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CTEP \# P9771 Clinical Center \# 16-C-0087 TLE:  Phase I Study of Veliparib (ABT-888), an Oral PARP Inhibitor, and M6620 (VX-
90), an ATR Inhibitor, in Combination with Cisplatin in Patients with Refractory Solid Tumors Abbreviated Title : Ph I Veliparib + M6620 (VX-970) + cisplatin  
| Coordinating Center:         | Developmental Therapeutics Clinic (NCIDTC)   |
|------------------------------|----------------------------------------------|
| National Cancer Institute    |                                              |
| 10 Center Drive              |                                              |
| Bethesda, MD 20892           |                                              |
| Principal Investigator:      | DTC, NCI                                     |
| 31 Center Drive              |                                              |
| Bethesda, MD 2089)           |                                              |
| Phone:                       | Fax:                                         |
| Study Chair:                 | D, NCI                                       |
| Participating Sites:         | MD Anderson Cancer Center                    |
| Dana-Farber Cancer Institute |                                              |
| NIH Associate Investigators: | DCTD                                         |
| CTEP, DCTD                   |                                              |
| CTEP, DCTD                   |                                              |
| CTEP, DCTD                   |                                              |
| DCTD                         |                                              |
| CCT                          |                                              |
| DCTD                         |                                              |
| DCTD                         |                                              |
| Non-NIH Associate            |                                              |
| Investigators:               | Leidos Biomed., FNLCR                        |
| Leidos Biomed., FNLCR        |                                              |
| Leidos Biomed., FNLCR        |                                              |
| Referral Contact Nurse:      | DCTD                                         |  
  
1  
| MD Anderson Cancer Center              | Site Coordinator:                                 |
|----------------------------------------|---------------------------------------------------|
| FWA #0000363                           | Department of Investigational Cancer Therapeutics |
| Principal Investigator:                | A Phase I Clinical Trials Program                 |
| Department of Investigational Cancer   | M. D. Anderson Cancer Center                      |
| Therapeutics                           | Phone:                                            |
| A Phase I Clinical Trials Program      |                                                   |
| M. D. Anderson Cancer Center           |                                                   |
| Office phone:                          |                                                   |
| Clinic phone:                          | IRB of Record:                                    |
| U.T. MD Anderson Cancer Center         |                                                   |
| Institutional Review Board             |                                                   |
| Pharmacy Contact:                      | 7007 Bertner Avenue, Unit 1637                    |
| Investigational Pharmacy - Unit 376    | Houston, TX 77030-3907                            |
| MD Anderson Cancer Center              | Phone: 713-792-2933; Fax: 713-794-4589            |
| 1515 Holcombe Blvd., Room B1.4392      | IORG #000083                                      |
| Houston, TX 77030                      |                                                   |
| Phone:                                 |                                                   |
| Dana-Farber Cancer Institute           | Site Coordinators:                                |
| FWA #00001121                          |                                                   |
| Principal Investigator:                | Early Drug Development Center                     |
| Dana Farber Cancer Institute           |                                                   |
| Early Drug Development Center          | 450 Brookline Ave., D1B-01J                       |
| Boston, MA 02215                       |                                                   |
| Department of Medical Oncology         |                                                   |
| Dana Farber Cancer Institute           | Phone:                                            |
| 450 Brookline Ave., Boston, MA 02215   |                                                   |
| Phone:                                 | Early Drug Development Center                     |
| Dana Farber Cancer Institute           |                                                   |
| Pharmacy Contact:                      | 450 Brookline Ave., DL266E                        |
| Boston, MA 02215                       |                                                   |
| Dana-Farber Cancer Institute           |                                                   |
| Pharmacy - Yawkey 5                    | Phone:                                            |
| 450 Brookline Ave.                     |                                                   |
| Boston, MA 02215                       |                                                   |
| Phone:                                 | IRB of Record: Dana Farber Cancer Institute IRB   |
| 450 Brookline Avenue OS-229            |                                                   |
| Boston, MA 02215                       |                                                   |
| Phone: 617-632-3029; Fax: 617-632-2686 |                                                   |
| IORG #000035                           |                                                   |  
CTP\# P9771 Clinical Center \# l 6-C-0087 Statistician:
CTEP Drug Monitor:
DCTD, NCI
CTEP  
  
| Study Sponsor:  NCI Supplied Agents:  IND Number:  NCTNumber:  Version Date:   |
|--------------------------------------------------------------------------------|  
| 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
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precis 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.
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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
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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
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exploratory objective

