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8.2 veliparib (nsc 737664)

| Other Names:               | ABT-888, A-861695.0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
|----------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Chemical Name:             | 1H-Benzimidazole-7-carboxamide, 2-[(2R)-2-methyl-2- pyrrolidinyl]-                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Classification:            | Poly (ADP-ribose) polymerase (PARP) Inhibitor                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| CAS Registry No.           | 912444-00-9                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| Mode of Action:            | Veliparib is an inhibitor of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme that recognizes DNA damage and  facilitates DNA repair.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| Molecular                  | C13H16N4O                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| Formula: Molecular Weight: | 244.29                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Description:               | White to light yellow solid                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| Solubility:                | Freely soluble at 37 °C at a pH < 6.9, soluble at pH 6.9 to 7.1,  and slightly soluble at pH > 7.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| How Supplied:              | AbbVie supplies and DCTD distributes Veliparib. Veliparib capsules are available in 10 mg, 20 mg, 40 mg, 50 mg, and 100 mg  immediate release capsules. The inactive ingredients are  microcrystalline cellulose, colloidal silicon dioxide, magnesium  stearate, gelatin, sodium lauryl sulfate, and titanium dioxide. It  may contain FD&C blue#1, FD&C yellow #6, or FD&C yellow  #5. The capsules are packaged in HDPE bottles, and each HDPE  bottle contains 16 capsules or 64 capsules. Veliparib capsules may be repackaged from the supplied HDPE  bottles into amber (or other low-actinic) child resistant pharmacy  dispensing bottles. Expiration will be 30 days from the  repackaging date (or the original retest date, whichever is earlier)  when stored at 15°C to 25°C (59°F to 77°F). |
| Storage:                   | Capsules should be stored in the original container at 15° to  25°C (59° to 77°F).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Route of                   | Oral                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Administration: Method of  | Administer Veliparib orally without regards to meals; the capsules                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| administration             | should not be crushed or chewed. If a dose is vomited, it may be  re-administered if whole/intact capsules are observed in vomitus.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Potential Drug             | Nonclinical studies suggest ABT-888 is a substrate of P-gp, OCT2,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Interaction                | and MATE1/MATE2K transporters. Co-administration of ABT888 with strong inhibitors of P-gp, OCT2, and MATE1/MATE2K                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |  
| may result in a decrease of ABT-888 renal clearance and an  increase in ABT-888 plasma concentration. Therefore, use caution  when administering ABT-888 with strong inhibitors of P-gp,  OCT2, and MATE1/MATE2K. At high dose (e.g., 400 mg BID),  ABT-888 may inhibit OCT1 in the liver and MATE1/MATE2K in  the kidney.  ABT-888 is not a potent inhibitor of the major human CYPs and  does not significantly induce activities of major human CYP  isoforms, suggesting a negligible potential for CYP-mediated drugdrug interactions as a perpetrator at the anticipated therapeutic  concentrations. In human, ABT-888 clears primarily in the urine as intact parent  drug along with metabolites suggesting that renal function plays an  important role in the drug clearance and its metabolites. Drugassociated kidney toxicities or kidney diseases could change ABT888 pharmacokinetics. Use cautions when concomitantly  administer oxalipaltin, carboplatin, cisplatin, and topotecan in  patients with pre-existing renal impairment.                        |                                                                                                                                                                                                                                   |             |
|------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|
| Availability           | Veliparib is an investigational agent supplied to investigators by  DCTD, NCI. Veliparib is provided to the NCI under a  Collaborative Agreement between the Pharmaceutical  Collaborator and DCTD, NCI.                          |             |
| 8.3                    | Cisplatin Other Names:                                                                                                                                                                                                            | cisplatinum |
| Chemical Name:         | cis-diamminedichloroplatinum(II)                                                                                                                                                                                                  |             |
| Classification:        | DNA crosslinking agent                                                                                                                                                                                                            |             |
| CAS Registry           | 15663-27-1                                                                                                                                                                                                                        |             |
| No.:  Molecular        | (SP-4-2)-diamminedichloroplatinum                                                                                                                                                                                                 |             |
| Formula:  Mechanism of | Cisplatin is a DNA crosslinking agent that forms intra- and                                                                                                                                                                       |             |
| Action:                | interstrand crosslinks with DNA, interfering with DNA replication  and repair.                                                                                                                                                    |             |
| How Supplied:          | Cisplatin is commercially available in amber, multiple-dose vials  containing 50, 100, or 200 mg cisplatin in solution. Each milliliter  of solution contains 1 mg of cisplatin and 9 mg sodium chloride in  water for injection. |             |  
| Clinical Center # 16-C-0087 Storage:                                                                                     | Intact vials and reconstituted solution must be maintained at room  temperature. Store intact vials at 15° - 25°C (59° - 77°F). Do not  refrigerate cisplatin in vials or after dilution. Cisplatin that remains in an amber vial after initial entry is stable for  28 days if protected from light or for 7 days under fluorescent room  light. Large-volume solutions do not need to be protected from  light if used within 6 hours after preparation. For longer time  periods, light protection is recommended. Light protection is  required for intensive lighting conditions; e.g., direct sunlight  exposure. Although cisplatin slowly degrades to  trichloroaminoplatinate (TCAP) on exposure to ambient lighting  conditions, solution pH is the predominant factor affecting cisplatin  stability. Solutions with pH > 4.3 (especially > 6.3) were associated  with loss of cisplatin and a more rapid formation of TCAP.   |
|--------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Stability:                                                                                                               | Vials bear the manufacturer's expiration date. Cisplatin dilution to  0.05 or 0.5 mg/mL with 0.9% normal saline yields a solution that is  stable for at least 24 hours at room temperature.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| Preparation:                                                                                                             | Cisplatin will be diluted in 100 mL 0.9% sodium chloride injection,  USP, for intravenous administration over 60 minutes on Day 1 (and  Day 8 from DL3 and higher) of a 21-day cycle.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Route of                                                                                                                 | Cisplatin is administered intravenously on Day 1 (and Day 8 for                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| Administration:                                                                                                          | DL3 and higher) of a 21-day cycle.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Method of                                                                                                                | Prior to cisplatin administration, at least 500 mL of 0.9% sodium                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| administration:                                                                                                          | chloride with KCl 10 mEq/L and magnesium sulfate 4 mEq/L  injection should be administered over at least 60 minutes.  Following administration of cisplatin, at least an additional 500 mL  of 0.9% sodium chloride with KCl 10 mEq/L and magnesium  sulfate 4 mEq/L injection should be administered over at least 60  minutes.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Availability:                                                                                                            | Commercially available.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| 8.4                                                                                                                      | Useful Links and Contacts:  - CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/  - NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  - PMB policies and guidelines:  http://ctep.cancer.gov/branches/pmb/agent_management.htm  - PMB Online Agent Order Processing (OAOP) application:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| https://ctepcore.nci.nih.gov/OAOP - CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/ |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |  
- CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ - NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov - PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm - PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP  
- CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/ - CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov - PMB email: PMBAfterHours@mail.nih.gov  
- IB Coordinator: IBCoordinator@mail.nih.gov - PMB phone and hours of service: (240) 276-6575 Monday through Friday
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8.5 agent ordering

