 13.1. 
 
5.1 
Agent Administration 
5.1.1 M6620 (VX-970) Administration 
M6620 (VX-970) will be administered intravenously, over one hour (± 10 minutes) 
on days 2 and 9 of each 21-day cycle (or on days 1 and 8 of any cycle in which 
cisplatin is not administered).  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 Veliparib administration 
Veliparib will be administered orally on days 1 through 3 and days 8 through 10  of 
each 21-day cycle.  Veliparib should be administered before cisplatin and M6620 
(VX-970). 


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5.1.3 Cisplatin administration 
Cisplatin will be administered at 40 mg/m2 intravenously over one hour (± 10 
minutes), via central or peripheral access on day 1 (and day 8 on DL3 and higher) of 
each 21-day cycle.  As of Amendment I (12/7/2017), patients who have been on trial 
for at least 6 cycles may have cisplatin administration held or discontinued while 
continuing on trial at the discretion of the PI, Dr. 
 to address the potential for 
cumulative neurotoxicity observed with extended cisplatin treatment. 
• 
Prior to cisplatin administration, at least 500 mL of 0.9% sodium chloride with 
KCl 10 mEq/L and magnesium sulfate 4 mEq/L injection should be 
administered over at least 60 minutes.  Following administration of cisplatin, 
at least an additional 500 mL of 0.9% sodium chloride with KCl 10 mEq/L 
and magnesium sulfate 4 mEq/L injection should be administered over at least 
60 minutes.   
• 
Patients will additionally receive pre-medication with anti-emetics. The 
following regimen is recommended for initial antiemetic prophylaxis; 
administration of steroids will be at the discretion of the investigator: 
− 
Dexamethasone 12 mg orally at least 60 minutes prior to cisplatin on 
day 1 (and day 8 on DL 3 and above) of each 21-day cycle. 
− 
Aprepitant 125 mg orally given at least 60 minutes prior to cisplatin on day 
1 (and day 8 on DL 3 and above) of each 21-day cycle, followed by 80 mg 
orally daily for days 2 and 3 (and days 9 and 10 on DL 3 and higher)* 
− 
Ondansetron 8 mg orally given at least 60 minutes prior to cisplatin on 
day 1 (and day 8 on DL 3 and above) of each 21-day cycle, and 
continued every 8 hours for days 1-5 (and days 8-12 on DL 3 and 
higher) 
For patient convenience, pre-medications can alternatively be given 
intravenously 30 minutes prior to therapy.   
*A single 150 mg dose of fosaprepitant IV may be given prior to cisplatin in 
lieu of the oral aprepitant, or another anti-emetic may be used if aprepitant is 
not tolerated. 
 
 
Dosing Schema: 
Dose 
Level 
Veliparib 
(PO q12 hours ± 1 hour) 
M6620 (VX-970) 
 (IV Days 1/2 and 8/9) 
Cisplatin 
(IV Day 1 or Days 1 
and 8) 
-2 
20 mg days 1-3, 8-10 
40 mg/m2 
40 mg/m2 day 1 
-1 
40 mg days 1-3, 8-10 
60 mg/m2 
40 mg/m2 day 1 
1 
100 mg days 1-3, 8-10 
 90 mg/m2 
40 mg/m2 day 1 
2 
100 mg days 1-3, 8-10 
140 mg/m2 
40 mg/m2 day 1 


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3 
100 mg days 1-3, 8-10 
120 mg/m2 
40 mg/m2 days 1, 8 
4 
100 mg days 1-3, 8-10 
210 mg/m2 
40 mg/m2 days 1, 8 
5 
150 mg days 1-3, 8-10 
210 mg/m2 
40 mg/m2 days 1, 8 
6 
200 mg days 1-3, 8-10 
210 mg/m2 
40 mg/m2 days 1, 8 
7 
300 mg days 1-3, 8-10 
210 mg/m2 
40 mg/m2 days 1, 8 
8 
400 mg days 1-3, 8-10 
210 mg/m2 
40 mg/m2 days 1, 8 
 
Doses will be calculated based on body surface area per institutional SOP. 
As of Amendment L (dated 4/22/2019), the MTD for this combination has been established 
as DL6. 
5.2 
Intra-patient Dose Escalation   
Intra-patient dose escalation is permitted ONLY if: a) there is no toxicity > grade 1 that is 
possibly, probably, or definitely related to the study drugs after one cycle at the patient’s initially 
assigned dose level (subsequent cycles may be delayed up to 14 days past the end of the previous 
21-day cycle to allow for toxicities to resolve), b) higher doses have been evaluated and 
completed without DLT, and c) disease has not progressed.  Doses may be escalated by one dose 
level for every subsequent cycle, provided conditions a–c are met, up to the last evaluated dose 
level NOT associated with DLT. 
 
Intra-patient dose reductions: If a patient experiences DLT during a cycle, the dose will be 
reduced by one level (if there is a lower dose level) for the next cycle, provided toxicity has 
recovered to ≤ Grade 1 within 14 days after completing a 21-day cycle, and the patient’s disease 
is stable or responding.  If a patient is dose reduced twice and still experiences a DLT, then the 
patient would be removed from the study unless the patient is experiencing clinical benefit and, at 
the PI’s discretion, should be allowed to continue on study.  If no lower dose level exists, then the 
patient will be removed from the study.   
 
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. 
5.3 
Definition of Dose-Limiting Toxicity 
Determination of dose-limiting toxicity (DLT) will be based on toxicities observed in the first 
cycle of therapy.  Dose escalation will proceed within each cohort according to the following 
scheme.  DLT is defined below: 
 
Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 


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0 out of 3 
Enter 3 patients at the next dose level. 
≥ 2 
Dose escalation is stopped, and this dose is declared the maximally 
administered dose.  Three (3) additional patients will be entered at the 
next lowest dose level if only 3 patients were treated previously at that 
dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the next dose level. 
• If 1 or more of this group suffer DLT, then dose escalation is stopped, 
and this dose is declared the maximally administered dose.  Three (3) 
additional patients will be entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
≤ 1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is generally the recommended phase 2 dose.  At least 6 patients must 
be entered at the recommended phase 2 dose. 
 
Dose limiting toxicity (DLT) is defined as an adverse event that is related (possibly, 
probably, or definitely) to administration of study drugs and fulfills one of the following 
criteria. 
5.3.1 Grade ≥ 3 Non-Hematological Toxicity 
Grade ≥ 3 non-hematological toxicity thought to be related to study medications will 
be considered dose-limiting with the following clarifications: 
Diarrhea Grade 3 will only be considered dose-limiting if it is refractory to treatment 
as outlined in Section 5.3.2, Supportive Care Guideline, and unable to be corrected to 
Grade 2 or less within 24 hours.  Bloody or Grade 4 diarrhea will be dose-limiting. 
 
Vomiting Grade 3 will only be considered dose-limiting if it is refractory to anti-
emetic therapy and unable to be corrected to Grade 2 or less as outlined in Section 
5.3.1.   
 
Nausea Grade 3 will only be considered dose limiting if symptoms and severity persist 
beyond 48 hours despite continuation of anti-emetics. 
Rise in creatinine to Grade 3, not corrected to Grade 1 or less within 48 hours with IV 
fluids will be considered dose-limiting.  All Grade 4 rises in creatinine will be dose 
limiting. 
 
Grade ≥ 3 metabolic toxicities unable to be corrected to Grade 1 or baseline within 48 
hours (hypocalcemia, hypercalcemia, hypomagnesemia, and hyponatremia) will be 
considered dose limiting.  For hypokalemia or hyperkalemia, grade ≥ 2 toxicities 
unable to be corrected to grade 1 or less within 48 hours will be considered dose 
limiting.   
 
Grade 4 metabolic toxicities that are symptomatic will be considered dose limiting 
regardless of duration or ability to correct. 


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5.3.2 Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding. 
5.3.3 Grade 4 neutropenia ≥ 5 days or febrile neutropenia will be considered dose limiting. 
5.3.4 Any degree of leukopenia in the absence of grade 4 neutropenia ≥ 5 days, or 
lymphopenia will not be considered dose limiting. 
5.3.5 Any degree of alopecia will not be considered dose limiting. 
5.3.6 Grade 3 fatigue of greater than 1 week duration. 
5.3.7 Failure to tolerate 100% of the dosing in the first cycle. 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
The predominant toxicity observed in clinical and non-clinical toxicology studies was 
hematologic.  Weekly blood counts and chemistry panels will be obtained prior to treatment each 
week.  If any weekly evaluation demonstrates grade 2 neutropenia or thrombocytopenia, treatment 
will proceed but a repeat hematology assessment will be obtained within 48 hours for interval 
evaluation.  Platelet count must improve to Grade 1 or better and neutrophil count must improve 
to Grade 2 or better on repeat hematology assessment prior to the next cycle. 
 
All patients will be provided with the best available supportive care.  All concomitant medications 
should be documented prior to initiation of treatment, and be periodically reviewed with the 
patient.  Because there is a potential for interaction of M6620 (VX-970) and Veliparib with other 
concomitantly administered drugs, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies.  The PI should be alerted if the 
patient is taking any agent known to affect or with the potential for drug interactions.  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.  Veliparib is metabolized by CYP1A1, 2D6, 2C19, and 3A4; it is not 
known whether its metabolism is affected by drugs that are strong inhibitors or inducers of these 
enzymes.  To date, no clinically significant pharmacokinetic drug-drug interaction has been 
reported for Veliparib.  The study team should check a frequently-updated medical reference for a 
list of drugs to avoid or minimize use of. 
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. 
To minimize the possibility of phlebitis, M6620 (VX-970) should be administered through a 
large-bore catheter into a large-caliber peripheral vein or through central venous access.  The 
intravenous infusion site should be monitored closely for the development of erythema, 
induration, purulence, tenderness, or warmth. 
 


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5.4.1 Nausea/Vomiting 
As cisplatin is known to be highly emetogenic, patients will receive pre-medication with the 
following anti-emetics prior to administration of cisplatin (steroids at the discretion of the 
investigator): 
- 
Dexamethasone 12 mg orally at least 60 minutes prior to cisplatin on day 1 (and day 8 
on DL 3 and higher) of a 21-day cycle, every 21 days 
- 
Aprepitant 125 mg orally given at least 60 minutes prior to cisplatin on day 1 (and day 
8 on DL 3 and above) of each 21-day cycle, followed by 80 mg orally daily for days 2 
and 3 (and days 9 and 10 on DL 3 and higher) 
- 
Ondansetron 8 mg orally given at least 60 minutes prior to cisplatin on day 1 (and day 8 
on DL 3 and above) of each 21-day cycle, and continued every 8 hours for days 1-5 
(and days 8-12 on DL 3 and higher) 
For patient convenience, pre-medications can alternatively be given intravenously 30 minutes 
prior to therapy.  A single 150 mg dose of fosaprepitant IV may be given prior to cisplatin, in 
lieu of the 3 days of oral aprepitant, or another anti-emetic may be used if aprepitant is not 
tolerated.   
 
If the patient is well and beyond the first cycle, steroid dose reduction may be considered at 
the discretion of the investigator. 
 
The addition of dopamine receptor antagonists or benzodiazepines will be at the discretion of 
the investigator.  Vomiting will be considered refractory if it does not resolve to ≤ Grade 1 
within 24 hours.  Nausea ≤ Grade 2 will be considered refractory if symptoms and severity 
persist past 48 hours after cisplatin dosing despite continuation of anti-emetics. 
 
5.4.2 Diarrhea 
If diarrhea develops and does not have an identifiable cause other than study agents, 
anti-motility agents (e.g., loperamide, diphenoxylate/atropine) with be given after the 
first unformed stool, with continuation until the first formed stool.  Diarrhea will be 
considered refractory if it does not resolve within 24 hours to ≤ Grade 1 with the 
above measures.  If the patient develops blood or mucous in the stool, dehydration, or 
hemodynamic instability, or fever along with the diarrhea, patient will receive IV 
fluids and antibiotics as medically indicated. 
5.4.3 Seizures 
Seizures were seen in some animal toxicology studies for veliparib, although at doses 
higher than those anticipated in this study.  In the phase I single agent trial, seizures 
were seen at 400-500 mg BID.  Seizures were successfully treated with lorazepam, 
which will be considered the drug of first choice for controlling seizures, should they 
occur on this study.  Any seizure occurring in a patient on this study will be 
considered a DLT.  


CTEP # P9771 
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5.4.4 Neutropenia 
To reduce the risk of severe myelosuppression events, a complete blood count (CBC) 
should be performed on weeks 1 and 2 of each cycle prior to cisplatin or M6620 (VX-
970) treatment and again on days 2, 9, and 15 of the first cycle.  Pegfilgrastim should 
be avoided as it requires 14 days between dosing and the next administration of 
chemotherapy.  Febrile neutropenia is a life-threatening complication requiring 
hospitalization and urgent broad-spectrum antibiotics, as well as an aggressive search 
for the source and microbial cause of the episode.  Growth factors to prevent 
neutropenia will not be administered prophylactically.  If necessary, they may be 
administered according to accepted American Society of Clinical Oncology (ASCO) 
guidelines to allow re-treatment.  
5.4.5 Anemia 
Symptomatic anemia should be treated with red blood cell transfusion as clinically 
indicated, and is recommended if the hemoglobin falls below 8 g/dL.  The initiation of 
erythropoietic therapy for the management of chemotherapy-induced anemia follows 
the American Society of Hematology/ASCO clinical practice guidelines 
(http://www.asco.org).  
5.4.6 Thrombocytopenia 
Thrombocytopenia will be closely monitored on study.  In the absence of bleeding, or 
a necessary invasive procedure, platelet transfusions should be considered for a 
platelet count ≤ 25,000/mm3.  If invasive procedure(s) is (are) planned, or the patient 
develops bleeding, platelet transfusions will be administered as clinically indicated.  
5.4.7 Acute hypersensitivity reaction/severe infusion reaction 
Patients should be monitored during M6620 (VX-970) infusion for these reactions, 
which may include loss of consciousness and/or hemodynamic instability, including 
hypotension.  In the event of one of these reactions, the infusion should be stopped 
immediately and standard supportive measures should be applied according to the 
presentation.  This may include administration of fluids and epinephrine. 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until one 
of the following criteria applies: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Pregnancy 
• 
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. 


CTEP # P9771 
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5.6 
Duration of Follow Up 
Patients will be followed for 30 days after the last dose is administered or until one of the 
following occurs: patient enrolls on another protocol, patient receives standard of care, or death, 
whichever comes first.  The follow-up will consist of a phone call between Days 27-30 after the 
last dose to evaluate adverse events that were ongoing and any new events that might be deemed 
related to the therapy.  Toxicities considered to be possibly, probably, or definitely related to the 
study drugs that have not resolved or stabilized by Day 30 post-treatment will be followed until 
stabilization or resolution via phone calls as clinically indicated. 
5.7 
Criteria for Removal from Study 
Patients will be removed from study for one of the following reasons: completed 30-day follow up 
period or toxicities are unresolved but stabilized, patient enrolls on another protocol, or patient 
receives standard of care.  The reason for study removal and the date the patient was removed 
must be documented in the medical record and communicated by fax to the NCI Central 
Registration Office per Section 4. 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
Toxicities should have resolved to ≤ Grade 2 (Grade 1 for some hematologic toxicities) prior to 
starting the next cycle.  Treatment may be delayed for a maximum of 3 weeks beyond the actual 
cycle length of 21 days for toxicities that develop and do not resolve as defined above.  Beyond 3 
weeks, the patient may remain in the study at the discretion of the PI unless noted otherwise.  
Treatment may be delayed for a maximum of ± 1 day during a cycle due to unavoidable 
scheduling conflicts.  If treatment is held during a cycle, that week’s treatment will be omitted for 
the cycle and treatment will proceed with the following week’s treatment as scheduled (e.g., if 
Day 2 M6620 (VX-970) treatment is held, the next treatment will be Day 9).  Missed doses of 
veliparib will not be made up and will be documented in the patient’s diary (see Appendix C).  
This applies starting with cycle 2 and beyond.  If this occurs during cycle 1, the patient will be 
considered not evaluable and will need to be replaced on study. 
 