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

| Cycle 1 (duration 21 days)   | Cycle 2 (duration 21 days)   |          |        |        |        |
|------------------------------|------------------------------|----------|--------|--------|--------|
| Week 1                       | Week 2                       | Week 3   | Week 1 | Week 2 | Week 3 |
| Velipariba                   | D1-3                         | D8-10    | D1-3   | D8-10  |        |
| Cisplatinb                   | D1                           | (D8)D9   | D2     | D9     |        |
| D1                           | (D8)                         |          |        |        |        |
| M6620 (VX-970) c             | D2                           |          |        |        |        |
| Tumor  biopsies†             | D1                           | D9       |        |        |        |
| CTCs‡ Baseline D2            | D8 D9                        | C2 D1 D2 | C3D1   |        |        |  
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, 25 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.  
| Dose   | Veliparib               | M6620 (VX-970)        | Cisplatin                   |
|--------|-------------------------|-----------------------|-----------------------------|
| Level  | (PO q12 hours ± 1 hour) | (IV Days 1/2 and 8/9) | (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         |  
Dosing Schema:
As of Amendment L (dated 4/22/2019), the MTD for this combination has been **established as** DL6.  
7  
| TABLE OF CONTENTS                                                                                                                                             |                                                                                                                                                     |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|
| PRÉCIS .....................................................................................................................................................4 |                                                                                                                                                     |
| SCHEMA                                                                                                                                                        |                                                                                                                                                     |
| 1                                                                                                                                                             | OBJECTIVES ......................................................................................................................................10 |
| 2                                                                                                                                                             | BACKGROUND ...................................................................................................................................10    |
| 2.1                                                                                                                                                           | Rationale for combining cisplatin with ATR and PARP inhibitors                                                                                      |
| 2.2                                                                                                                                                           | M6620 (VX-970) ...................................................................................................................13                |
| 2.3                                                                                                                                                           | Veliparib (ABT-888) ....................................................................................................................17          |
| 2.4                                                                                                                                                           | CC                                                                                                                                                  |
| 2.5                                                                                                                                                           | Correlative Studies Background .................................................................................................22                  |
| 3                                                                                                                                                             | PATIENT SELECTION                                                                                                                                   |
| 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                                                        |
| S                                                                                                                                                             | TREATMENT PLAN                                                                                                                                      |
| 5.1                                                                                                                                                           | Agent Administration                                                                                                                                |
| 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                                                                                                                                                           | D Duration of Therapy                                                                                                                               |
| 5.6                                                                                                                                                           | D Duration of Follow Up                                                                                                                             |
| 5.7                                                                                                                                                           | Criteria for Removal from Study ...................................................................................36                               |
| 6                                                                                                                                                             | DOSING DELAYS/DOSE MODIFICATIONS                                                                                                                    |
| 6.1                                                                                                                                                           | Dose Modifications                                                                                                                                  |
| 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)                                                                                                                               |                                                                                                                                                     |
| 7.2                                                                                                                                                           | Comprehensive Adverse Events and Potential Risks list (CAEPR) for                                                                                   |
| M6620 (VX-970) (NSC 780162)                                                                                                                                   |                                                                                                                                                     |
| 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                                                                                                                                |
| 7.7                                                                                                                                                           | Second Malignancy                                                                                                                                   |
| 8                                                                                                                                                             | PHARMACEUTICAL INFORMATION                                                                                                                          |
| 8.1                                                                                                                                                           | M6620 (VX-970) (NSC 780162)                                                                                                                         |  
| Clinical Center # 16-C-0087                                                                                                                                     |                                                                                                                                                |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|
| 8.2                                                                                                                                                             | Veliparib (NSC 737664) .                                                                                                                       |
| 8.3                                                                                                                                                             | CC                                                                                                                                             |
| 8.4                                                                                                                                                             | Useful Links and Contacts: ............................................................................................................57      |
| Agent Ordering .                                                                                                                                                |                                                                                                                                                |
| 8.5                                                                                                                                                             |                                                                                                                                                |
| 8.6                                                                                                                                                             | Agent Accountability .......................................................................................................................58 |
| 9                                                                                                                                                               | CORRELATIVE/SPECIAL STUDIES                                                                                                                    |
| 9.1                                                                                                                                                             | Pharmacodynamic Assays .............................................................................................................59         |
| 9.2                                                                                                                                                             | Genomic Analyses ...................................................................................................................64         |
| 9.3                                                                                                                                                             | Human Data Sharing Plan..................................................................................................65                    |
| STUDY CALENDAR ..................................................................................................................................66             |                                                                                                                                                |
| 10                                                                                                                                                              |                                                                                                                                                |
| 11                                                                                                                                                              | MEASUREMENT OF EFFECT........................................................................................................68                |
| Antitumor Effect - Solid Tumors ...................................................................................68                                           |                                                                                                                                                |
| 11.1                                                                                                                                                            |                                                                                                                                                |
| 1.2                                                                                                                                                             | Response Criteria                                                                                                                              |
| 1.3                                                                                                                                                             | D Duration of Response                                                                                                                         |
| 12                                                                                                                                                              | DATA REPORTING/REGULATORY REQUIREMENTS                                                                                                         |
| 12.1                                                                                                                                                            | Study Oversight ............................................................................................................................74 |
| 12.2                                                                                                                                                            | DATA Reporting .                                                                                                                               |
| 12.3                                                                                                                                                            | CTEP Multicenter Guidelines                                                                                                                    |
| 12.4                                                                                                                                                            | Collaborative Agreements Language                                                                                                              |
| 12.5                                                                                                                                                            | Genomic Data Sharing Plan                                                                                                                      |
| 13                                                                                                                                                              | STATISTICAL CONSIDERATIONS                                                                                                                     |
| 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 .                                                                                                                                                    |                                                                                                                                                |
| APPENDIX A: PERFORMANCE STATUS CRITERIA                                                                                                                         |                                                                                                                                                |
| 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                                                                                                                      |                                                                                                                                                |
| APPENDIX F: CTEP MULTICENTER GUIDELINES                                                                                                                         |                                                                                                                                                |
| APPENDIX G: PROCEDURE FOR SAMPLES FOR PHARMACODYNAMIC                                                                                                           |                                                                                                                                                |
| STUDIES                                                                                                                                                         |                                                                                                                                                |
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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.
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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
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exploratory objective