 
6.1 
Dose Modifications 
Dose modifications are defined below: 
6.1.1 Grade 2 drug-related toxicity: The dose of cisplatin will be reduced to 30 mg/m2 
without a concomitant dose reduction in M6620 (VX-970) or veliparib for any Grade 
2 ototoxicity, neurotoxicity, or persisting Grade 2 rise in creatinine.  A second 
recurrence of Grade 2 nephrotoxicity, ototoxicity, or neurotoxicity despite dose 
reduction will result in discontinuation of treatment.  Treatment will not be held for 
Grade 2 hematologic toxicities. 
Grade 3-4 drug-related non-hematologic toxicities attributed to all 3 drugs: Treatment 
will be held until toxicities recover to ≤ Grade 2 or baseline prior to re-initiating 
treatment at the next lower dose level.  If electrolyte abnormalities do not resolve to 
 


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grade 2 or less within 48 hours, dose reduction will be required.  Dose modifications 
for nausea, vomiting, and diarrhea will be made only if they are refractory to 
treatment and symptoms and severity persist beyond 48 hours for nausea and 
vomiting, or beyond 24 hours for diarrhea (See Section 5.2).  
6.1.2 Grade 3 drug-related hematologic toxicities: 
Treatment will be held for a maximum of 3 weeks until hematologic toxicities, except  
leucopenia in the absence of Grade 3 or higher neutropenia, have resolved to ≤ Grade 
1 prior to re-initiating treatment at a lower dose level.   See also Section 6.2. 
6.1.3 Grade 4 Drug-related Hematologic Toxicities: Treatment will be held for a maximum 
of 3 weeks until hematologic toxicities, except leucopenia in the absence of Grade 4 
neutropenia, have resolved to ≤ Grade 1 prior to re-initiating treatment at a lower dose 
level. See also Section 6.2. 
6.1.4 Anaphylactic reaction attributed to cisplatin: Symptoms have included facial edema, 
wheezing, tachycardia, and hypotension during or within a few minutes after drug 
administration.  Treatment will be held and supportive measures implemented 
including administration of epinephrine 1:1000 (1 mg/mL) 0.3 mg SQ/IM, and 
intravenous fluid support for hypotension.  Treatment may not be restarted.  
6.1.5 Infusional reaction attributed to M6620 (VX-970): Symptoms may include pruritis, 
flushing, shortness of breath, chest tightness, dizziness, headache, increased or 
decreased blood pressure, loss of consciousness, and increased heart rate. 
Severity of Symptoms 
 
Mild transient reaction 
Give diphenhydramine HCl 25 mg to 50 mg IV, continue 
treatment, close monitoring of vitals q 5 min.  for 15 min. after 
onset of symptoms.   
Mild to moderate persistent reaction 
Stop treatment; give dexamethasone 10 mg IV and 
diphenhydramine HCl 25 mg to 50 mg IV; may resume treatment 
after recovery of symptoms; premedication indicated for 
subsequent drug administration: pre-medication indicated prior to 
re-initiation: dexamethasone 12 mg PO and diphenhydramine HCl 
25 mg to 50 mg PO approximately 4 to 6 hours prior to re-
challenge 
Severe symptoms (e.g., hypotension 
requiring pressor therapy or IV 
fluids, angioedema, respiratory 
distress requiring bronchodilator 
therapy, or generalized urticaria) 
Stop treatment; give dexamethasone 10 mg IV and 
diphenhydramine HCl 25 mg to 50 mg IV; add bronchodilators as 
needed; patients may not receive further treatment; the patient will 
be taken off study.   
 
6.2 
Agent-specific Dose Modifications: Veliparib 
To date, four cases of grade 4 myelodysplastic syndrome (MDS) and two cases of 
leukemia secondary to oncology therapy (one grade 4 and one grade 5) were observed on 
CTEP-sponsored studies utilizing veliparib.  It is possible veliparib contributed to these 


CTEP # P9771 
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adverse events; it is also possible that prior therapy with platinum or alkylating agents 
contributed to the development of MDS or leukemia. 
 
If a patient is taking veliparib in combination with other therapies, but develops bone 
marrow findings consistent with acute myeloid leukemia (AML)/MDS or severe persistent 
anemia requiring transfusion to maintain ≥10 g/dL hemoglobin, the patient may be allowed 
to continue the other therapies if they are experiencing clinical benefit and the toxicity is 
not related to the other therapies, based on the opinion of the treating investigator, and 
after discussion with the Principal Investigator.  Patients who develop MDS/AML on 
treatment should discontinue ABT-888 treatment and be managed appropriately. 
 
In addition, patients should be monitored for persistent myelosuppression, including 
anemia, thrombocytopenia, and neutropenia that does not recover to normal or grade 1 
between courses of treatment, as per Good Clinical Practice.  If peripheral blood counts do 
not recover to normal or are persistently abnormal, the patient should be evaluated for the 
possible development of AML/MDS using a bone marrow aspirate with cytogenetics.  
veliparib therapy should be held and discontinued if AML/MDS is documented.  A 
complete history of prior therapy should be documented, particularly prior platinum-based 
or alkylating agent therapies.  Documentation of germline BRCA mutation (gBRCAm) 
status, if known, should be recorded. 
 
Management of neutropenia and thrombocytopenia 
 
 
CTCAE Grade Definition 
Veliparib Dose 
1-2 
ANC >1.0 G/L or Platelet 
count >50 G/L 
Investigator judgement to continue treatment 
or allow dose interruption; dose interruptions 
should be for a maximum of 3 weeks; 
appropriate supportive treatment and causality 
investigation. 
3-4 
ANC <1.0 G/L or Platelet 
count <50 G/L 
Dose interruption until recovered to CTCAE 
Grade ≤1 for a maximum of 3 weeks.  Upon 
recovery, veliparib dose should be reduced by 
one dose level.  If repeat CTCAE Grade 3-4 
occurrence, further dose reduce one veliparib 
dose level. 
ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events 
 
Use of hematopoietic agents 
 
Use erythropoietin-stimulating agents per standard of care National Comprehensive 
Cancer Network (NCCN) and/or institutional guidelines, iron supplements, and/or 
transfusions as clinically indicated for management of anemia.   Prescribing information 
for the erythropoiesis stimulating agents (including Aranesp, Epogen and Procrit) 
highlight that there is a potential risk of shortening the time to tumor progression or 
disease-free survival.   Primary prophylaxis with granulocyte colony-stimulating factor 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
39 
 
(G-CSF) is not recommended.  Aranesp, Epogen and Procrit may not alleviate fatigue or 
increase energy, and should not be used in patients with uncontrolled hypertension.  The 
package inserts for these agents should be consulted. 
 
If a patient develops febrile neutropenia, veliparib should be stopped and appropriate 
management including G-CSF should be given according to local hospital guidelines.   
Please note that G-CSF should not be used within at least 24 hours of the last dose of 
veliparib unless absolutely necessary. 
 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
 
Dose modifications for hematologic toxicity 
 
Patients who have veliparib held for hematologic toxicities should have blood counts 
and differentials checked at least weekly until recovery; these data should be recorded in 
eCRF as extra laboratory examinations.   If counts do not improve to CTCAE Grade 1 
or better despite drug cessation for 3 weeks, patients should be referred to a 
hematological oncologist for further assessment.   A bone marrow analysis should be 
considered. 
 
For AEs that are unrelated to the study drug, study drug may be withheld for up to 3 
weeks at the discretion of the treating Investigator. 
 
 
Management of anemia 
 
 
CTCAE Grade Definition 
ABT-888 Dose 
2 
Hb <10 but ≥8 g/dL 
Give appropriate supportive treatment and 
investigate causality.  Investigator judgement 
to continue veliparib or interrupt dose for a 
maximum of 3 weeks.  If repeat Hb <10 but ≥8 
g/dL, dose interrupt until Hb ≥10 g/dL for 
maximum of 3 weeks and upon recovery dose 
reduce per the schema.   
3 
Hb <8 g/dL 
Give appropriate supportive treatment and 
investigate causality.  Interrupt veliparib until 
improved to Hb ≥10 g/dL.  Upon recovery, 
dose reduce veliparib. 
BID = twice daily; Hb = hemoglobin 
 
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases, 
management of anemia may require blood transfusions.  Any subsequently required 
dose interruptions related to development of anemia, or coexistent with newly 
developed neutropenia, and/or thrombocytopenia, will require veliparib dose reductions 
per the dosing schema.   


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
40 
 
 
If Hb drops to <8 g/dL despite the dose reduction or more than one blood transfusion is 
required to recover Hb levels with no alternative explanation for the anemia, veliparib 
should be permanently discontinued. 
 
Management of prolonged hematological toxicities while on study treatment 
 
If a patient develops prolonged hematological toxicity such as: 
• ≥2 week interruption/delay in veliparib due to CTCAE Grade ≥3 anemia (Hb <8 
g/dL) and/or development of blood transfusion dependence 
• ≥2 week interruption/delay in veliparib due to CTCAE Grade ≥3 neutropenia (ANC <1 x 
109/L) 
• ≥2 week interruption/delay in veliparib due to CTCAE Grade ≥3 thrombocytopenia 
and/or development of platelet transfusion dependence (Platelets <50 x 109/L) 
 
Check weekly differential blood counts including reticulocytes and peripheral blood 
smear.   If any blood parameters remain clinically abnormal after 3 weeks of dose 
interruption, the patient should be referred to a hematological oncologist for further 
investigations.   Bone marrow for evaluation and cytogenetics should be considered at 
this stage according to standard hematological oncology practice.   Veliparib should be 
discontinued if blood counts do not recover to CTCAE Grade ≤1 within 3 weeks of dose 
interruption. 
 
 
 
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 CTEP-AERS) in addition to 
routine reporting. 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for ABT-888 
(Veliparib, NSC 737664) 
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. Frequency is provided based on 2310 patients. Below is the CAEPR for 
ABT-888 (Veliparib). 




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42 
 
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. 
 
2Thromboembolic events, including deep vein thrombosis and pulmonary embolism, have been 
observed at a higher frequency compared to control arm when administered in combination with 
temozolomide. 
 
 
Adverse events reported on ABT-888 (Veliparib) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that ABT-888 (Veliparib) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Blood and 
lymphatic system disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Cardiac disorders - Other (Takotsubo cardiomyopathy); Heart 
failure; Left ventricular systolic dysfunction; Palpitations; Sinus bradycardia; Sinus tachycardia 
Ear and labyrinth disorders - Vertigo 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Colonic 
obstruction; Dental caries; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; 
Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; Lower gastrointestinal 
hemorrhage; Mucositis oral; Obstruction gastric; Rectal hemorrhage; Rectal pain; Small intestinal 
obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
limbs; Fever; Flu like symptoms; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (cirrhosis) 
INFECTIONS AND INFESTATIONS - Appendicitis; Catheter related infection; Infections and 
infestations - Other (peritonsillar abscess); Lung infection; Lymph gland infection; Mucosal 
infection; Sepsis; Shingles; Skin infection; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis 
radiation; Radiation recall reaction (dermatologic) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; Cardiac troponin I increased; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypernatremia; 
Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; 
Back pain; Bone pain; Generalized muscle weakness; Muscle cramp; Myalgia; Neck pain; Pain in 
extremity 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) -Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of 
consciousness; Dysarthria; Extrapyramidal disorder; Intracranial hemorrhage; Lethargy; Memory 
impairment; Movements involuntary; Paresthesia; Peripheral motor neuropathy; Peripheral 






CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
45 
 
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 
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. 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
46 
 
 
 
 
7.3 
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. 
 
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. 
7.4 
Expedited Adverse Event Reporting 
7.4.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Expedited Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov).  
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).  These requirements are briefly outlined in the tables below 
(Section 7.4.2). 
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. 
 
For participating sites: The site PI must immediately report to the coordinating 
center PI any serious adverse event, whether or not considered drug related, including 
those listed in the protocol or investigator brochure and must include an assessment of 
whether there is a reasonable possibility that the drug caused the event within 24 
hours of PI awareness of the event.  The Site PI must also report any protocol 
deviations to the coordinating center PI within 7 days of PI awareness. Participating 
centers must also submit the report to their IRB in accordance with their institutional 
policies. 
7.4.2 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during 




CTEP # P9771 
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48 
 
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 
 
7.4.3 Protocol-specific expedited AE reporting exclusions 
For this protocol only, certain AEs/grades are exceptions to the Expedited Reporting 
Guidelines and do not require expedited reporting (i.e., CTEP-AERS).  These are any 
grade lymphopenia, any grade alopecia, Grade 2 electrolyte (sodium, potassium, 
phosphorous, magnesium) abnormalities, Grade 2 anemia, Grade 2 hypoalbuminemia, 
Grade 2 hyperglycemia, Grade 2 INR, Grade 2 PTT, and Grade 2 hyperuricemia will 
NOT be reported through CTEP-AERS but will be reported in the routine data 
submissions. 
7.4.4 Pregnancy, Fetal Death, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Neonatal loss”, the Pregnancy Information Form should also be completed for 
patients who became pregnant on study, and faxed along with any additional medical 
information to 301-230-0159.  The potential risk of exposure of the fetus to the 
investigational agent(s) or chemotherapy agent(s) should be documented in the 
“Description of Event” section of the CTEP-AERS report. 
 
Pregnancy 
• Because patients who become pregnant on study risk intrauterine exposure of 
the fetus to agents which may be teratogenic, DCTD/DCP is requesting that 
pregnancy should be reported in an expedited manner via CTEP-AERS as 
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal conditions 
SOC. 
• The pregnancy outcome for patients on study should be reported via CTEP-
AERS at the time the outcome becomes known, accompanied by the same 
Pregnancy Report Form used for the initial report. 
 
Pregnancy loss 
• Pregnancy loss is defined in CTCAE as “Death in utero.” 
• Any Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy 
loss” under the Pregnancy, puerperium and perinatal conditions SOC. 
• A Pregnancy loss should NOT be reported as a Grade 5 event under 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
49 
 
the Pregnancy, puerperium and perinatal conditions SOC, as currently 
CTEPAERS recognizes this event as a patient death. 
 
Death Neonatal 
• Neonatal death, defined in CTCAE as “A disorder characterized by cessation 
of life occurring during the first 28 days of life” that is felt by the investigator 
to be at least possibly due to the investigational agent/intervention, should be 
reported expeditiously. 
• A neonatal death should be reported expeditiously as Grade 4, “Death 
neonatal” under the General disorders and administration SOC. 
• Neonatal death should NOT be reported as “Death neonatal” under the 
General disorders and administration SOC, a Grade 5 event.  If reported as 
such, the CTEP-AERS interprets this as a death of the patient being treated. 
7.4.5 NIH-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, and 
Deaths 
Definitions 
 
Adverse event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs 
during the course of the clinical trial associated with the use of a drug in humans, 
whether or not the event is considered related to the treatment or clinically significant.  
For this study, AEs will include events reported by the patient, as well as clinically 
significant abnormal findings on physical examination or laboratory evaluation.  A new 
illness, symptom, sign or clinically significant laboratory abnormality or worsening of 
a pre-existing condition or abnormality is considered an AE.  All AEs must be recorded 
on the AE case report form unless otherwise noted above in Section 7.3.3. 
 
All AEs, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until satisfactory resolution.  AEs should be 
reported up to 30 days following the last dose of study drug.   
 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms 
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including 
hospitalization 
• Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the 
investigator will provide details about the action taken with respect to the test 
drug and about the patient’s outcome. 
 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
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Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. 
 
Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application.  “Unexpected” also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug 
under investigation. 
 
Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of 
a Serious Adverse Event or if it compromises the safety, welfare or rights of subjects 
or others.  
 
Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of 
the investigator or the sponsor, it results in any of the following:  
• 
Death 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience when, 
based upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
 
Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
 
Life-threatening adverse drug experience 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
51 
 
Any adverse event or suspected adverse reaction that places the patient or subject, in 
the view of the investigator or sponsor, at immediate risk of death from the reaction as 
it occurred, i.e., it does not include a reaction that had it occurred in a more severe 
form, might have caused death. 
 
Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
 
Non-compliance (NIH Definition) 
Failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human 
research subjects. 
 
Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to 
(a) the research risks that are described in the IRB-approved  
 
research protocol and informed consent document; Investigator’s  
 
Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
7.5 
NIH-IRB and Clinical Director Reporting Requirements 
7.5.1 NIH-IRB and NCI Clinical Director Expedited Reporting of Unanticipated Problems 
and Deaths 
The Protocol PI will report in the NIH Problem Form to the NIH-IRB and NCI 
Clinical Director: 
 
• All deaths, except deaths due to progressive disease 
• All protocol deviations 
• All unanticipated problems 
• All non-compliance 
 
Reports for serious events must be received by the NIH IRB within 7 days of PI 
awareness via iRIS.  Reports for not serious events must be received by the NIH IRB 
within 14 days of PI awareness via iRIS. 
 
 
7.5.2 NIH-IRB Requirements for PI Reporting at Continuing Review 
System 
CTCAE 
Grade 
# of Events 
Total # 
Attribution 
Serious? 
Unexpected? 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
52 
 
Organ Class 
Term 
since last CR 
of Events 
to Research 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The protocol PI will report to the NIH-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related 
to the research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.   
 
7.5.3 NIH-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that require a sponsor-recommended change to the protocol 
or the consent form or in the opinion of the PI increase risks to study participants will 
need to be reported to the NIH IRB. 
 
7.6 
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 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.   
7.7 
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 
reporting unless otherwise specified.   
 


CTEP # P9771 
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53 
 
8 PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational drugs 
administered in this study can be found in Section 7. 
8.1 
M6620 (VX-970) (NSC 780162)  
Other Names: VRT-0768079, MSC2527093A, VX-970 
 
Chemical Name: 5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4-
((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2- amine 
 
Classification: ATR inhibitor  
 
 
CAS Registry Number: 1232416-25-9 
 
Molecular Formula: C24H25N5O3S                 M.W.: 463.55 Da 
 
Mode of Action: Ataxia telangiectasia mutated and Rad3-related (ATR) kinase is an apical 
regulator of checkpoint pathways triggered by DNA damage.  The DNA damage response (DDR) 
is regulated by ATR kinase and ataxia telangiectasia mutated (ATM) kinase, which are recruited 
to distinct DNA damage structures.  M6620 (VX-970) disrupts ATR-mediated DNA damage 
response signaling and leads to sustained accumulation of DNA damage in cancer cells co-treated 
with DNA-damaging agents. 
 
Description: The drug substance for M6620 (VX-970) is the free base. 
 
How Supplied: M6620 (VX-970) is supplied by Merck KGaA/EMD Serono, Inc. and distributed 
by the Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 200 mg vials 
containing a sterile solution (20 mg/mL).  M6620 (VX-970) solution for injection is a yellow 
liquid formulated in 20% betadex sulfobutyl ether sodium (w/v) and 86 mM acetate buffer, 10 
mL total volume, supplied in clear glass vials in cardboard boxes with foam inserts. 
 
Preparation: M6620 (VX-970) solution for injection must be diluted with 5% dextrose in water 
solution prior to administration.  Do not use 0.9% Sodium Chloride due to incompatibility with 
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. 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
54 
 
 
Stability: Stability testing of the intact vials is on-going.  Prepared solutions must be protected 
from light and used within 4 hours from time of preparation if stored at room temperature or 24 
hours if stored refrigerated (2-8°C).  
 
Route of Administration: Intravenous (IV) infusion. 
 
Method of Administration: Prior to administration the solution should be given one hour at 
ambient temperature to warm up if stored refrigerated following preparation. Infuse over 60 
minutes using an infusion set containing low-sorption or non-PVC, DEHP-free tubing and an in-
line 0.2 micron filter.  5% dextrose in water solution must be used for IV line priming and 
flushing.  M6620 (VX-970) should not come in contact with 0.9% Sodium Chloride due to 
incompatibility. The infusion time may be extended beyond 60 minutes (as tolerated) but no 
more than 90 minutes if standard procedures to limit symptoms of an infusion reaction are 
insufficient or if the total volume of the infusion exceeds 600 mL.  To minimize the possibility of 
phlebitis, M6620 (VX-970) should be administered through a large bore catheter into a large 
caliber peripheral vein or central venous access. 
 
Patient Care Implications: Monitor for infusion site reactions, irritation, and phlebitis. M6620 
(VX 970) absorbs in the UV-visible radiation spectrum and is widely distributed including skin, 
so patients receiving M6620 (VX-970) should take protective measures to minimize sun 
exposure. 
 
Women of childbearing potential and men should use appropriate contraception while on study 
drug and for 6 months after discontinuation of M6620 (VX-970). 
 
Potential Drug Interactions: M6620 (VX-970) is primarily metabolized by CYP3A4.  M6620 
(VX-970) has a low potential to inhibit CYP1A2, 2C9, 2C19, 2D6, and 3A4, and a moderate 
potential to reversibly inhibit CYP2E1.  The potential for M6620 (VX-970) to induce CYP450 
enzymes is low.  Concomitant administration with strong inhibitors or inducers of CYP3A4 
should be avoided. 
 
M6620 (VX-970) is a weak/moderate inhibitor of UGT1A1, UGT1A14, UGT1A9, UGT2B15, 
and UGT2B17.  UGT2B7, UGT1A3, and UGT1A6 were weakly or not inhibited.  M6620 (VX-
970) is predicted to not inhibit significantly the metabolic clearance of SN-38 (active metabolite 
of irinotecan) at therapeutic exposures.   
 
M6620 (VX-970) is a moderate inhibitor of P-gp and BCRP.  Use caution when administered 
with substrates of P-gp and BCRP transporters. 
 
             1/2019 ew 
 
 


CTEP # P9771 
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55 
 
8.2 
Veliparib (NSC 737664) 
Other Names: 
ABT-888, A-861695.0 
Chemical Name: 
1H-Benzimidazole-7-carboxamide, 2-[(2R)-2-methyl-2-
pyrrolidinyl]- 
 
Classification: 
Poly (ADP-ribose) polymerase (PARP) Inhibitor 
CAS Registry No. 
912444-00-9 
Mode of Action: 
Veliparib is an inhibitor of poly(ADP-ribose) polymerase 
(PARP), a nuclear enzyme that recognizes DNA damage and 
facilitates DNA repair. 
Molecular 
Formula: 
C13H16N4O 
Molecular Weight: 
244.29 
Description: 
White to light yellow solid 
Solubility: 
Freely soluble at 37 °C at a pH < 6.9, soluble at pH 6.9 to 7.1, 
and slightly soluble at pH > 7.1 
How Supplied: 
AbbVie supplies and DCTD distributes Veliparib.  Veliparib 
capsules are available in 10 mg, 20 mg, 40 mg, 50 mg, and 100 mg 
immediate release capsules.  The inactive ingredients are 
microcrystalline cellulose, colloidal silicon dioxide, magnesium 
stearate, gelatin, sodium lauryl sulfate, and titanium dioxide.  It 
may contain FD&C blue#1, FD&C yellow #6, or FD&C yellow 
#5.  The capsules are packaged in HDPE bottles, and each HDPE 
bottle contains 16 capsules or 64 capsules. 
Veliparib capsules may be repackaged from the supplied HDPE 
bottles into amber (or other low-actinic) child resistant pharmacy 
dispensing bottles.  Expiration will be 30 days from the 
repackaging date (or the original retest date, whichever is earlier) 
when stored at 15°C to 25°C (59°F to 77°F).   
Storage: 
Capsules should be stored in the original container at 15° to 
25°C (59° to 77°F). 
Route of 
Administration: 
Oral 
Method of 
administration 
Administer Veliparib orally without regards to meals; the capsules 
should not be crushed or chewed.  If a dose is vomited, it may be 
re-administered if whole/intact capsules are observed in vomitus. 
Potential Drug 
Interaction 
Nonclinical studies suggest ABT-888 is a substrate of P-gp, OCT2, 
and MATE1/MATE2K transporters.  Co-administration of ABT-
888 with strong inhibitors of P-gp, OCT2, and MATE1/MATE2K 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
56 
 
may result in a decrease of ABT-888 renal clearance and an 
increase in ABT-888 plasma concentration.  Therefore, use caution 
when administering ABT-888 with strong inhibitors of P-gp, 
OCT2, and MATE1/MATE2K.  At high dose (e.g., 400 mg BID), 
ABT-888 may inhibit OCT1 in the liver and MATE1/MATE2K in 
the kidney.  
 
ABT-888 is not a potent inhibitor of the major human CYPs and 
does not significantly induce activities of major human CYP 
isoforms, suggesting a negligible potential for CYP-mediated drug-
drug interactions as a perpetrator at the anticipated therapeutic 
concentrations. 
 
In human, ABT-888 clears primarily in the urine as intact parent 
drug along with metabolites suggesting that renal function plays an 
important role in the drug clearance and its metabolites.  Drug-
associated kidney toxicities or kidney diseases could change ABT-
888 pharmacokinetics.  Use cautions when concomitantly 
administer oxalipaltin, carboplatin, cisplatin, and topotecan in 
patients with pre-existing renal impairment.   
Availability 
Veliparib is an investigational agent supplied to investigators by 
DCTD, NCI.  Veliparib is provided to the NCI under a 
Collaborative Agreement between the Pharmaceutical 
Collaborator and DCTD, NCI. 
 
8.3 
Cisplatin 
Other Names: 
cisplatinum 
Chemical Name: cis-diamminedichloroplatinum(II) 
Classification: 
DNA crosslinking agent 
CAS Registry 
No.: 
15663-27-1 
Molecular 
Formula: 
(SP-4-2)-diamminedichloroplatinum 
Mechanism of 
Action: 
Cisplatin is a DNA crosslinking agent that forms intra- and 
interstrand crosslinks with DNA, interfering with DNA replication 
and repair. 
How Supplied: 
Cisplatin is commercially available in amber, multiple-dose vials 
containing 50, 100, or 200 mg cisplatin in solution.  Each milliliter 
of solution contains 1 mg of cisplatin and 9 mg sodium chloride in 
water for injection.   


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
57 
 
Storage: 
Intact vials and reconstituted solution must be maintained at room 
temperature.  Store intact vials at 15° - 25°C (59° - 77°F).  Do not 
refrigerate cisplatin in vials or after dilution. 
Cisplatin that remains in an amber vial after initial entry is stable for 
28 days if protected from light or for 7 days under fluorescent room 
light.  Large-volume solutions do not need to be protected from 
light if used within 6 hours after preparation.  For longer time 
periods, light protection is recommended.  Light protection is 
required for intensive lighting conditions; e.g., direct sunlight 
exposure.  Although cisplatin slowly degrades to 
trichloroaminoplatinate (TCAP) on exposure to ambient lighting 
conditions, solution pH is the predominant factor affecting cisplatin 
stability.  Solutions with pH > 4.3 (especially > 6.3) were associated 
with loss of cisplatin and a more rapid formation of TCAP. 
Stability: 
Vials bear the manufacturer’s expiration date.  Cisplatin dilution to 
0.05 or 0.5 mg/mL with 0.9% normal saline yields a solution that is 
stable for at least 24 hours at room temperature. 
Preparation: 
Cisplatin will be diluted in 100 mL 0.9% sodium chloride injection, 
USP, for intravenous administration over 60 minutes on Day 1 (and 
Day 8 from DL3 and higher) of a 21-day cycle. 
 
Route of 
Administration: 
Cisplatin is administered intravenously on Day 1 (and Day 8 for 
DL3 and higher) of a 21-day cycle. 
Method of 
administration: 
Prior to cisplatin administration, at least 500 mL of 0.9% sodium 
chloride with KCl 10 mEq/L and magnesium sulfate 4 mEq/L 
injection should be administered over at least 60 minutes.  
Following administration of cisplatin, at least an additional 500 mL 
of 0.9% sodium chloride with KCl 10 mEq/L and magnesium 
sulfate 4 mEq/L injection should be administered over at least 60 
minutes.   
Availability: 
Commercially available. 
8.4 
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  


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
58 
 
• IB Coordinator: IBCoordinator@mail.nih.gov  
• PMB phone and hours of service: (240) 276-6575 Monday through Friday  
 
8.5 
Agent Ordering  
NCI-supplied agents may be requested by the responsible investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained).  The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there 
are several participating investigators at one institution, CTEP-supplied investigational agents for 
the study should be ordered under the name of one lead investigator at that institution. 
 
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 (https://ctepcore.nci.nih.gov/OAOP ).  Access to OAOP requires the establishment of 
a CTEP Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam/) and 
the maintenance of an “active” account status, a “current” password, and an active registration 
status.  For questions about drug orders, transfers, returns, or accountability, call (240) 276-6575 
Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
8.6 
Agent Accountability 
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. 
8.6.1 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, a “current” password, and an 
active registration status. Questions about IB access may be directed to the PMB IB 
coordinator via email. 
 
 


CTEP # P9771 
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59 
 
9 CORRELATIVE/SPECIAL STUDIES 
We plan to evaluate the effect of the combination of M6620 (VX-970), veliparib, and cisplatin on 
markers of DNA damage, such as γH2AX, RAD51, pNbs1, and pATR, in tumor biopsies and 
circulating tumor cells (CTCs).  For patients on the expansion cohort, two biopsies will be 
obtained, one on C1D1 after administration of cisplatin and again on C1D9, 2-5 hours after the 
day 9 dose of M6620 (VX-970), with a third progression or restaging follow-up biopsy optional.  
Biopsies are mandatory for patients on the expansion phase.  Based on the availability of tissue 
and various histologies, additional markers of DNA damage will be evaluated. 
9.1 
Pharmacodynamic Assays 
Evaluation of drug effect on DNA damage response in tumor and CTCs will be performed by 
immunofluorescence assays for measurement of DNA damage-repair markers, such as γH2AX, 
RAD51, pNbs1, and pATR. 
 
Histone H2AX is one of the H2A histones present in nucleosomes from normal tissues as well as 
cancer tissues.  H2AX is phosphorylated at its C-terminus (serine 139) following DNA double-
strand breaks.  Phosphorylated H2AX, referred to as γH2AX, can be selectively detected using 
antibodies by Western blots or immunofluorescence.  The levels of γH2AX are directly correlated 
to the amounts of double-strand breaks per cell, and can be used as a dosimeter and biomarker for 
DNA double-strand breaks. 
 
Nbs1 is an adapter protein, linking Mre11 and Rad50 to form the MRN complex involved in 
recognition of DNA damage and initiation of the signaling cascade in response to DNA double-
strand breaks. 
 
Rad51 plays a central role in recognition of double-strand breaks and homologous recombination. 
 
ATR phosphorylation in response to DNA damage will be used as a marker of direct target effect.  
A quantitative immunofluorescence assay for pT1989-ATR will be used as a marker of ATR 
inhibitor activity.   
9.1.1 Laboratory Contact (NCI only) 
At least 24 hours prior to tumor biopsy or blood sample collection, the research nurse 
will contact the NCI Phase I/II PK/PD Support Group in NIH Building 10:  
E-mail (preferred): NCIPK-PDsupport@mail.nih.gov, Pager (preferred): 102-12798 
Phone: (240) 858-3963 Fax: 301-480-5871.  For biopsies, tubes pre-labeled with the 
information specified in Section 9.1.4, biopsy date, and site of tissue biopsy will be 
provided.  Initial processing and shipping of the samples will be completed as 
described below. 
9.1.2 Tumor Biopsies 
Biopsies will be optional during the escalation phase but mandatory during the 
expansion phase.  Biopsies will be collected at the following time points: 
• On C1D1 after administration of cisplatin 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
60 
 
• On C1D9, 2-5 hours after the dose of M6620 (VX-970) 
An optional third biopsy may also be collected, either at restaging follow-up (on day 
1 (± 2 days) of the cycle following any restaging at which a 10-19% increase in 
tumor volume is observed, according to RECIST criteria, for patients on study 4 or 
more cycles) or at the time of disease progression (a 20% or more increase in tumor 
volume by RECIST). 
 
 
9.1.2.1 Biopsy Procedure 
Serial tumor biopsies will be obtained by the Interventional Radiology team by a 
percutaneous approach, a dermatologist for skin lesions, or an ENT for lesions that 
are easily biopsiable through ENT exam.  If a site is deemed appropriate for biopsy 
with minimal risk to the participant by agreement between the investigators and the 
biopsy team, an attempt for biopsy will be made.  Because approximately 20% of 
tumor biopsies collected on research trials are not usable due to the presence of 
stroma or normal and/or necrotic tissue and paired biopsies are necessary for 
analysis, up to 5 core biopsies 18-gauge in diameter and ≥1 cm in length, or 
equivalent, will be obtained during each procedure to try and ensure adequate tumor 
content and quality.  If possible, the lesion from which each biopsy is taken will be 
documented.  Acceptable biopsy procedures are:  
• Percutaneous biopsy with local anesthetic.  
• Excisional cutaneous biopsy with local anesthetic  
• Other biopsy with local anesthetic and/or sedation that has been shown to have a 
risk of severe complications < 2%  
 
The use of imaging to facilitate biopsies will be decided by members of the biopsy 
team and may include ultrasound, CT scan, or MRI.  Should a CT scan be needed for 
biopsy, the number of scans for each procedure will be limited to the minimum 
number needed to safely obtain a biopsy.  Tumor biopsies and local anesthesia will 
be administered only if they are considered to be of low risk to the participant, as 
determined by the investigators and the biopsy team.  The clinical, radiologic, 
dermatologic, ENT, and pharmacodynamic members of the research team will meet 
monthly to review the adequacy of the biopsy specimens for analysis. 
 
C1D1 and C1D9 tumor biopsies are optional during the escalation phase and 
mandatory during the expansion phase (the progression/restaging follow-up biopsy is 
always optional).  Baseline biopsies will be performed following patient enrolling on 
study.  If an initial attempt at biopsy is unsuccessful, the patient will be given an 
option to proceed with a repeated attempt.  A separate consent form must be signed 
for each biopsy procedure, so patients may choose not to undergo subsequent 
biopsies.  If the baseline biopsy is unsuccessful or the patient refuses to undergo 
subsequent biopsies, no further biopsies will be performed but the patient will 
remain on study, receive study medication, and other correlative studies will be 
performed.   
 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
61 
 
9.1.2.2  Solid Tumor Biopsy Processing 
• All biopsy specimens should be collected, placed in pre-chilled cryogenic vials, and 
flash frozen in liquid nitrogen within 2 minutes of collection per DCTD SOP340507 
(https://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507_Biops
y_Frozen.pdf) 
 
• See Appendix G for the collection and shipment procedures for all biopsy samples. 
 