- To investigate tumor genomic alterations potentially associated with acquired resistance to the combination of M6620 (VX-970), veliparib, and cisplatin
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2 background 2.1 rationale for

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.  
Early preclinical studies of ATR depletion with siRNA demonstrate sensitization of ovarian cancer cells to chemotherapy and PARP inhibition, independent of BRCA status (Figure 1) [7].  
Strong preclinical evidence exists for the enhancement of synthetic lethality of tumor cells through simultaneous inhibition of multiple DNA repair pathways.  Impairment of homologous recombination through inhibition of ATR effectively creates a "BRCA-null" phenotype in tumor cells, increasing sensitivity to PARP inhibition.  We hypothesize that dual inhibition of HR and BER through co-administration of M6620 (VX-970), a potent inhibitor of ATR, and veliparib, a potent inhibitor of PARP 1/2, results in accumulation of lethal DSBs induced by cisplatin, chemopotentiation, and enhancement of antitumor activity.  
  
Figure 1.  ATR depletion sensitizes OVCAR-8 cells to multiple chemotherapy agents, including cisplatin (panel A), and veliparib (panel B) [7].  OVCAR-8 cells were transfected with control (Luc) or ATR siRNA.  After transfection, cells were plated, allowed to adhere for 4-6 hrs, and treated with cisplatin (A), and veliparib (B) for 8 days.  
More recent preclinical studies show synergism of the combination based on Bliss analysis of MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(-4-sulfophenyl)-2H-
tetrazolium) cell viability assays (Figure 2).  
  
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.  
-Control (Vehicle)  
  
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].
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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].
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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.
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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 dosedependent 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).
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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 drugdrug 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 (VX970) 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 drugefflux pumps on the cellular activity of M6620 (VX-970) activity was tested in MDR-1 and MRP1 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].
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preclinical safety pharmacology studies and

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 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].
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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].
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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 (VX970) 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. 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.
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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].
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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].
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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 DNAdamaging 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.
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nonclinical toxicology studies

In a variety of nonclinical models, veliparib increased the sensitivity of tumor cells to DNAdamaging agents, including temozolomide, irinotecan, cyclophosphamide, cisplatin, carboplatin, and radiation at therapeutic doses that do not increase the toxicity of chemotherapeutic agents.
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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. 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].
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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].
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summary of clinical studies