• C1D1 and C1D9 biopsies should be transferred to PADIS on dry ice, where they 
are stored at -80°C, or colder, and subsequently processed within 7-10 days for 
analysis or as directed by the Principal Investigator.  Biopsy samples will be 
analyzed for γH2AX, Rad51, pNbs1, and pATR as described above; any additional 
tissue will be flash-frozen and kept for future analysis in the Frederick National 
Laboratories CR Biorepository in liquid nitrogen freezers.  Additional studies, if 
performed, will be conducted following an amendment to the current protocol. 
 
• Restaging follow-up or progression biopsies should be processed as follows: 
o As the first priority, two cores, or equivalent tissue from dermatology or ENT 
biopsy, should be flash frozen as described above and transferred on dry ice to 
Dr. Mickey Williams’ laboratory (MoCha) at the Frederick National Laboratory 
for Cancer Research (FNLCR).   
 
Following processing, one tissue section will be stained with H&E for 
histopathological examination by a designated pathologist.    The remaining 
biopsy tissue will be extracted for nucleic acids.  DNA will be assessed for 
quantity and quality by spectroscopy (OD 260/280) and a PCR-based 
amplification quality assessment test.  All specimens that meet necessary 
quantity and quality will be sequenced using a targeted sequencing assay.   
 
o Any remaining tissue collected (up to 5 cores or equivalent) will be transferred to 
PADIS on dry ice and stored for analysis of γH2AX, Rad51, pNbs1, and pATR. 
 
o Note: Per the discretion of the PI, restaging follow-up or progression biopsies may 
be used for other analyses, including analyses carried out as a part of other DTC 
clinical trials, providing that the tissue is collected per SOP for those analyses. 
 
9.1.2.3 Optional Archival Tissue Submission for Additional Studies 
Patients may choose to submit an additional, archival tumor tissue specimen that 
has been collected within 3 months prior to patient registration if the patient has 
not received any intervening cancer therapy since collection of the specimen and 
the tissue was collected and processed according to SOP340507 
(https://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507_Bi
opsy_Frozen.pdf), including flash-freezing in liquid nitrogen, minimal cold 
ischemia time (< 5 minutes), and shipment on dry ice.  Archival tissue 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
62 
 
submissions do not fulfill the requirement for a baseline (C1D1) biopsy 
because the baseline biopsy must be collected after the C1D1 cisplatin 
administration; however, qualifying archival tissue submissions will be analyzed 
for the same PD biomarkers as C1D1 and C1D9 biopsies to provide additional 
context for interpreting PD changes after drug administration. 
Please send an email to FNLCR PD Specimen Central Receiving 
(NCI_PD_Support@mail.nih.gov) to advise that archival tissue is being prepared 
for shipment.  State “P9771 PD Specimens Ready for Shipment” in the subject 
line.  If needed, FNLCR PD Central Receiving can be contacted directly at 301-
846-1951 or 301-846-6747. 
 
9.1.3  Blood Collection for CTC Studies (Optional) 
Whole blood (at least 7.5 mL) will be collected aseptically by venipuncture or from a 
venous port into one 10 mL CellSave preservative tube.  Prior to CTC collection, 
each participating site should e-mail a request for specimen collection and shipping 
materials from NCIPDSupportPADIS@mail.nih.gov .  See Appendix G for the 
collection procedure for CTC samples for pharmacodynamic studies. 
 
At the NCI only, whole blood (at least 7.5 mL) will be collected aseptically by 
venipuncture or from a venous port into one 10 mL Streck tube (catalog number 
218962).  One 10 mL RareCyte tube (catalog number 24-1070-005) is also 
acceptable. Tubes must be inverted 8 times to ensure adequate mixing of the 
additive. 
Blood samples for CTCs will be collected at the following times:  
• at baseline 
• on cycle 1 day 2 prior to administration of M6620 (VX-970)  
• on cycle 1 day 2, 8 hours (± 30 minutes) after the start of M6620 (VX-970) 
administration  
• on cycle 1 day 8 prior to administration of veliparib/cisplatin administration 
• on cycle 1 day 9 prior to M6620 (VX-970) administration,  
• on cycle 2 day 1 prior to veliparib/cisplatin administration 
• on cycle 2 day 2 prior to M6620 (VX-970) administration  
• on cycle 2 day 2, 10 hours (± 2 hours) after the start of M6620 (VX-970) 
administration* 
• on the first day of every subsequent cycle prior to veliparib/cisplatin 
administration 
• at the time of restaging follow-up biopsy or progression biopsy, if applicable 
 
*At the NCI only: CTC collection on cycle 2 day 2 is fixed at 7:00pm (± 30 
minutes) in order to make the timing of the procedure more feasible and convenient 
for study participants.  The time elapsed between M6620 (VX-970) administration 
and blood collection will be recorded. 
 


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
63 
 
Testing and data analysis will be performed by Dr. Bob Kinders (PADIS/FNLCR).   
 
9.1.4 Sample Collection and Processing 
Biospecimens will be collected and processed using validated SOPs that will ensure 
both specimen quality and patient confidentiality pursuant to informed consent 
provisions.  Information about each specimen (e.g., blood, tumor biopsy, per specific 
protocol) will be recorded on a PK/PD collection worksheet. 
 
Using a computerized inventory system and a backup hardcopy process, all specimen 
collection and processing steps will be documented and the specific location of each 
specimen will be tracked.  Each new specimen collected will be assigned a unique 
barcode identifier that can be linked to the original specimen collected and other 
relevant information within the inventory system.  To ensure patient confidentiality, 
only containers used for the initial specimen collections will be labeled with patient 
identifiers.   
 
Only the barcode identifier will be applied to all subsequent specimen containers.  
When specimens are processed and aliquoted, no patient information will be included 
on the new containers.  Original specimen containers will be discarded.  Only 
barcode-labeled specimens without patient identifiers will be shipped for analysis 
and/or storage.  Specimen labels will indicate: CTEP protocol number, unique patient 
accession number, 3-digit sample number (see list below), collection time, and total 
volume collected, as appropriate.  Samples from sets of at least three patients will be 
grouped for scientific analysis. 
 
Standardized 3-digit sample collection numbers: 
400 series: CTCs 
500 series: tumor biopsies 
 
The inventory process contains other security provisions sufficient to safeguard 
patient privacy and confidentiality.  Access to the inventory system and associated 
documents will be restricted to appropriate individuals.  Requests to use specimens 
stored in the repository must be approved.  The only patient information available in 
the inventory system will be the patient sex, diagnosis, and level of informed consent 
given.  SOPs ensure that any changes in informed consent made by a patient and 
relayed to the PI will be reflected in the inventory system to ensure that specimens are 
destroyed as appropriate.  All laboratory personnel will be trained to adhere to SOPs 
and will be monitored for high-quality performance. 
 
Any new use of these samples will require prospective IRB review and approval.  
Access to these samples will only be granted following IRB approval of an additional 
protocol, granting the rights to use the material. 
 
If at any time, a patient withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request.  Following 


CTEP # P9771 
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64 
 
receipt of this request, the samples will be destroyed (or returned to the patient, if so 
requested), and reported as such to the IRB.  Any samples lost (in transit or by a 
researcher) or destroyed due to unknown sample integrity (i.e., broken freezer allows 
for extensive sample thawing, etc.) will be reported as such to the IRB. 
 
9.2 
Exploratory Genomic Analyses 
As of Amendment L (dated 4/22/2019), the MoCha laboratory at FNLCR will investigate the 
occurrence of tumor genomic alterations potentially associated with acquired drug resistance for 
only those patients who agree to undergo an optional progression or restaging follow-up biopsy. 
9.2.1 Optional Restaging Follow-Up and Progression Biopsies 
With patient consent, tumor tissue collected at the (optional) restaging follow-up or 
progression biopsy may be analyzed by the CLIA-certified OCAv3 assay and results 
will be returned to patients in the form of the Oncomine report.  If additional tumor 
tissue is available after the OCAv3 analysis, exploratory, non-CLIA certified genomic 
analyses such as WES may be conducted but the results will not be returned to 
patients or used for clinical decision making (Figure 5).  Note: Per the discretion of the 
PI, restaging follow-up or progression biopsies may be used for other analyses, including 
analyses carried out as a part of other DTC clinical trials, providing that the tissue is 
collected per SOP for those analyses. 




CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
66 
 
X Identified data in BTRIS (automatic for activities in the Clinical Center)  
X De-identified or identified data with approved outside collaborators under appropriate 
agreements  
 
How and where will the data be shared?  
Data will be shared through:  
X An NIH-funded or approved public repository: clinicaltrials.gov 
X BTRIS (automatic for activities in the Clinical Center)  
X Approved outside collaborators under appropriate individual agreements  
X Publication and/or public presentations  
 
When will the data be shared?  
X At the time of publication or shortly thereafter 
 
10 STUDY CALENDAR 
Eligibility screening evaluations are to be conducted within 8 days prior to enrollment, with the 
exception of informed consent and diagnostic imaging, which must be done within 28 days prior 
to enrollment.  Baseline history, physical examination, laboratory evaluations, and ECG are to be 
conducted within 8 days prior to the start of protocol therapy.  If protocol therapy is started 
within 8 days of the eligibility screening evaluations, values from the screening evaluations may 
be used as baseline measurements; if > 8 days have passed since the screening evaluations, the 
medical history, physical examination, laboratory evaluations, and ECG must be repeated prior to 
starting protocol therapy.  Baseline imaging scans must be done within 28 days prior to the start 
of protocol therapy.  Start of next cycle may be changed by 1 day or delayed for up to 1 week to 
accommodate scheduling conflicts.  Treatments within a cycle may be delayed ± 1 day to 
accommodate scheduling conflicts.  History and physical examination and laboratory evaluations 
can be performed up to 3 days before the start of the next cycle.  


CTEP # P9771 
Clinical Center # 16-C-0087 
 
 
 
67 
 
 
Study Procedure 
Pre-Study 
Eligibility 
Screen 
Study Treatment  
Cycle 1  
Cycle 2 and subsequent 
cycles 
Off 
Treatment 
Wk 1 
Wk 2 
Wk 3 
Wk 1 
Wk 2 
Wk 3 
 
M6620 (VX-970)a 
 
X 
X 
 
X 
X 
 
 
Veliparibb 
 
X 
X 
 
X 
X 
 
 
Cisplatinc 
 
X 
 
 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
Xl 
 
 
 
 
 
 
Concomitant meds 
X 
X---------------------------------------------------------------------X 
 
Physical examd 
X 
Xl 
X 
 
X 
X 
 
X 
Vital signsd 
X 
Xl 
X 
 
X 
X 
 
X 
Heightd 
X 
 
 
 
 
 
 
 
Weightd 
X 
Xl 
X 
 
X 
X 
 
X 
Performance statusd 
X 
Xl 
X 
 
X 
X 
 
X 
ECGe 
X 
X 
 
 
 
 
 
 
CBC w/diff, pltsf 
X 
Xl 
X 
X 
X 
X 
optional 
X 
Serum chemistryf 
X 
Xl 
X 
X 
X 
X 
optional 
X 
PT, INR, PTTg 
 
X 
X 
 
 
 
 
 
β-HCGh 
X 
 
 
 
 
 
 
 
Adverse event 
evaluation 
X 
X-------------------------------------------------------------------X 
 
Tumor  
measurementsi 
X 
Xl 
Tumor measurements are repeated per Section 11.1 
Documentation (radiologic) must be provided for 
patients removed from study for progressive disease. 
X 
Tumor biopsyj 
 
X 
X 
 
 
 
 
 
Circulating Tumor 
Cellsk 
X 
X 
X 
 
X 
 
 
 
a.  M6620 (VX-970) will be administered intravenously as a 1-hour infusion ± 10 minutes on days 
2 and 9 of a 21-day cycle (or on days 1 and 8 of any cycle in which cisplatin is not 
administered).   
b.  Veliparib will be administered orally q12 hours ± 1 hour on days 1 through 3 and 8 through 10 
of a 21-day cycle.  Veliparib should be administered before cisplatin and M6620 (VX-970). 
c.  Cisplatin will be administered intravenously as a 1-hour infusion ± 10 minutes on day 1 of a 21-
day cycle (days 1 and 8 for patients on dose level 3 and higher). As of Amendment I 
(12/7/2017), patients who have been on trial for at least 6 cycles may have cisplatin 
administration held or discontinued while continuing on trial at the discretion of the PI, Dr. 
 
d.  Physical examination, including vitals, weight, and performance status, will be performed at the 
Clinical Center at the start of each cycle of treatment (up to 3 days before the start of a new 
cycle) and on day 8 or 9 (±1 day) of each cycle.  Weight will be used to calculate doses per 
institutional SOP.  Height will be performed prior to enrollment and will not need to be repeated 


CTEP # P9771 
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68 
 
prior to each treatment. 
e. ECG for eligibility screening and at baseline (within 8 days prior to enrolling or starting study 
drug, respectively), within approximately 1 hour after the end of M6620 (VX-970) infusion 
during cycle 1, and as clinically indicated. 
f.  Serum chemistry (albumin, total bilirubin, calcium, creatinine, phosphorus, magnesium, 
potassium, sodium, SGOT [AST], SGPT [ALT]); CBC w/diff, and platelets should be 
performed for eligibility screening and at baseline (within 8 days prior to enrollment or starting 
treatment, respectively), and prior to treatment on days 2, 8, 9, and 15 (±1 day for all) of cycle 1.  
For all subsequent cycles, these labs should be performed prior to treatment on day 1 (±1 day) 
and prior to the first IV treatment on week 2 of the cycle (day 8 or 9, ±1 day).  C1D1 values 
need to re-meet eligibility criteria.  C1D15 labs may be obtained by the patient’s local physician 
and day 15 labs in subsequent cycles are optional. 
g.  PT, INR, PTT required within 1 week prior to all biopsies, and may also be performed as 
clinically indicated. 
h.  Serum or urine pregnancy test (women of childbearing potential) within 8 days prior to 
enrollment and as clinically indicated. 
i.  Radiologic examination (CT scan or MRI) will be performed for eligibility screening and at 
baseline (within 28 days prior to enrolling or starting study drug, respectively) and then every 2 
cycles (every 3 or 4 cycles for patients on study for more than one or three years, respectively).   
j.  Tumor biopsies will be obtained after the administration of cisplatin on C1D1 and again on C1D 
9 2-5 hours after the day 9 dose of M6620 (VX-970).  Tumor biopsies are optional during the 
escalation phase and mandatory during the expansion phase. 
k.  Circulating tumor cells (optional) will be drawn as defined in Section 9.1.3.  
l: Eligibility screening results may be used for these baseline measurements if conducted within 8 
days (for medical history, physical exam, vital signs, weight, performance status ECG, serum 
chemistry, and CBC) or 28 days (for tumor measurements) prior to the start of protocol therapy. 
 
11 MEASUREMENT OF EFFECT 
11.1 
Antitumor Effect – Solid Tumors 
Although response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard criteria.  For the purposes of this study, patients should be re-evaluated 
for response every 6 weeks (every 2 cycles; every 3 cycles for patients on study for more than 
one year or every 4 cycles for more than three years).  In addition to a baseline scan, 
confirmatory scans should also be obtained at least 4 weeks following initial documentation of 
objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [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. 


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11.1.1 Definitions 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with the combination of M6620 (VX-970), veliparib, and cisplatin. 
 
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 by chest x-ray or as ≥10 mm 
with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).  
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  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 or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.  
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above.  However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.  
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 


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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 Guidelines 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 diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.   
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.   
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g., for body scans).   
 
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.  
 


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PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances.  
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint.  
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 
2000].  
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).  
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.  
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 


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b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive 
CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
11.2 Response Criteria 
11.2.1 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. 
 
Partial Response (PR): 
 At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
 
Progressive Disease (PD): 
 At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (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. 
11.2.2 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 short axis). 


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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). 
11.2.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks.  Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
≥4 wks.  Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once ≥ 4 
wks.  from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 


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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 
11.3 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.   
 
12 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 
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.  
 


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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. 
12.2 
Data Reporting 
12.2.1 Method 
 This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  
On-site audits will be conducted three times annually (one annual site visit and two 
data audits).  For CTMS monitored studies, after users have activated their accounts, 
please contact the Theradex Help Desk at (609) 799-7580 or by email at 
ctms@theradex.com for additional support with Rave and completion of CRFs.  
 