As of March 24, 2014, approximately 1255 patients have been treated with veliparib in AbbViesponsored 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 mutationassociated 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]. 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].
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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.
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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.
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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. 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.
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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.
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adverse reactions nephrotoxicity

Dose-related and cumulative renal insufficiency, including acute renal failure, is the major doselimiting 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 cisplatin infusion. Chronic salt wasting and hyponatremia may persist after discontinuation of cisplatin.
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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.
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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 blueyellow axis. Findings on fundoscopic exam include irregular pigmentation of the macular area.
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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.
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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.
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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.
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hepatotoxicity

Transient elevations of liver enzymes and bilirubin have been reported to be associated with cisplatin administration at the recommended doses.
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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 after drug administration. Reactions may be controlled by intravenous epinephrine with corticosteroids and/or antihistamines as indicated.
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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 Cterminus (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.
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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 (nonCLIA) whole exome sequencing (WES) analysis of tumor tissues, and (2) the CLIA-
certified Oncomine Comprehensive Assay v3 (OCAv3), a next generation sequencing (NGS) assay designed to find gene mutations within tumors (somatic mutations).
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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.
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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-eay131designated-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. 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.
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3 patient selection 3.1 eligibility

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 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 marrowsuppressive 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.
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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.  
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.
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3.3 inclusion of women and

Both men and women of all races and ethnic groups are eligible for this trial.
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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.
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4 registration procedures 4.1 nci

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 encrypted email to the NCI Central Registration Office (HOIS; ncicentralregistrationl@mail.nih.gov).  After confirmation of eligibility at the Central Registration Office, CRO staff will call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release of any investigational agents.  Verification of Registration will be forwarded electronically via e-mail.  Patient enrollment data entered in IWRS will automatically transfer to the NCI's clinical data management system, Medidata Rave.  
Please note that it is very important for all registrars to acquire encrypted e-mail from NIH Help Desk, since the verification of registration includes patient's information.  
Off Protocol Therapy and Off-Study Procedure: Authorized staff must notify the Central Registration Office (CRO) when a patient is taken off protocol therapy and when a patient is taken off-study.  The Participant Status Updates Form from the Web site
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and sent via encrypted email to the NCI Central Registration Office (HOIS; ncicentralregistrationl@mail.nih.gov).
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4.2 participating site patient registration

Authorized staff must register an eligible candidate through the Theradex Interactive Web Response System (IWRS).  Access IWRS through https://iwrs.theradex.com under the ''Patient''
tab utilizing your CTEP-IAM Username and Password.  Patient enrollment data entered in IWRS
will automatically transfer to the NCI's clinical data management system, Medidata Rave.  
Off-Study Procedure: Authorized staff must update the patient status in Medidata Rave when a patient is taken off study.
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4.3 investigator and research associate

Food and Drug Administration (FDA) regulations require IND sponsors to select qualified investigators.  NCI policy requires all persons participating in any NCI-sponsored clinical trial to register and renew their registration annually.  To register, all individuals must obtain a CTEP
Identity and Access Management (IAM) account ( https://ctepcore.nci.nih.gov/iam ).  In addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their annual registration using CTEP's web-based Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements  
| per registration type are outlined in the table below.   |     |       |    |    |
|----------------------------------------------------------|-----|-------|----|----|
| Documentation Required                                   | IVR | NPIVR | AP | A  |
| FDA Form 1572                                            | A   | v     |    |    |
| Financial Disclosure Form                                | <   | '     | '  |    |
| NCI Biosketch (education, training, employment,          | v   | v     | v  |    |
| license, and certification)                              |     |       |    |    |
| HSP/GCP training                                         | <   | '     | >  |    |  
| Documentation Required              | IVR   | NPIVR   | AP   | A   |
|-------------------------------------|-------|---------|------|-----|
| Agent Shipment Form (if applicable) | >     |         |      |     |
| CV (optional)                       | <     | >       |      |     |  
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA
Form 1572 in RCR to allow the following:
.  
Add to a site roster  
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN
.  
Act as the site-protocol PI on the IRB approval
.  
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
.
Additional information can be found on the CTEP website at https://ctep.cancer.gov/investigatorResources/default.htm .  For questions, please contact the RCR
Help Desk by email at RCRHelpDesk@nih.gov
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s treatment plan

This is an open-label Phase I trial evaluating the combination of M6620 (VX-970), an ATR
inhibitor, veliparib, an oral PARP inhibitor, and cisplatin in patients with refractory solid tumors.  
Reported adverse events and potential risks for M6620 (VX-970), veliparib, and cisplatin are described in Section 7.  Appropriate dose modifications for M6620 (VX-970), veliparib, and cisplatin are described in Section 6. Patient evaluations will be performed throughout the study as described below.  Baseline history, physical examination, and laboratory evaluations must be conducted within 8 days prior to start of protocol therapy.  If protocol therapy is started within 8 days of the eligibility screening evaluations (see Section 3.4 ), the results from these screening evaluations may be used as baseline measurements.  If >8 days have passed since the screening evaluations, the medical history, physical examination, and laboratory evaluations must be repeated prior to starting protocol therapy.  
History and physical examination can be done up to 3 days before the start of a new cycle prior to treatment with cisplatin on day 1.  Patients will also be examined on day 8 or 9 (± 1 day due to scheduling conflicts) of each cycle.  Each cycle is 21 days (± 1 day due to scheduling conflicts).  
Labs (CBC with differential; serum chemistries) will be performed as follows (±1 day for all dates):
Cycle 1
.  
Day 1 prior to treatment (or within 8 days prior to treatment)
o Day 2 prior to M6620 (VX-970)
o Day 8 prior to prescribing veliparib for week 2 o Day 9 prior to M6620 (VX-970)
o 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.
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5.1 agent administration 5.1.1 m6620

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.
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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.  
| Dose   | Veliparib               | M6620 (VX-970)        | Cisplatin                   |
|--------|-------------------------|-----------------------|-----------------------------|
| Level  | (PO q12 hours ± 1 hour) | (IV Days 1/2 and 8/9) | (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             |  
Dosing Schema:  
| 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.
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as of amendment l (dated

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.
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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  
| 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.
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5.3.1 grade >= 3 non-hematological

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 antiemetic 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.  
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.
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5.4 general concomitant medication and

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.
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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.
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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.
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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 (VX970) 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.
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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).
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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.
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5.4.7 acute hypersensitivity reaction/severe infusion

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.
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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.
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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.
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5.7 criteria for removal from

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.
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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.
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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 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).
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6.1.2 grade 3 drug-related hematologic

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 rechallenge                                                                                                                                                                                                          |
| 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. |
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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 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 (*gBRCA*m) status, if known, should be recorded.  
| CTCAE Grade                                                                             | Definition                                                                                                                                                                                    | Veliparib Dose                               |
|-----------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------|
| 1-2                                                                                     | ANC >1.0 G/L or Platelet                                                                                                                                                                      | Investigator judgement to continue treatment |
| count >50 G/L                                                                           | 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                                                                                                                                                                      | Dose interruption until recovered to CTCAE   |
| count <50 G/L                                                                           | 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 |                                                                                                                                                                                               |                                              |
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management of neutropenia and thrombocytopenia

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 (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.
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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.
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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. 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.
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management of prolonged hematological toxicities

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.
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7 adverse events list and

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.
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7.1 comprehensive adverse events and