Note: All adverse events that have occurred on the study, including those reported 
through CTEP-AERS, must be reported via the monitoring method identified above. 
12.2.2 Responsibility for Data Submission 
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. 
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. 
Guidelines may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.h
tm) 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 


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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. 
12.3 
CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix F. 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions for 
submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
 
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 


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proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b.  Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own Agent. 
 
c.  Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R.  Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and 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: E-mail: 
ncicteppubs@mail.nih.gov 
 
 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 


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12.5 
Genomic Data Sharing Plan 
The NIH Genomic Data Sharing (GDS) Policy does not apply to this protocol as the genomic 
analysis will be performed will be for no more than 30 patient samples; therefore, this study 
does not meet GDS criteria, and a GDS plan is not warranted. 
 
13 STATISTICAL CONSIDERATIONS 
13.1 
Study Design/Endpoints 
This Phase I study will use a standard 3+3 design with a slight modification as outlined in Section 
5.3.  Accrual will not proceed to a higher dose level until all patients have been treated at the 
current dose level, and the last patient treated has been observed for at least one cycle.  The MTD 
dose for the combination of M6620 (VX-970), veliparib, and cisplatin is defined as the dose level 
at which no more than 1 of 6 patients experience a DLT during the first cycle of the treatment, and 
the dose level below that at which at least 2 (of ≤ 6) patients have DLT as a result of the drugs.  
Patients will receive cisplatin intravenously on day 1 (and day 8 from DL3 onwards; at the 
discretion of the PI, Dr. 
 after cycle 6), M6620 (VX-970) intravenously on days 1/2 and 8/9, 
and veliparib orally q12 hours ± 1 hour on days 1-3 and 8-10 of each 21-day cycle.   
 
Once the MTD is established, up to 15 additional patients will be enrolled to the expansion phase 
of the trial at the MTD.  Mandatory tumor biopsies will be obtained in the expansion phase to 
assess for pharmacodynamic endpoints.  With up to 15 patients and a tumor biopsy QA criteria 
failure rate of 50% with respect to paired (pre- and post-dose) biopsies, we have an 85% 
likelihood of having at least 6 usable PD samples, and 95% likelihood of having at least 5 usable 
samples.     
13.2 
Sample Size/Accrual Rate 
We plan to accrue up to 55 patients in this study.  To allow for some patients who may have only 
evaluable and not measurable disease, the accrual ceiling is set at 60.  It is anticipated that 2-3 
patients may be enrolled per month onto this study.  It is expected that 12-18 months will be 
required to accrue the number of patients necessary to complete the trial.   
13.3 
Secondary Endpoints 
• 
To assess the effect of the combination of M6620 (VX-970), veliparib, and cisplatin on markers 
of DNA damage and apoptosis. 
• 
To assess the antitumor activity of the combination  
 
14 HUMAN SUBJECTS PROTECTIONS 
14.1 
Justification for Subject Selection 
This study will be open to all individuals regardless of gender, ethnicity, or race, provided that the 
aforementioned inclusion and exclusion criteria are met.  Patients for this study will be recruited 
through internal referral, our physician referral base, and through various cancer information 


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hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer).  To date, there is no information 
that suggests that differences in drug metabolism or effect on tumor would be expected in one 
ethnic group compared to another.  Efforts will be made to extend accrual to each representative 
population, but a balance must be struck between participant safety considerations and limitations 
on the number of individuals exposed to potentially ineffective treatments on the one hand and the 
need to explore racial/ethnic aspects of clinical research on the other hand.  If differences in 
outcome that correlate to ethnic identity are noted, a follow-up study may be written to investigate 
those differences more fully. 
 
Due to lack of knowledge of the effects of the combination of M6620 (VX-970), veliparib, and 
cisplatin on the fetus or infants, as well as the possibility of teratogenic effects, pregnant and 
nursing women will be excluded from this trial.  Patients with unstable or serious medical 
conditions are excluded due to the possibility that the combination of M6620 (VX-970), veliparib, 
and cisplatin may worsen their condition and the likelihood that the underlying condition may 
obscure the attribution of adverse events to M6620 (VX-970), veliparib, and cisplatin.  HIV-
positive patients are excluded from the study per Section 3.1.9. 
14.1.1 Participation of Children 
This study includes patients 18 years of age and older.  Because insufficient dosing or 
adverse event data are currently available on the use of combination of M6620 (VX-
970), veliparib, and cisplatin in patients <18 years of age, children are excluded from 
this study, but may be eligible for future pediatric trials.  Studies will be performed in 
patients <18 years of age when it is appropriate to do so. 
14.2 
Evaluation of Benefits and Risks/Discomforts 
There may or may not be any clinical benefit to a patient from participation in this trial.  Their 
participation will benefit future cancer patients.  Potential risks include the possible occurrence of 
any of a range of side effects that are listed in the consent document.  The procedure for protecting 
against or minimizing risks will be to medically evaluate patients as described in Section 5 and 
Section 6.  Although no compensation is available, any injury will be fully evaluated and treated 
in keeping with the benefits or care to which participants are entitled under applicable regulations. 
14.3 
Consent and Assent Process and Documentation 
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
drug administration plan, research objectives, and follow-up of this trial.  The patient will be 
provided an IRB-approved consent for review and signature and his/her questions will be 
answered.  After a decision is made to enroll into the study, a signature will be obtained from the 
patient.  The original signed consent goes to Medical Records; a copy will be placed in the 
research record.  Patients will not be consented by telephone. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 
 
Adults who are unable to provide initial informed consent are excluded from participation on this 
study.  All patients > 18 years old will be offered the opportunity to assign a substitute decision 


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maker on the “NIH Advance Directive for Health Care and Medical Research Participation” form, 
so that another person can make decisions about their medical care if they become incapacitated or 
cognitively impaired. 
 
14.3.1 Participation of subjects unable to give consent 
At the NCI only: Adults unable to give consent are excluded from enrolling in the 
protocol.  However, re-consent may be necessary and there is a possibility, though 
unlikely, that subjects could become decisionally impaired. For this reason and 
because there is a prospect of direct benefit from research participation, all subjects ≥ 
age 18 at the NCI only will be offered the opportunity to fill in their wishes for 
research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become 
incapacitated or cognitively impaired during the course of the study. Note: The PI or 
AI will contact the NIH Ability to Consent Assessment Team for evaluation.  For 
those subjects that become incapacitated and do not have pre-determined substitute 
decision maker, the procedures described in MEC Policy 87-4 for appointing a 
surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) 
who do not have a legal guardian or durable power of attorney, will be followed. 
14.3.2 Informed consent of non-English speaking subjects 
If there is an unexpected enrollment of a research participant for whom there is no 
translated extant IRB approved consent document, the principal investigator and/or 
those authorized to obtain informed consent will use the Short Form Oral Consent 
Process as described in MAS Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2).  
The summary that will be used is the English version of the extant IRB approved 
consent document.  Signed copies of both the English version of the consent and the 
translated short form will be given to the subject or their legally authorized 
representative, and the signed original will be filed in the medical record. 
 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be 
present to facilitate the conversation (using the Short Form process).  Preferably, 
someone who is independent of the subject (i.e., not a family member) will assist in 
presenting information and obtaining consent.  Whenever possible, interpreters will be 
provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible). 
 
We request prospective IRB approval of the use of the short form process for non-
English speaking subjects and will notify the IRB at the time of continuing review of 
the frequency of use of the Short Form.  The Short Form process will be used no more 
than 5 times per language, after which the full consent document will be translated 
into that language. 
 


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14.4 
Procedure for Protecting Against or Minimizing Any Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity.  This study may involve risks to patients, which are currently unforeseeable.  All patients 
will be monitored for side effects from taking study medication.  This research represents a 
greater than minimal risk to participants, but presents the prospect of direct benefit to individual 
subjects. 
 
The research component of this study required to obtain 3 CT tumor biopsies confers radiation 
exposure at an effective dose of 2.4 rem.  This dose is below NIH RSC guidelines of less than 5.0 
rem per year in adults, and represents a slightly greater than minimal risk to patients.   
 
14.5 
Patient Advocate 
The patients’ rights representative is available to patients receiving treatment on this protocol at 
the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical Research Center, Room 
1-3521, on the Bethesda NIH campus.  Patients will be informed that they can contact the study PI 
or RN at any time with questions about their medical care, and that the patients’ rights 
representative is also available to answer non-medical questions about the study. 


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REFERENCES  
 
1. 
Chen, X., et al., Platinum-based agents for individualized cancer treatment. Curr Mol Med, 
2013. 13(10): p. 1603-12. 
2. 
Zhu, G., P. Chang, and S.J. Lippard, Recognition of platinum-DNA damage by poly(ADP-
ribose) polymerase-1. Biochemistry, 2010. 49(29): p. 6177-83. 
3. 
Jazayeri, A., et al., ATM- and cell cycle-dependent regulation of ATR in response to DNA 
double-strand breaks. Nat Cell Biol, 2006. 8(1): p. 37-45. 
4. 
Serrano, M.A., et al., DNA-PK, ATM and ATR collaboratively regulate p53-RPA interaction 
to facilitate homologous recombination DNA repair. Oncogene, 2013. 32(19): p. 2452-62. 
5. 
El-Khamisy, S.F., et al., A requirement for PARP-1 for the assembly or stability of XRCC1 
nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res, 2003. 31(19): p. 5526-33. 
6. 
Haince, J.F., et al., PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to 
multiple DNA damage sites. J Biol Chem, 2008. 283(2): p. 1197-208. 
7. 
Huntoon, C.J., et al., ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy 
independent of BRCA status. Cancer Res, 2013. 73(12): p. 3683-91. 
8. 
Reaper, P.M., et al., Selective killing of ATM- or p53-deficient cancer cells through inhibition 
of ATR. Nat Chem Biol, 2011. 7(7): p. 428-30. 
9. 
Yap, T.A., et al., Abstract PR14: Phase I trial of first-in-class ataxia telangiectasia-mutated 
and Rad3-related (ATR) inhibitor VX-970 as monotherapy (mono) or in combination with 
carboplatin (CP) in advanced cancer patients (pts) with preliminary evidence of target modulation 
and antitumor activity. Molecular Cancer Therapeutics, 2015. 14(12 Supplement 2): p. PR14. 
10. 
Helleday, T., The underlying mechanism for the PARP and BRCA synthetic lethality: clearing 
up the misunderstandings. Mol Oncol, 2011. 5(4): p. 387-93. 
11. 
Donawho, C.K., et al., ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that 
potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res, 2007. 13(9): p. 
2728-37. 
12. 
Peralta-Leal, A., M.I. Rodriguez, and F.J. Oliver, Poly(ADP-ribose)polymerase-1 (PARP-1) 
in carcinogenesis: potential role of PARP inhibitors in cancer treatment. Clin Transl Oncol, 2008. 
10(6): p. 318-23. 
13. 
Kummar, S., et al., Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-
888 in patients with advanced malignancies. J Clin Oncol, 2009. 27(16): p. 2705-11. 
14. 
Rodler, E.T., et al., Phase I: Veliparib with cisplatin (CP) and vinorelbine (VNR) in advanced 
triple-negative breast cancer (TNBC) and/or BRCA mutation-associated breast cancer. ASCO 
Meeting Abstracts, 2014. 32(15_suppl): p. 2569. 


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15. 
Wilsker, D.F., et al., Pharmacodynamic Responses to DNA Damage from Cancer 
Therapeutic Agents. Clin Cancer Res, 2019. in press. 
16. 
Caulfield, T., et al., Research Ethics Recommendations for Whole-Genome Research: 
Consensus Statement. PLoS Biol, 2008. 6(3): p. e73. 
17. 
Berg, J.S., M.J. Khoury, and J.P. Evans, Deploying whole genome sequencing in clinical 
practice and public health: Meeting the challenge one bin at a time. Genet Med, 2011. 13(6): p. 499-
504. 
 


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APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
5 
Dead. 


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APPENDIX B:  PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD  
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis:  
      
Trial #: 
      
Study 
Doctor: 
      
Study Doctor 
Phone #:  
      
Study 
Drug(s): 
      
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse 
practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the 
National Cancer Institute.  
 
These are the things that your healthcare providers need to know: 
M6620 (VX-970) interacts with specific enzymes in the liver or other tissues like the gut and 
certain transport proteins that help move drugs in and out of the cell. 
 
 
Explanation 
CYP 
isoenzymes 
The enzyme in question is CYP3A4.  M6620 (VX-970) is metabolized by 
CYP3A4 and may be affected by other drugs that inhibit or induce this 
enzyme.  
Protein 
transporters 
The proteins in questions are P-gp and BCRP.  M6620 (VX-970) is a 
moderate inhibitor of these proteins and may affect drugs that are moved in 
and out of cells/organs by these transport proteins. 
 
 
Veliparib (ABT-888) is cleared from the body by certain specific drug transporter proteins.  
 
• The transporters in question are P-gp, OCT2, and MATE1/MATE2K.  Co-administration of 
veliparib (ABT-888) with other drugs that inhibit P-gp, OCT2, or MATE1/MATE2K may result 
in decreased veliparib (ABT-888) clearance by the kidneys and as a result, an increase in 
veliparib (ABT-888) concentration in the blood.   
• Because the lists of these agents are constantly changing, it is important to regularly consult a 
frequently updated medical reference 
• Kidney function plays an important role in the clearance of veliparib (ABT-888).  Veliparib 
(ABT-888) levels may therefore be affected by drug-associated kidney toxicities or kidney 
diseases.  Caution should be used when concomitantly administering veliparib (ABT-888) with 
oxalipaltin, carboplatin, cisplatin, and topotecan in patients with pre-existing kidney impairment. 
 
 
These are the things that you need to know: 
The study drugs M6620 (VX-970) and veliparib (ABT-888) 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-




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APPENDIX C: PATIENT STUDY CALENDAR AND DIARY 
 
The study drugs are given over a 21-day period of time called cycles.  The 21-day treatment 
cycle will be repeated as long as you are tolerating the medications and your cancer is either 
stable or getting better.   
The chart below shows what will happen to you during cycle 1 and future cycles after you sign 
the consent form and start the study.  Each cycle is numbered.  The left-hand column shows the 
day in the cycle, and the right-hand column tells you what will happen on that day.   
 
Day 
What to do and what will happen to you 
Before 
starting 
study 
drug 
• Check in at ________________ [name of outpatient clinic] 
• Get routine blood tests  
• Pregnancy test for women who are able to become pregnant 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• CT or MRI scan will be done 
• Research blood samples will be drawn 
Cycle 1,  
Day 1  
• Admitted to ________________ [name of clinical center] 
• Get routine blood tests 
• Research blood samples will be drawn 
• Receive the first dose of veliparib (ABT-888) by mouth 
• Receive the first dose of cisplatin through a vein 
• Tumor biopsies will be taken for some patients 
Cycle 1,  
Day 2 
• Get routine blood tests 
• Receive the first dose of M6620 (VX-970) through a vein 
• Tumor biopsies will be taken for some patients 2 to 5 hours after receiving M6620 
(VX-970) 
• Research blood samples will be drawn 
• Continue to take veliparib (ABT-888) by mouth twice a day about 12 hours apart 
for a total of 3 days 
Cycle 1,  
Days 8-10 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• Get routine blood tests  
• Research blood samples will be drawn 
• Take veliparib (ABT-888) by mouth twice a day about 12 hours apart for 3 days 
• Receive cisplatin through a vein on day 8 
• Receive M6620 (VX-970) through a vein on day 9 
• Tumor biopsies will be taken for some patients 2 to 5 hours after receiving M6620 
(VX-970) 


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Day 
What to do and what will happen to you 
Cycle 1,  
Day 15 
• Get routine blood tests at your clinical center or by your home physician 
 
Cycle 2, 
Day 1 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• Get routine blood tests 
• Research blood samples will be drawn 
• Start taking veliparib (ABT-888) by mouth twice a day about 12 hours apart for 
days 1 through 3 
• Receive cisplatin through a vein 
Cycle 2, 
Day 2 
• Research blood samples will be drawn 
• Receive M6620 (VX-970) through a vein 
Cycle 2, 
Days 8-10 
• Check in at ________________ [name of outpatient clinic] 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider  
• Get routine blood tests  
• Continue taking veliparib (ABT-888) by mouth twice a day about 12 hours apart on 
days 8 through 10 
• Receive cisplatin through a vein on day 8 
• Receive M6620 (VX-970) through a vein on day 9 
Cycle 2, 
Day 15 
• Get routine blood tests at your clinical center or by your home physician (optional) 
Cycle 3, 
and 
onward 
• Check in at ________________ [name of outpatient clinic] 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• Get routine blood tests  
• CT scan to determine how your tumor is responding to the treatment will be done 
every 6 weeks (every 2 cycles, or every 3 cycles if you have been on study for more 
than one year, every 4 cycles if on study for more than 3 years) 
• Research blood samples will be drawn before Cycle 3 treatment 
• Cisplatin will be given through a vein on Day 1 and 8 of each cycle 
• M6620 (VX-970) will be given through a vein on Day 2 and 9 of each cycle 
• veliparib (ABT-888) will be taken orally twice a day about 12 hours apart on 
days 1 through 3 and 8 through 10 of each cycle 
 
 


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Study Diary 
 
 
Patient Name:  __________________                                    _______________________ 
 
Instructions: 
 
Please complete this form and return to the research nurse or doctor every cycle (21 days) 
 
Dose of veliparib (ABT-888) (number of capsules):  
Time of dosing:   Take veliparib (ABT-888) capsules twice each day (morning and evening, 
about 12 hours apart) on days 1 to 3 and 8-10  
 
Cycle number:      _________ 
Start date:  
_________ 
 
 
Patient Signature:  _____________________________________ 
 
 
Date 
Day 
Time taken 
AM                    PM 
Comments: 
Side effects/missed dose 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
No veliparib (ABT-
888) taken today 
 
 
5 
No veliparib (ABT-
888) taken today 
 
 
6 
No veliparib (ABT-
888) taken today 
 
 
7 
No veliparib (ABT-
888) taken today 
 
 
8 
 
 
 


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9 
 
 
 
 
10 
 
 
 
 
11 
No veliparib (ABT-
888) taken today 
 
 
12 
No veliparib (ABT-
888) taken today 
 
 
13 
No veliparib (ABT-
888) taken today 
 
 
14 
No veliparib (ABT-
888) taken today 
 
 
15 
No veliparib (ABT-
888) taken today 
 
 
16 
No veliparib (ABT-
888) taken today 
 
 
17 
No veliparib (ABT-
888) taken today 
 
 
18 
No veliparib (ABT-
888) taken today 
 
 
19 
No veliparib (ABT-
888) taken today 
 
 
20 
No veliparib (ABT-
888) taken today 
 
 
21 
No veliparib (ABT-
888) taken today 
 










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APPENDIX E: INFORMED CONSENT FORM TEMPLATE 
 
Study Title: Phase I Study of Veliparib (ABT-888), an Oral PARP Inhibitor, and M6620 (VX-
970), an ATR Inhibitor, in Combination with Cisplatin in Patients with Refractory Solid Tumors 
 
Introduction 
 
We invite you to take part in this research study. 
 