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).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| Version 2.4, May 13, 2018¹                                  |                                   |                            |
|-------------------------------------------------------------|-----------------------------------|----------------------------|
| Adverse Events with Possible                                | Specific Protocol Exceptions to   |                            |
| Relationship to ABT-88 (Veliparib)                          | Expedited Reporting (SPEER)       |                            |
| (CTCAE 5.0 Term)                                            |                                   |                            |
| [n= 2310]                                                   |                                   |                            |
| Likely (>20%)                                               | Less Likely (<=20%)               | Rare but Serious (<3%)     |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS                        |                                   |                            |
| Anemia                                                      | Anemia (Gr 3)                     |                            |
| Febrile neutropenia                                         | Febrile neutropenia (Gr 3)        |                            |
| GASTROINTESTINAL DISORDERS                                  |                                   |                            |
| Abdominal pain                                              |                                   |                            |
| Constipation                                                | Constipation (Gr 2)               |                            |
| Diarrhea                                                    | Diarrhea (Gr 3)                   |                            |
| Nausea (Gr 3)                                               |                                   |                            |
| Nausea                                                      | Vomiting (Gr 3)                   |                            |
| Vomiting                                                    |                                   |                            |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS        |                                   |                            |
| Fatigue                                                     | Fatigue (Gr 3)                    |                            |
| INVESTIGATIONS                                              | Lymphocyte count decreased        | Lymphocyte count decreased |
| (Gr 4)                                                      |                                   |                            |
| Neutrophil count decreased                                  | Neutrophil count decreased (Gr 4) |                            |
| Platelet count decreased                                    | Platelet count decreased (Gr 4)   |                            |
| Weight loss                                                 | Weight loss (Gr 2)                |                            |
| White blood cell decreased                                  | White blood cell decreased (Gr 4) |                            |
| METABOLISM AND NUTRITION DISORDERS                          |                                   |                            |
| Anorexia                                                    | Anorexia (Gr 2)                   |                            |
| Dehydration                                                 | Dehydration (Gr 3)                |                            |
| Hypophosphatemia                                            | Hypophosphatemia (Gr 3)           |                            |
| NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND |                                   |                            |
| POLYPS)                                                     | Leukemia secondary to             |                            |
| oncology chemotherapy                                       |                                   |                            |
| Myelodysplastic syndrome                                    |                                   |                            |
| Treatment related secondary                                 |                                   |                            |
| malignancy                                                  |                                   |                            |
| NERVOUS SYSTEM DISORDERS                                    |                                   |                            |
| Dizziness                                                   |                                   |                            |
| Dysgeusia                                                   | Dysgeusia (Gr 2)                  |                            |
| Headache                                                    | Headache (Gr 3)                   |                            |
| Seizure                                                     |                                   |                            |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS                      |                                   |                            |
| Rash maculo-papular                                         |                                   |                            |
| VASCULAR DISORDERS                                          | Thromboembolic event 2            |                            |  
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
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ctep # p9771

Clinical Center \# 16-C-0087 sensory neuropathy; Presyncope; Reversible posterior leukoencephalopathy syndrome; Stroke; Syncope; Tremorr PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Psychiatric disorders - Other (emotional instability); Psychosis; Restlessness RENAL AND URINARY DISORDERS - Dysuria; Hematuria; Proteinuria RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Hypoxia; Nasal congestion; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Respiratory failure SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail changes; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Purpura; Rash acneiform VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; Vascular disorders - Other (brainstem infarction)
Note : ABT-888 (Veliparib) 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.
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7.2 comprehensive adverse events and

The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI
Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. The CAEPR does not provide frequency data; refer to the Investigator's Brochure for this information. Below is the CAEPR for M6620 (VX-970).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| Version 1.4, April 30, 2019¹                                |                                 |
|-------------------------------------------------------------|---------------------------------|
| Adverse Events with Possible Relationship to M6620 (VX-970) | Specific Protocol Exceptions to |
| (CTCAE 5.0 Term)                                            | Expedited Reporting (SPEER)     |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS                        |                                 |
| Anemia                                                      | Anemia (Gr 3)                   |
| GASTROINTESTINAL DISORDERS                                  |                                 |
| Diarrhea                                                    | Diarrhea (Gr 2)                 |
| Nausea                                                      | Nausea (Gr 2)                   |  
CTEP \# P9771  
| Clinical Center # 16-C-0087                                                                                       |                                          |
|-------------------------------------------------------------------------------------------------------------------|------------------------------------------|
| Adverse Events with Possible Relationship to M6620 (VX-970)                                                       | Specific Protocol Exceptions to          |
| (CTCAE 5.0 Term)                                                                                                  | Expedited Reporting (SPEER)              |
| Vomiting                                                                                                          | Vomiting (Gr 2)                          |
| GENERAL DISORDERS AND ADMINISTRATION SITE                                                                         |                                          |
| CONDITIONS                                                                                                        |                                          |
| Fatigue                                                                                                           | Fatigue (Gr 2)                           |
| IMMUNE SYSTEM DISORDERS                                                                                           |                                          |
| Anaphylaxis                                                                                                       |                                          |
| INFECTIONS AND INFESTATIONS                                                                                       |                                          |
| Urinary tract infection                                                                                           |                                          |
| INJURY, POISONING AND PROCEDURAL COMPLICATIONS                                                                    |                                          |
| Infusion related reaction                                                                                         | Infusion related reaction (Gr 2)         |
| INVESTIGATIONS                                                                                                    |                                          |
| Alanine aminotransferase increased                                                                                | Alanine aminotransferase increased (Gr   |
| 2)                                                                                                                |                                          |
| Aspartate aminotransferase increased                                                                              | Aspartate aminotransferase increased (Gr |
| 2)                                                                                                                |                                          |
| Blood bilirubin increased                                                                                         |                                          |
| Creatinine increased                                                                                              |                                          |
| Lymphocyte count decreased                                                                                        | Lymphocyte count decreased (Gr 2)        |
| Neutrophil count decreased                                                                                        |                                          |
| Platelet count decreased                                                                                          |                                          |
| White blood cell decreased                                                                                        |                                          |
| METABOLISM AND NUTRITION DISORDERS                                                                                |                                          |
| Hyperglycemia                                                                                                     |                                          |
| NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL                                                                 |                                          |
| CYSTS AND POLYPS)                                                                                                 |                                          |
| Tumor pain                                                                                                        |                                          |
| NERVOUS SYSTEM DISORDERS                                                                                          |                                          |
| Dizziness                                                                                                         |                                          |
| Headache                                                                                                          | Headache (Gr 2)                          |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS                                                                            |                                          |
| Pruritus                                                                                                          |                                          |
| Rash maculo-papular                                                                                               |                                          |
| VASCULAR DISORDERS                                                                                                |                                          |
| Flushing                                                                                                          |                                          |
| 1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all |                                          |  
Principal Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV .  Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. Adverse events reported on M6620 (VX-970, NSC 780162) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that M6620 (VX-970, NSC 780162) caused the adverse event: CARDIAC DISORDERS - Palpitations GASTROINTESTINAL DISORDERS - Abdominal pain; Ascites; Colonic obstruction; Mucositis oral GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Fever IMMUNE SYSTEM DISORDERS - Allergic reaction 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.
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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.
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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 CTEPAERS 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 trial registration on all reports.  
Note:  A death on study requires both routine and expedited reporting regardless of causality, unless as noted below.  Attribution to treatment or other cause must be provided.  
Death due to progressive disease should be reported as Grade 5 "Disease progression" under the system organ class (SOC) "General disorders and administration site conditions".  Evidence that the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration associated with a disease process) should be submitted.  
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention 1, 2  
  