First, we want you to know that: 
Taking part in this research study is entirely voluntary. 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either 
case, you will not lose any benefits to which you are otherwise entitled. 
 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may 
help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your doctors or research team before you agree to the 
study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with family, friends or your personal 
physician or other health professional. 
 
Why is this study being done? 
 
The purpose of this study is to test the safety of a combination of 3 drugs (M6620 (VX-970), 
veliparib (ABT-888), and cisplatin) to find out the doses of these drugs that can be safely given 
to humans and to learn if these drugs have activity against tumors.  Although we hope this 
experimental therapy will decrease the size of your tumor, we cannot promise or predict the 
benefits of the treatment at this time.  The drugs used in this study have known side effects that 
will be reviewed with you by your medical team before you sign this consent form. 
  
Cisplatin is currently approved by the US Food and Drug Administration (FDA) for the 
treatment of patients with bladder, ovarian, and testicular cancers in combination with other 
chemotherapy agents.  Veliparib (ABT-888) and M6620 (VX-970) are not approved by the FDA.  
Combining veliparib (ABT-888) and M6620 (VX-970) with cisplatin is thought to block proteins 
that are known to be important for cancer cell growth. 
 
We are also studying the genes in your tumor to help us understand how your tumor responds to 
these 3 drugs.  Blood, tissue, and tumor cells contain genes that are made up of DNA and serve as 
the “instruction book” for each cell in the body.  We know that variations in some tumor genes play 
an important role in how cancers respond to drugs.  Determining whether different tumor gene 


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variations affect how veliparib (ABT-888), M6620 (VX-970), and cisplatin work against tumors 
will help scientists understand why some patients might stop responding to these drugs. 
 
 
Why are you being asked to take part in this study? 
 
You are being asked to take part in this research study because you have advanced cancer that 
has progressed after receiving standard treatment, or for which no effective therapy exists.  We 
hope that this combination of study drugs will slow down the growth of your cancer. 
 
How many people will take part in this study? 
 
Up to 60 patients will take part in this study at multiple sites around the US. 
 
What will happen if I take part in this study? 
 
If you are accepted and you choose to take part, you will begin receiving veliparib (ABT-888) 
and cisplatin on the first day, followed by M6620 (VX-970) on the second day.  Cisplatin and 
M6620 (VX-970) are given as an infusion through a vein.  The drugs are given in cycles, and 
each cycle is 21 days (3 weeks) long. 
• Cisplatin is given the first day of each cycle and on day 8 for some patients, for at least the 
first 6 cycles     
• M6620 (VX-970) is given on day 2 and day 9 of each cycle (or day 1 and day 8 if no 
cisplatin is given during that cycle)   
• Veliparib (ABT-888) is given orally twice a day on days 1 through 3 and days 8 through 
10 of each cycle  
 
Each patient may receive a different dose based on when he or she entered the study.  Your dose of 
study drugs may be decreased by the study doctor if you are not tolerating it well, or increased if 
you are tolerating it well.  
 
Most of the exams, tests, and procedures you will have are part of your regular care such as a 
complete medical history, blood tests, and scans to measure your tumors.  We would also do a 
pregnancy test in women who are able to become pregnant.  The team will also give you a chart 
describing the tests and procedures that will be done each day during the study. 
 
Standard procedures being done because you are in this study; these may be done more 
often because you are in the study: 
• Clinic visit: to ask how you are feeling and to evaluate you with a physical examination during 
week 1 and 2 of each cycle before you receive treatment. 
• Vital signs and physical examinations: will be performed during the clinic visits. 
• Blood tests: Measurement of your white blood cells, red blood cells, platelets, blood sugar, 
electrolytes, and of how your liver and kidneys work will be done during the first two days of 
the first week of each cycle, the second week before you receive treatment every cycle, and the 


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third week of the first cycle (this third week visit can be done with your home physician).  
About 1 tablespoon (15 mL) of blood will be drawn per visit. 
• CT scans or other imaging tests such as MRI (an examination using magnetic field and radio 
waves) that detect your tumor will be done before the study and every 6 weeks while you are 
receiving study drugs.  This is done so that any benefit of the treatment can be determined, and 
if your cancer is not responding to the treatment, the study team can tell you and discuss other 
treatment options (discussed further below).   
• EKGs (a recording of the heart’s electrical activity) to check for signs of possible damage to 
your heart.  
 
You will also have tests and procedures done because you are in the study to see how the study 
drugs are affecting your body.  If you develop any side effects, you may be asked to visit more 
often.  You will be asked to keep a diary to record the exact time you took veliparib (ABT-888), 
and to report any side effects you may have.  If you miss a dose or vomit the dose, please make a 
note of this in your diary and contact your team immediately to receive further instructions.  Please 
bring the study diary with you to each clinic visit.  
 
Tests and procedures being done to see how the drug is affecting your body: 
 
• Research blood tests: We will also be collecting blood samples from some patients to find out 
the effects of the drug on any tumor cells in the blood.  Blood samples will be collected from 
patients at the beginning of the study, and prior to receiving study drugs on days 1, 2, and 9 of 
cycle 1, days 1 and 2 of cycle 2, and on day 1 of cycle 3 and every subsequent cycle.  The total 
blood for all these tests will be up to 2 tablespoons (about 30 mL). 
• Tumor Biopsy: You may be asked to undergo imaging-directed biopsy of your tumor 
(removal of a small bit of tissue for microscopic examination) once on day 1 and again on day 
9 in the first cycle only.  We are collecting biopsy samples to study the effects of study drugs 
on your tumor and to search for any gene variations in your tumor that may help us understand 
how it responds to these drugs.  Biopsies are an important part of this trial and are done for 
research purposes.  Biopsies are optional in the early part of this study (called the dose 
escalation phase) but mandatory at a certain point in the study called the expansion phase.  
If you decide not to have biopsies collected, you will still receive study drugs and other tests 
that are part of the study and detailed above.  However, at the expansion phase, willingness 
to undergo tumor biopsies will be required for taking part in this study.  We will tell you if 
biopsies are required before you decide to take part in the study. 
 
No more than three biopsy procedures will be performed during the study.  After the first 
biopsy, if you decide not to have further biopsies, you will still receive study drugs and have 
other tests that are part of the study.  You will be asked to sign a separate consent form for 
each biopsy procedure. 
 
Tumor biopsies are only collected by trained personnel.  Biopsies are collected using a small 
needle under imaging guidance (CT, MRI, or ultrasound as deemed appropriate by the 
interventional radiologist performing the biopsy).  Imaging helps the specialized radiologist 
know that the needle has been placed into the tumor mass.   


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Typical risks of biopsy collection include, but are not limited to, bleeding, infection, pain, 
and scarring.  If you experience any complications from the biopsy, medical care will be 
offered to you.  You will be counseled in more detail about biopsies, and you will be asked 
to sign a separate consent form that will describe the procedures and risks at that time.  Your 
safety is the most important thing at all times.  If upon attempting the first biopsy, no tissue 
can be obtained or it has caused you harm, further biopsies will not be done.  After you are 
enrolled in this study, if for any reason the biopsies cannot be done safely, you may still 
receive the study drugs but the biopsies will not be done. 
 
The biopsies are for research purposes and will not benefit you.  They might help other 
people in the future.  Even if you sign “yes” to have biopsies, you can change your mind at 
any time.  Please read each sentence below and think about your choice.  After reading the 
sentence, circle the initial answer that is right for you: 
 
Have you been informed regarding what phase of the study you will be in?  
Escalation phase_______  Expansion phase________ Initials __________ 
 
 
I agree to have the tumor biopsies for the escalation phase of the research study (optional). 
 
Yes              No               Initials_________ 
 
I agree to have the tumor biopsies for the expansion phase of the research study (mandatory). 
 
Yes              No               N/A ______  Initials_________ 
 
Optional Tumor Genomic Sequencing 
Targeted Sequencing—If your cancer looks like it is getting worse, you may choose to 
have another, optional tumor biopsy before leaving the study and have a targeted genomic 
sequencing test done on this tumor tissue in a clinically approved laboratory.  You and your 
doctor will receive the results of this test, and the results will be in your electronic medical 
record.  Your doctor will discuss these results with you and tell you about any gene 
variations that might make you able to take part in targeted therapy clinical trials in the 
future, such as the NCI MATCH (NCT02465060) and MPACT (NCT01827384) trials. 
Exome Sequencing—If you choose to have the optional, third tumor biopsy, we are also 
requesting your permission to perform exome sequencing on your tumor biopsies and link 
this information to information from your medical history.  You are not required to agree to 
exome sequencing to take part in this trial.  Your tumor tissue contains genes, which are 
made up of DNA (deoxyribonucleic acid) and serve as the "instruction book" for the cells 
that make up our bodies.  Exome sequencing will determine the exact order of the base pairs 
(DNA building blocks) in your tumor.  We know that variations in the base pairs of some 
tumor genes play an important role in how cancers respond to drugs.  Information about 
your gene variations combined with information from your medical history may help us 
understand how your tumor responds to the study drugs and why it has stopped responding.     


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If you agree, we will identify gene variants in your tumor biopsy samples collected at the 
beginning and end of treatment with exome sequencing, but this information will be for 
research purposes only and we will not give you any individual results from this sequencing 
or add this information to your medical records.  This is because it will probably take a long 
time for this project to produce health-related information that we will know how to 
interpret accurately.  However, we will tell you if we find that you have a communicable 
disease that we are required by law to report. 
I agree to allow genomic sequencing for research purposes:  
Yes              No               Initials_________ 
 
How long will I be in this study?  
 
You will stay in the study as long as you are tolerating the drugs and your tumors are either 
stable or getting better, but you can choose to leave the study at any time. 
 
For some study procedures, we will need you to come to ________________ [name of center].   
 
Stopping Therapy 
You can decide to stop at any time.  If you decide to stop for any reason, it is important to let 
your study doctor know as soon as possible so you can stop safely.  If you stop, you can decide 
whether or not to let the study doctor continue to include your medical information in the study. 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
Your study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow the study rules 
• If the study is stopped by the sponsor, IRB, or FDA 
 
Follow-up  
You will be followed for 30 days after taking the last dose of study drugs.  We will call you 
between days 27- 30 to ask about any side effects that were ongoing when you stopped therapy, 
or any new side effects that might be related to the study therapy.  If you have side effects that 
might be related to the study drugs that have not gotten better after 30 days, we will call you 
every 2 weeks until the side effects have become stable or gotten better.  The follow-up period 
will end if you enroll in another study or start receiving standard therapy.   
 
Alternative Approaches or Treatments 
 
What other choices do I have if I do not take part in this study?  
 
Instead of being in this study, you have these options: 
• you may choose to have the usual approaches described above  


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• you may choose to take part in a different study, if one is available 
• you may continue your standard care as usual (see table below), and not take part in this 
study 
• or you may choose not to be treated, but you may want to receive comfort care to relieve 
symptoms  
Please talk to your doctor about these and other options.  Your doctor may decide that it is not 
safe for you to receive a particular treatment or you have the right to refuse a treatment, but 
before you decide to take part in this study you should discuss all available treatment options 
with your local doctor. 
 
Risks or Discomforts of Participation 
 
What side effects or risks can I expect from being in the study? 
 
If you choose to take part in this study, there is a risk that the treatment may not be as good as 
the usual approach for your cancer or condition at shrinking or stabilizing your cancer. 
 
You also may have the following discomforts: 
• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies. 
 
The agents used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood.  The study doctor will test your blood and will let you know if 
changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important things to know about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, and some may never go 
away. 
• Some side effects may make it hard for you to have children. 
• Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
• Your study doctor will give you a drug interactions handout and wallet card that lists 
possible interactions. 
 


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The tables below show the most common and the most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
• Some patients on this study have had low platelet counts and low red and white blood cell 
counts in their blood, possibly due to this drug combination.  These conditions can cause 
bruising, bleeding, slow blood clotting after an injury, tiredness, weakness, shortness of 
breath, and can keep your body from fighting off infections.   
 
Risks and side effects related to veliparib (ABT-888) may include: 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving ABT-888 (veliparib), more than 20 and up to 100 may have: 
• Nausea 
• Tiredness 
• Bruising, bleeding 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving ABT-888 (veliparib), from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Infection, especially when white blood cell count is low 
• Belly pain 
• Constipation, diarrhea, vomiting 
• Weight loss, loss of appetite 
• Dehydration 
• Dizziness, headache 
• Changes in taste 
• Rash 
 
RARE, AND SERIOUS 
In 100 people receiving ABT-888 (veliparib), 3 or fewer may have: 
• Cancer of bone marrow caused by chemotherapy 
• Damage to the bone marrow (irreversible) which may cause infection, bleeding, may 
require transfusions 
• A new cancer resulting from treatment of earlier cancer 
• Seizure 
• Blood clot which may cause swelling, pain, shortness of breath 
 
 
 
Risks and side effects related to M6620 (VX-970) may include: 
POSSIBLE, SOME MAY BE SERIOUS 
 


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• 
Anemia which may require blood transfusion 
• 
Diarrhea, nausea, vomiting 
• 
Tiredness 
• 
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath,  
swelling of the face or throat 
• 
Infection, especially when white blood cell count is low which may cause painful and 
frequent urination 
• 
Bruising, bleeding 
• 
Pain in tumor 
• 
Dizziness, headache 
• 
Itching, rash 
• 
Flushing 
 
While taking M6620 (VX-970), you should take protective measures to minimize sun exposure. 
 