| in this definition.  (FDA, 21 CFR 312.32; ICH E2A and ICH E6).                                            |                                |            |
|-----------------------------------------------------------------------------------------------------------|--------------------------------|------------|
| ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP- |                                |            |
| AERS within the timeframes detailed in the table below.                                                   | Grade 3-5                      |            |
| Hospitalization                                                                                           | Grade 1 and Grade 2 Timeframes | Timeframes |
| Resulting in                                                                                              |                                |            |
| Hospitalization                                                                                           | 10 Calendar Days               |            |
| ≥ 24 hrs                                                                                                  | 2-Hour 5 Calendar              |            |
| Days                                                                                                      |                                |            |
| Not resulting in                                                                                          |                                |            |
| Hospitalization                                                                                           | Not required                   |            |
| ≥ 24 hrs                                                                                                  |                                |            |  
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Expedited AE reporting timelines are defined as:
"24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report.  
"10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar days o of learning of the AE.  
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: Expedited 24-hour notification followed by complete report within 5 calendar days for:
- All Grade 3, 4, and Grade 5 AEs Expedited 10 calendar day reports for:
- Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above applies after this reporting period. Effective Date: May 5, 2011
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7.4.3 protocol-specific expedited ae reporting

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.
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7.4.4 pregnancy fetal death and

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 CTEPAERS at the time the outcome becomes known, accompanied by the same Pregnancy Report Form used for the initial report.
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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 the Pregnancy, puerperium and perinatal conditions SOC, as currently CTEPAERS recognizes this event as a patient death.
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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
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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.
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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.
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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.
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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.
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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.
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disability

A substantial disruption of a person's ability to conduct normal life functions.
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life-threatening adverse drug experience

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.
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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.
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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 g*reater risk of harm*
(including physical, psychological, economic, or social harm) than was previously known or recognized.
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7.5 nih-irb and clinical director

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.  
| 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.
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7.5.3 nih-irb reporting of ind

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.
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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.
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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.
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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.
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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.  
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 inline 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 (VX970) is predicted to not inhibit significantly the metabolic clearance of SN-38 (active metabolite of irinotecan) at therapeutic exposures. M6620 (VX-970) is a moderate inhibitor of P-gp and BCRP. Use caution when administered with substrates of P-gp and BCRP transporters.  
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