Risks and side effects related to cisplatin may include: 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving cisplatin, more than 20 and up to 100 may have: 
• Nausea, vomiting 
• Infection, especially when white blood cell count is low 
• Anemia which may cause tiredness, or may require blood transfusions 
• Bruising, bleeding 
• Kidney damage which may cause swelling, may require dialysis 
• Hearing loss including ringing in ears 
 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving cisplatin, from 4 to 20 may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Confusion 
• Difficulty with balance 
 
 
 
RARE, AND SERIOUS 
In 100 people receiving cisplatin, 3 or fewer may have: 
• Cancer of bone marrow caused by chemotherapy later in life 
• 
Seizure 
 
 
Risks associated with genomic sequencing: 


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Privacy Risks 
Your privacy is very important to us and we will use many safety measures to protect your 
privacy.  Your research samples will be stored with a coded identifier, not your name.  Any 
personal data about you will also be stored in a sequence computer database with that code 
identifier.  All information that can directly link you to the tissue or personal information 
will not be shared with investigators using your specimens for research.  This includes 
information that contains your name, medical record number, date of birth, or address. 
There are protections in place that restrict who can see the results of your genetic tests.  
However, there remains a risk someone could get unauthorized access or break into the 
system that stores information about you.  Every precaution will be taken to minimize this 
risk.  There also may be other privacy risks that we have not foreseen. 
Genetic variant results that we return to you will become part of your medical record at the 
NIH.  In spite of all of the safety measures that we will use, we cannot guarantee that your 
identity will ever become known.  For instance, if you or a family member releases 
information about you or your involvement in this study, or an insurer, employer, or other 
person obtains your written consent to receive information from your NIH medical record, 
your identity, information about your enrollment in this study and genetic variant results 
may be included in a release of your medical records. 
Protections against misuse of genetic information 
Since some genetic variations can help to predict the future health problems of you and 
your relatives, this information might be of interest to health providers, life insurance 
companies, and others.  Patterns of genetic variation also can be used by law enforcement 
agencies to identify a person or his/her blood relatives.  
There are state and federal laws that protect against genetic discrimination.  There is a 
federal law called the Genetic Information Nondiscrimination Act (GINA).  In general, this 
law makes it illegal for health insurance companies, group health plans, and most 
employers to discriminate against you based on your genetic information.  GINA also does 
not apply to members of the United States military, to veterans obtaining health care 
through the Veteran’s Administration or the Indian Health Service.  GINA does not forbid 
insurance medical underwriting based on your current health status, including your cancer.  
GINA also does not protect you against discrimination by companies that sell life 
insurance, disability insurance, or long-term care insurance.  However, your cancer 
diagnosis will often be considered more important that genetic information about risk for 
developing another condition when evaluating you during medical underwriting. 
Emotional and psychological risks 
As part of the research study, it is possible that you could learn that you have genetic risks 
for another disease or disability.  This may be upsetting and, depending on what you learn, 
might create a need to make challenging decisions about how to respond.  Although your 
genomic information is unique to you, you share some genomic similarities with your 
children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 


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testing results could mean something about your family members and might cause you or 
your family distress.  Before joining the study, it may be beneficial to talk with your family 
members about whether and how they want you to share your results with them. 
 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child.  If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
and your partner will need to practice an effective form of birth control before starting study 
treatment, during study treatment, and for 6 months after you finish study treatment.  If you think 
that you or your partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include using at least two of the following:  
• abstinence  
• intrauterine device (IUD) 
• tubal ligation 
• vasectomy 
• barrier methods (condoms) 
 
• hormonal (birth control pills, injections, or implants) 
Also, if you are a woman taking hormonal birth control, please tell your study doctor or nurse.  
Some patients on this study may be given medication to control the side effects of nausea and 
vomiting that can make some forms of hormonal birth control stop working or work less well.  
You may need to use an alternative form of birth control during this time. 
 
Potential Risks Related to Blood Samples 
Possible side effects from drawing the blood sample include mild pain, bleeding, bruising, and 
infection at the site of the needle insertion.  Fainting or light-headedness can sometimes occur, but 
usually last only a few minutes.  
 
Potential Benefits of Participation 
 
Are there benefits to taking part in this study? 
 
The aim of this study is to see if this experimental treatment will cause your tumors to shrink.  We 
do not know if you will receive personal, medical benefit from taking part in this study.  These 
potential benefits could include shrinking of your tumor or lessening of your symptoms, such as 
pain, that are caused by the cancer.  Because there is not much information about the drugs’ effect 
on your cancer, we do not know if you will benefit from taking part in this study, although the 
knowledge gained from this study may help others in the future who have cancer.   
 
Research Subject’s Rights 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
this study.  If you decide to take part, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you, and you will not lose any of your regular 
benefits.  Leaving the study will not affect your medical care.  You can still get your medical 


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care from our institution if you are eligible and choose to participate in another trial.  We will tell 
you about new information or changes in the study that may affect your health or your 
willingness to continue in the study.  In the case of injury resulting from this study, you do not 
lose any of your legal rights to seek payment by signing this form. 
 
Will my medical information be kept private? 
 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people. 
 
• Designated investigators from other cancer centers participating in this study, including 
MD Anderson Cancer Center and Dana-Farber Cancer Institute. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.] 
 
Certificate of Confidentiality 
To help us protect your privacy, the NIH has obtained a Certificate of Confidentiality from the 
Department of Health and Human Services.  The Certificate is designed to prevent us from being 
forced to disclose identifying information for use in any federal, state, or local civil, criminal, 
administrative, legislative, or other court proceeding, even if faced with a court subpoena.  You 
should understand, however, that a Certificate of Confidentiality does not prevent you or a 
member of your family from voluntarily releasing information about yourself or your 
involvement in this research.  We may not withhold information if you give your insurer or 
employer or a law enforcement agency permission to receive information about your 
participation in this project.  This means that you and your family must also actively protect your 
own privacy. 
The Certificate does not prevent us from taking steps, including reporting to authorities, to 
prevent serious harm to yourself or others. Such disclosures will be made as described below. 
The research team may share your information with: 
• 
The Department of Health and Human Services (HHS), to complete federal 
responsibilities for audit or evaluation of this project; 
• 
Public health agencies, to complete public health reporting requirements; 
• 
NIH representatives, to complete NIH responsibilities for oversight of this study;  


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• 
Your primary care physician if a medical condition that needs urgent attention is 
discovered;  
• 
Appropriate authorities to the extent necessary to prevent serious harm to yourself 
or others.  
 
What are the costs of taking part in this study? 
 
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
The NCI will supply the study agents veliparib (ABT-888) and M6620 (VX-970) at no charge 
while you take part in this study.  Even though it is unlikely, there is a possibility that at some 
point the supply of study agents may run out, necessitating taking you off-study.  The NCI will 
not provide cisplatin free-of-charge, so you or your health plan may need to pay for cisplatin and 
the personnel who give it to you.  
 [If applicable, inform the patient of any tests, procedures or agents for which there is no charge.  
The explanation, when applicable, should clearly state that there are charges resulting from 
performance of the test or drug administration that will be billed to the patient and/or health 
plan.  For example, “The NCI is supplying (drug) at no cost to you.  However, you or your 
health plan may need to pay for costs of the supplies and personnel who give you the (drug).”] 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment.   
 


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Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone number).  
[Note to Local Investigator: Contact information for patient representatives or other individuals 
in a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can be listed here.]    
 
Where can I get more information? 
 
You may call the National Cancer Institute’s Cancer Information Service at: 1-800-4-CANCER 
(1-800-422-6237).  You may also visit the NCI Web site at http://cancer.gov/. 
• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
• For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor.  
 
Signature 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this study. 
 
Participant ________________________________ 
 
 
Date _____________________________________ 


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APPENDIX F: CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
• Prior to the activation of the protocol at each participating institution, an OHRP Form 
310 (documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
• Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 


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Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
• The title page must include the name and address of each participating institution and the 
name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
• The Coordinating Center must be designated on the title page. 
• Central registration of patients is required.  The procedures for registration must be stated 
in the protocol. 
• Data collection forms should be of a common format.  Sample forms should be submitted 
with the protocol.  The frequency and timing of data submission forms to the 
Coordinating Center should be stated. 
• Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center. 
• Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
 
Agent Ordering 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
investigational agents directly from CTEP (see Section 8.4).  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been forwarded 
by the Coordinating Center to the CTEP PIO.  
 


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APPENDIX G: PROCEDURE FOR SAMPLES FOR PHARMACODYNAMIC STUDIES 
 
 
Collection of Biopsies 
 
Materials for shipping biopsy specimens will not be provided.  Core needle biopsies and biopsies 
from dermatologic and ENT lesions should be collected, placed in pre-chilled cryogenic vials, 
flash frozen in liquid nitrogen within 2 minutes of collection, and shipped on dry ice.  Refer to 
SOP 340507 
(https://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507_Biopsy_Frozen.pd
f ) for detailed instructions on core needle biopsy collection and handling, including the sample 
shipping manifest, batch record, and instructions for requesting FedEx labels.  Sample handling 
SOPs are still in development for biopsies collected from dermatologic and ENT lesions; please 
contact FNLCR PD Central Receiving (NCI_PD_Support@mail.nih.gov, 301-846-1951, or 301-
846-6747) for additional instructions regarding these tissue types. 
Participating site biopsy samples will shipped via FedEx to: 
 
Attention: 
 
NCI-F/FNLCR 
1073 Beasley Street, 
 
Fort Detrick 
Frederick, MD 21701 
Phone: 
 
 
At the NCI only, biopsy samples will be shipped via courier to: 
Attn: 
 
Frederick National Laboratory for Cancer Research 
Leidos Biomedical Research, Inc. 
1050 Boyles Street 
 
Frederick, MD 21702 
Phone: 
 
 
Isolation of CTCs  
 
Prior to CTC collection, each participating site should e-mail a request for specimen 
collection and shipping materials from NCI_PD_Support@mail.nih.gov.  Allow at least six 
business days for receipt of the blood shipment containers; a confirmation e-mail with the 
expected shipping date will be sent.  Blood (at least 7.5 mL) will be collected aseptically by 
venipuncture or from a venous port into one 10 mL CellSave preservative tube; the collected 
blood samples are stable for up to 48 hours at room temperature (15˚C to 30˚C) prior to 
processing.   
Participating site CTC samples will be shipped to:  
Attention: 
 
NCI-F/FNLCR 
1073 Beasley Street, 
 


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Fort Detrick 
Frederick, MD 21701 
Phone: 
 
 
At the NCI only, CTC samples will be shipped via courier to: 
 
Attn: PADIS CTC Laboratory 
Frederick National Laboratory for Cancer Research 
Leidos Biomedical Research, Inc. 
1050 Boyles Street 
 
Frederick, MD 21702 
Phone: 301.846.4711 
E-mail NCIPDSupportPADIS@mail.nih.gov prior to shipping CTC samples with expected 
arrival date/time and a description of contents.  All shipments should include a description of 
contents on the outside label/shipping slip, and a detailed packing slip should be included with 
the samples.  Because of the 48-hour window of CTC sample stability, CTC samples should be 
shipped to arrive when specified below: 
 
Collection Day 
Day/time samples must arrive at PADIS 
Monday 
Wednesday (early morning) 
Tuesday 
Thursday (early morning) 
Wednesday 
Friday (early morning) 
Thursday 
Friday (early morning) 
CTC samples may not be collected on Fridays 
Saturday 
Monday (early morning) 
Sunday 
Tuesday (early morning) 
 

ICF_001.pdf: 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
Version Date: 01/11/21 
Page 1 of 17 
CC pre rCR ICF template v. 05.05.2020 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PRINCIPAL INVESTIGATOR: Alice P. Chen, M.D. 
STUDY TITLE: Phase I Study of Veliparib (ABT-888), an Oral PARP Inhibitor, and M6620 
(VX-970), an ATR Inhibitor, in Combination with Cisplatin in Patients with Refractory Solid 
Tumors 
STUDY SITE: NIH Clinical Center 
 
Cohort: Treatment  
Consent Version: 1/11/2021 
 
 
WHO DO YOU CONTACT ABOUT THIS STUDY?  
 
 
 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.   
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice. 
If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research.  
 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY 
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.   
 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to test the safety of a combination of 3 drugs [M6620 (VX-970), 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
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veliparib (ABT-888), and cisplatin] to find out the doses of these drugs that can be safely given 
to humans and to learn if these drugs have activity against tumors.  Although we hope this 
experimental therapy will decrease the size of your tumor, we cannot promise or predict the 
benefits of the treatment at this time.  The drugs used in this study have known side effects that 
will be reviewed with you by your medical team before you sign this consent form.  
 
Cisplatin is currently approved by the US Food and Drug Administration (FDA) for the treatment 
of patients with bladder, ovarian, and testicular cancers in combination with other chemotherapy 
agents.  Veliparib (ABT-888) and M6620 (VX-970) are not approved by the FDA.  Combining 
veliparib (ABT-888) and M6620 (VX-970) with cisplatin is thought to block proteins that are 
known to be important for cancer cell growth.  
 
We are also studying the genes in your tumor to help us understand how your tumor responds to these 
3 drugs.  Blood, tissue, and tumor cells contain genes that are made up of DNA and serve as the 
“instruction book” for each cell in the body.  We know that variations in some tumor genes play an 
important role in how cancers respond to drugs.  Determining whether different tumor gene variations 
affect how veliparib (ABT-888), M6620 (VX-970), and cisplatin work against tumors will help 
scientists understand why some patients might stop responding to these drugs. 
 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY? 
You are being asked to take part in this research study because you have advanced cancer that has 
progressed after receiving standard treatment, or for which no effective therapy exists.  We hope that 
this combination of study drugs will slow down the growth of your cancer. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
Up to 60 patients will take part in this study at multiple sites around the US. 
 
Description of Research Study 
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?   
If you are accepted and you choose to take part, you will begin receiving veliparib (ABT-888) and 
cisplatin on the first day, followed by M6620 (VX-970) on the second day.  Cisplatin and M6620 
(VX-970) are given as an infusion through a vein.  The drugs are given in cycles, and each cycle is 
21 days (3 weeks) long. 
   
• Cisplatin is given the first day of each cycle and on day 8 for some patients, for at least the 
first 6 cycles   
• M6620 (VX-970) is given on day 2 and day 9 of each cycle (or day 1 and day 8 if no 
cisplatin is given during that cycle)   
• Veliparib (ABT-888) is given orally twice a day on days 1 through 3 and days 8 through 10 
of each cycle  
 


 
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Each patient may receive a different dose based on when he or she entered the study.  Your dose of 
study drugs may be decreased by the study doctor if you are not tolerating it well, or increased if you 
are tolerating it well.  
 
Most of the exams, tests, and procedures you will have are part of your regular care such as a complete 
medical history, blood tests, and scans to measure your tumors.  We would also do a pregnancy test 
in women who are able to become pregnant.  The team will also give you a chart describing the tests 
and procedures that will be done each day during the study. 
 
While you are at the Clinical Center we will perform study tests and procedures to see how the study 
drugs are affecting your body.  If you develop any side effects, you may be asked to visit more often.  
You will be asked to keep a diary to record the exact time you took veliparib (ABT-888), and to report 
any side effects you may have.  If you miss a dose or vomit the dose, please make a note of this in 
your diary and contact your team immediately to receive further instructions.  Please bring the study 
diary with you to each clinic visit.  
 
HOW LONG WILL I BE IN THIS STUDY?  
You will stay in the study as long as you are tolerating the drugs and your tumors are either stable or 
getting better, but you can choose to leave the study at any time. 
 
TESTS AND PROCEDURES BEING DONE TO SEE HOW THE DRUGS ARE AFFECTING 
YOUR BODY: 
• Imaging scans, such as CT scans, MRI, or ultrasound (an examination using sound waves), 
that detect your tumor will be done before the study and every 6 weeks (or 9 or 12 weeks if 
you have been on study more than 1 or 3 years, respectively) while you are receiving study 
drugs.  This is done so that any benefit of the treatment can be determined, and if your 
cancer is not responding to the treatment, the study team can tell you and discuss other 
treatment options (discussed further below).   
o Computed Tomography (CT) scan: The CT scanner is a doughnut-shaped machine 
that uses x-rays to create computer pictures showing the inside of your body.  During 
the procedure, you will need to lie still on a table inside the CT machine.  The table 
will move you in and out of the machine during the scan and you will be instructed 
to hold your breath.  The scan itself will only take a few minutes to complete, the 
entire visit will take about 30 minutes 
o Magnetic resonance imaging (MRI): An MRI creates pictures of the inside of your 
body using strong magnets instead of x-ray energy.  At the time of each scan you 
will be asked to fill out a screening form to verify that it is safe for you to have the 
scan.  You will also be asked to remove any metallic objects you may be wearing 
(for example, watches, earrings or piercings) and possibly to change into a hospital 
gown.  Then you’ll be asked to lie on a narrow bed that will move into the MRI 
scanner.  Once you are comfortable, the table will be moved into the scanner (the 
scanner is a long, narrow tube that is open at each end).  You will need to lie still on 


 
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the table during the scan which will take about 60 minutes to complete.  You will 
hear normal “hammering” or clicking and squealing noises during the scan.  While 
in the scanner you will be fitted with earplugs or earmuffs to muffle the sound. You 
will be able to communicate with the technician running the scan the entire time and 
will be provided an emergency button to squeeze at any time if you decide you want 
the scan to stop. 
During part of the MRI you will receive gadolinium, a contrast agent, through an 
intravenous (IV) catheter. It will be done for both research and medical purposes.  
It is not known if MRI with contrast is completely safe for a developing fetus. 
Therefore, all women of childbearing potential will have a pregnancy test 
performed no more than 24 hours before each MRI scan with contrast. The scan 
will not be done if the pregnancy test is positive. 
• Research blood tests: We will also be collecting blood samples from some patients to find out 
the effects of the drug on any tumor cells in the blood.  Blood samples will be collected from 
patients at the beginning of the study, and prior to receiving study drugs on days 1, 2, and 9 of 
cycle 1, days 1 and 2 of cycle 2, and on day 1 of cycle 3 and every subsequent cycle.  The total 
blood for all these tests will be up to 2 tablespoons (about 30 mL). 
• Electrocardiogram: An electrocardiogram (ECG) is a test that is performed while you lie still 
for about 5 minutes.  It involves placing electrodes (small stickers that are attached to wires 
that go to the machine) on the chest and arms/legs and recording the electrical activity of your 
heart.  If you have a lot of hair on your chest, it may hurt a little bit when they remove these 
stickers 
• Tumor Biopsy: You may be asked to undergo imaging-directed biopsy of your tumor 
(removal of a small bit of tissue for microscopic examination) once on day 1 and again on day 
9 in the first cycle only.  We are collecting biopsy samples to study the effects of study drugs 
on your tumor and to search for any gene variations in your tumor that may help us understand 
how it responds to these drugs.  Biopsies are an important part of this trial and are done for 
research purposes.  Biopsies are optional in the early part of this study (called the dose 
escalation phase) but mandatory at a certain point in the study called the expansion phase.  
If you decide not to have biopsies collected, you will still receive study drugs and other tests that 
are part of the study and detailed above.  However, at the expansion phase, willingness to 
undergo tumor biopsies will be required for taking part in this study.  We will tell you if 
biopsies are required before you decide to take part in the study. 
No more than three biopsy procedures will be performed during the study.  After the first biopsy, 
if you decide not to have further biopsies, you will still receive study drugs and have other tests 
that are part of the study.  You will be asked to sign a separate consent form for each biopsy 
procedure. 
Tumor biopsies are only collected by trained personnel.  Biopsies are collected using a small 
needle under imaging guidance (CT, MRI, or ultrasound as deemed appropriate by the 


 
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interventional radiologist performing the biopsy).  Imaging helps the specialized radiologist 
know that the needle has been placed into the tumor mass.   
Typical risks of biopsy collection include, but are not limited to, bleeding, infection, pain, and 
scarring.  If you experience any complications from the biopsy, medical care will be offered to 
you.  You will be counseled in more detail about biopsies, and you will be asked to sign a separate 
consent form that will describe the procedures and risks at that time.  Your safety is the most 
important thing at all times.  If upon attempting the first biopsy, no tissue can be obtained or it 
has caused you harm, further biopsies will not be done.  After you are enrolled in this study, if 
for any reason the biopsies cannot be done safely, you may still receive the study drugs but the 
biopsies will not be done. 
The biopsies are for research purposes and will not benefit you.  They might help other people 
in the future.  Even if you sign “yes” to have biopsies, you can change your mind at any time.  
Please read each sentence below and think about your choice.  After reading the sentence, circle 
the initial answer that is right for you: 
Have you been informed regarding what phase of the study you will be in? 
 
Escalation phase_______  Expansion phase________ Initials __________ 
 
I agree to have the tumor biopsies for the escalation phase of the research study (optional). 
 
Yes              No               Initials_________ 
I agree to have the tumor biopsies for the expansion phase of the research study (mandatory). 
 
Yes              No               N/A ______  Initials_________ 
 
OPTIONAL TUMOR GENOMIC SEQUENCING 
Targeted Sequencing—If your cancer looks like it is getting worse, you may choose to 
have another, optional tumor biopsy before leaving the study and have a targeted genomic 
sequencing test done on this tumor tissue in a clinically approved laboratory.  You and your 
doctor will receive the results of this test, and the results will be in your electronic medical 
record.  Your doctor will discuss these results with you and tell you about any gene 
variations that might make you able to take part in targeted therapy clinical trials in the 
future, such as the NCI MATCH (NCT02465060) and MPACT (NCT01827384) trials. 
Exome Sequencing—If you choose to have the optional, third tumor biopsy, we are also 
requesting your permission to perform exome sequencing on your tumor biopsies and link 
this information to information from your medical history.  You are not required to agree to 
exome sequencing to take part in this trial.  Your tumor tissue contains genes, which are made 
up of DNA (deoxyribonucleic acid) and serve as the "instruction book" for the cells that make 
up our bodies.  Exome sequencing will determine the exact order of the base pairs (DNA 
building blocks) in your tumor.  We know that variations in the base pairs of some tumor 
genes play an important role in how cancers respond to drugs.  Information about your gene 
variations combined with information from your medical history may help us understand how 
your tumor responds to the study drugs and why it has stopped responding.     


 
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If you agree, we will identify gene variants in your tumor biopsy samples collected at the 
beginning and end of treatment with exome sequencing, but this information will be for 
research purposes only and we will not give you any individual results from this sequencing 
or add this information to your medical records.  This is because it will probably take a long 
time for this project to produce health-related information that we will know how to interpret 
accurately.  However, we will tell you if we find that you have a communicable disease that 
we are required by law to report. 
I agree to allow genomic sequencing for research purposes:  
 
Yes              No               Initials_________ 
 
 
RISKS OR DISCOMFORTS OF PARTICIPATION 
What side effects or risks can I expect from being in the study? 
If you choose to take part in this study, there is a risk that the treatment may not be as good as the 
usual approach for your cancer or condition at shrinking or stabilizing your cancer. 
 
You also may have the following discomforts: 
• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies. 
 
The agents used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood.  The study doctor will test your blood and will let you know if changes 
occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important things to know about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, and some may never go 
away. 
• Some side effects may make it hard for you to have children. 
• Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways to 
make side effects less of a problem: 
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 


 
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• Your study doctor may adjust the study drugs to try to reduce side effects. 
• Your study doctor will give you a drug interactions handout and wallet card that lists 
possible interactions. 
 
The tables below show the most common and the most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important new 
side effects are found, the study doctor will discuss these with you. 
• Some patients on this study have had low platelet counts and low red and white blood cell 
counts in their blood, possibly due to this drug combination.  These conditions can cause 
bruising, bleeding, slow blood clotting after an injury, tiredness, weakness, shortness of 
breath, and can keep your body from fighting off infections.   
 
Risks and side effects related to veliparib (ABT-888) may include: 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving ABT-888 (veliparib), more than 20 and up to 100 may have: 
• Nausea 
• Tiredness 
• Bruising, bleeding 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving ABT-888 (veliparib), from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Infection, especially when white blood cell count is low 
• Belly pain 
• Constipation, diarrhea, vomiting 
• Weight loss, loss of appetite 
• Dehydration 
• Dizziness, headache 
• Changes in taste 
• Rash 
 
RARE, AND SERIOUS 
In 100 people receiving ABT-888 (veliparib), 3 or fewer may have: 
• Cancer of bone marrow caused by chemotherapy 
• Damage to the bone marrow (irreversible) which may cause infection, bleeding, 
may require transfusions 
• A new cancer resulting from treatment of earlier cancer 
• Seizure 
• Blood clot which may cause swelling, pain, shortness of breath 


 
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Risks and side effects related to M6620 (VX-970) may include: 
POSSIBLE, SOME MAY BE SERIOUS 
• Anemia which may require blood transfusion 
• Diarrhea, nausea, vomiting 
• Tiredness 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath,  swelling of the face or throat 
• Infection, especially when white blood cell count is low which may cause painful 
and frequent urination 
• Bruising, bleeding 
• Pain in tumor 
• Dizziness, headache 
• Itching, rash 
• Flushing 
 
While taking M6620 (VX-970), you should take protective measures to minimize sun 
exposure. 
 
Risks and side effects related to cisplatin may include: 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving cisplatin, more than 20 and up to 100 may have: 
• Nausea, vomiting 
• Infection, especially when white blood cell count is low 
• Anemia which may cause tiredness, or may require blood transfusions 
• Bruising, bleeding 
• Kidney damage which may cause swelling, may require dialysis 
• Hearing loss including ringing in ears 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving cisplatin, from 4 to 20 may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Confusion 
• Difficulty with balance 
 


 
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RARE, AND SERIOUS 
In 100 people receiving cisplatin, 3 or fewer may have: 
• Cancer of bone marrow caused by chemotherapy later in life 
• Seizure 
 
Risks associated with genomic sequencing: 
Privacy Risks 
Your privacy is very important to us and we will use many safety measures to protect your 
privacy.  Your research samples will be stored with a coded identifier, not your name.  Any 
personal data about you will also be stored in a sequence computer database with that code 
identifier.  All information that can directly link you to the tissue or personal information 
will not be shared with investigators using your specimens for research.  This includes 
information that contains your name, medical record number, date of birth, or address. 
There are protections in place that restrict who can see the results of your genetic tests.  
However, there remains a risk someone could get unauthorized access or break into the 
system that stores information about you.  Every precaution will be taken to minimize this 
risk.  There also may be other privacy risks that we have not foreseen. 
Genetic variant results that we return to you will become part of your medical record at the 
NIH.  In spite of all of the safety measures that we will use, we cannot guarantee that your 
identity will ever become known.  For instance, if you or a family member releases 
information about you or your involvement in this study, or an insurer, employer, or other 
person obtains your written consent to receive information from your NIH medical record, 
your identity, information about your enrollment in this study and genetic variant results may 
be included in a release of your medical records. 
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict 
future health problems of you and your family and this information might be of interest to 
your employers or insurers. The Genetic Information Nondiscrimination Act (GINA) is a 
federal law that prohibits plans and health insurers from requesting genetic information or 
using genetic information. It also prohibits employment discrimination based on your health 
information. However, GINA does not address discrimination by companies that sell life 
insurance, disability insurance, or long-term care insurance. GINA also does not protect you 
against discrimination based on an already-diagnosed condition or disease that has a genetic 
component. 
Emotional and psychological risks 
As part of the research study, it is possible that you could learn that you have genetic risks 
for another disease or disability.  This may be upsetting and, depending on what you learn, 
might create a need to make challenging decisions about how to respond.  Although your 
genomic information is unique to you, you share some genomic similarities with your 


 
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children, parents, brothers, sisters, and other blood relatives. Therefore, learning your testing 
results could mean something about your family members and might cause you or your 
family distress.  Before joining the study, it may be beneficial to talk with your family 
members about whether and how they want you to share your results with them. 
 
Reproductive Risks: 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child.  If you are a woman 
who can become pregnant, or are the partner of a woman who can become pregnant, you and your 
partner will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 6 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include using at least two of the following:  
• abstinence  
• intrauterine device (IUD) 
• tubal ligation 
• vasectomy 
• barrier methods (condoms) 
 
• hormonal (birth control pills, injections, or implants) 
Also, if you are a woman taking hormonal birth control, please tell your study doctor or nurse.  Some 
patients on this study may be given medication to control the side effects of nausea and vomiting 
that can make some forms of hormonal birth control stop working or work less well.  You may need 
to use an alternative form of birth control during this time. 
 
Radiation Risks 
During your participation in this research study, you will be exposed to radiation from CT scans 
and CT-guided tumor biopsies.  The amount of radiation exposure you will receive from these 
procedures is equal to approximately 13.4 rem per year. A rem is a unit of absorbed radiation.  
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body.  
The CT scans that you get in this study will expose you to the roughly the same amount of radiation 
as 45 years’ worth of background radiation. Being exposed to too much radiation can cause 
harmful side effects such as an increase in the risk of cancer.  The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer 
during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from 
the radiation exposure in this study is 1.34 out of 100 (1.34%) and of getting a fatal cancer is 0.67 
out of 100 (0.67%). 


 
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Risks for MRI 
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body.  It 
may be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. You will be screened for 
these conditions before having any MRI scan.  If you have a question about metal in your body, 
you should inform the staff. You will be asked to complete an MRI screening form before each 
MRI scan you have.  
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room. 
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away. 
There are no known long-term risks of MRI scans. 
 
Risks for Gadolinium-Enhanced MRI 
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.   
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is given.    
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”.  This condition always involves the skin and can also 
involve the muscles, joints and internal organs.  NSF has resulted in a very small number of deaths.  
A blood test of your kidney function may be done within the month before an MRI scan with 
gadolinium contrast. You will not receive gadolinium for a research MRI scan if your kidney 
function is below the safe level.  
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA recently issued 
a safety alert that indicates small amounts of gadolinium may remain in the body for months to 
years.  The effects of the retained gadolinium are not clear. At this time, retained gadolinium has 
not been linked to health risks in people whose kidneys work well. Some types of gadolinium 


 
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contrast drugs are less likely to remain than others.  In this study, we will use the gadolinium 
contrast drugs that are less likely to remain.  
 
Electrocardiogram Risks 
Other than possibly experiencing some minor skin irritation from the electrodes there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram. 
 
Blood Draw Risks 
Blood draws may cause pain, redness, bruising or infection at the site of the needle stick.  Rarely 
some people faint.  The study team member may apply numbing cream to the area so that the 
needle stick won’t hurt as much. 
 
POTENTIAL BENEFITS OF PARTICIPATION 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental treatment will cause your tumors to shrink.  We 
do not know if you will receive personal, medical benefit from taking part in this study.  These 
potential benefits could include shrinking of your tumor or lessening of your symptoms, such as 
pain, that are caused by the cancer.  Because there is not much information about the drugs’ effect 
on your cancer, we do not know if you will benefit from taking part in this study, although the 
knowledge gained from this study may help others in the future who have cancer.   
 
ALTERNATIVE APPROACHES OR TREATMENTS 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• you may choose to have the usual approaches described above  
• you may choose to take part in a different study, if one is available 
• you may continue your standard care as usual, and not take part in this study 
• or you may choose not to be treated, but you may want to receive comfort care to relieve 
symptoms  
 
Please talk to your doctor about these and other options.  Your doctor may decide that it is not safe 
for you to receive a particular treatment or you have the right to refuse a treatment, but before you 
decide to take part in this study you should discuss all available treatment options with your local 
doctor. 
 
•  
 


 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
STOPPING THERAPY  
You can decide to stop at any time.  If you decide to stop for any reason, it is important to let your 
study doctor know as soon as possible so you can stop safely.  If you stop, you can decide whether 
or not to let the study doctor continue to include your medical information in the study. 
Your study doctor will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study. 
Your study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow the study rules 
• If the study is stopped by the sponsor, IRB, or FDA 
 
CONFLICT OF INTEREST  
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH 
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  Results of research 
done on your specimens and data will not be available to you or your doctor.  It might help people 
who have cancer and other diseases in the future.   


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
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MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 
COMPENSATION, REIMBURSEMENT, AND PAYMENT 
Will you receive compensation for participation in the study? 
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines. 
You will not receive compensation for participation in this study.  
Will you receive reimbursement or direct payment by NIH as part of your participation? 
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines. 
The NCI Developmental Therapeutics Clinic will cover some or all of your travel expenses related 
to participation in this study. This may include direct payments or reimbursements for expenses 
related to transportation, lodging, and meals. The amount and form of these payments are 
determined by the NCI Travel and Lodging Reimbursement Policy. We will give you a copy of 
this policy. 
Will taking part in this research study cost you anything?  
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center.  
 
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY   
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include: 
• The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people. 
• National Institutes of Health Intramural Institutional Review Board 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
• The study Sponsor, the NCI Cancer Treatment Evaluation Program, or their agent(s)  
• Qualified representatives from Merck and AbbVie, the pharmaceutical companies who 
produce M6620 and veliparib. 
 
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons. 
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.   
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act.  
Certificate of Confidentiality 
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.   
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.   
The Certificate does not protect your information when it:   
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or  
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA);  
3. is for other research; 
4. is disclosed with your consent.  
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research.  
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent. 
Privacy Act 
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
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MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act. 
 
POLICY REGARDING RESEARCH-RELATED INJURIES   
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action. 
PROBLEMS OR QUESTIONS 
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, 
 
. You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern. 
CONSENT DOCUMENT  
Please keep a copy of this document in case you want to read it again. 
 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
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MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study. 
 
 
 
 
 
Signature of Research Participant 
 
Print Name of Research Participant 
 
Date 
 
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study. 
 
 
 
 
 
Signature of LAR 
 
Print Name of LAR 
 
Date 
 
Investigator: 
 
 
 
 
 
Signature of Investigator 
 
 
 
Print Name of Investigator 
 
Date 
Witness to the oral short-form consent process only:  
 
Witness: 
 
 
 
 
 
Signature of Witness* 
 
Print Name of Witness 
 
Date 
 
 
 
 
 
 
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER: 
 
 
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated 
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness. 
 
 
 
 
 
 
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated 
the administration of informed consent but did not serve as a witness. The name or ID code of the person  
providing interpretive support is: 
 
.