NCI-supplied agents may be requested by the responsible investigator (or their authorized designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be shipped directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained). The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational agents. The responsible investigator at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP-supplied investigational agents for the study should be ordered under the name of one lead investigator at that institution. Active CTEP-registered investigators and investigator-designated shipping designees and ordering designees can submit agent requests through the PMB Online Agent Order Processing (OAOP) application (https://ctepcore.nci.nih.gov/OAOP ). Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam/) and the maintenance of an "active" account status, a "current" password, and an active registration status. For questions about drug orders, transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime.
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8.6 agent accountability

Agent Inventory Records - The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, dispensing and final disposition of all agents received from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and maintain separate NCI
Investigational Agent Accountability Records for each agent, strength, formulation and ordering investigator on this protocol.
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8.6.1 investigator brochure availability

The current versions of the IBs for the agents will be accessible to site investigators and research staff through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status, a "current" password, and an active registration status. Questions about IB access may be directed to the PMB IB coordinator via email.
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9 correlative/special studies

We plan to evaluate the effect of the combination of M6620 (VX-970), veliparib, and cisplatin on markers of DNA damage, such as γH2AX, RAD51, pNbs1, and pATR, in tumor biopsies and circulating tumor cells (CTCs). For patients on the expansion cohort, two biopsies will be obtained, one on C1D1 after administration of cisplatin and again on C1D9, 2-5 hours after the day 9 dose of M6620 (VX-970), with a third progression or restaging follow-up biopsy optional. Biopsies are mandatory for patients on the expansion phase. Based on the availability of tissue and various histologies, additional markers of DNA damage will be evaluated.
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9.1 pharmacodynamic assays

Evaluation of drug effect on DNA damage response in tumor and CTCs will be performed by immunofluorescence assays for measurement of DNA damage-repair markers, such as γH2AX,
RAD51, pNbs1, and pATR. Histone H2AX is one of the H2A histones present in nucleosomes from normal tissues as well as cancer tissues. H2AX is phosphorylated at its C-terminus (serine 139) following DNA doublestrand 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 doublestrand breaks.  
Rad51 plays a central role in recognition of double-strand breaks and homologous recombination. ATR phosphorylation in response to DNA damage will be used as a marker of direct target effect. A quantitative immunofluorescence assay for pT1989-ATR will be used as a marker of ATR inhibitor activity.
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9.1.1 laboratory contact (nci only)

At least 24 hours prior to tumor biopsy or blood sample collection, the research nurse will contact the NCI Phase I/II PK/PD Support Group in NIH Building 10: E-mail (preferred): NCIPK-PDsupport@mail.nih.gov, Pager (preferred): 102-12798 Phone: (240) 858-3963 Fax: 301-480-5871. For biopsies, tubes pre-labeled with the information specified in Section 9.1.4, biopsy date, and site of tissue biopsy will be provided. Initial processing and shipping of the samples will be completed as described below.
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9.1.2 tumor biopsies

Biopsies will be optional during the escalation phase but mandatory during the expansion phase. Biopsies will be collected at the following time points:
- On C1D1 after administration of cisplatin - On C1D9, 2-5 hours after the dose of M6620 (VX-970)
An optional third biopsy may also be collected, either at restaging follow-up (on day 1 (± 2 days) of the cycle following any restaging at which a 10-19% increase in tumor volume is observed, according to RECIST criteria, for patients on study 4 or more cycles) or at the time of disease progression (a 20% or more increase in tumor volume by RECIST).
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9.1.2.1 biopsy procedure

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

- All biopsy specimens should be collected, placed in pre-chilled cryogenic vials, and flash frozen in liquid nitrogen within 2 minutes of collection per DCTD SOP340507 (https://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507_Biops y_Frozen.pdf)
- See Appendix G for the collection and shipment procedures for all biopsy samples.  
- **C1D1 and C1D9 biopsies** should be transferred to PADIS on dry ice, where they are stored at -80°C, or colder, and subsequently processed within 7-10 days for analysis or as directed by the Principal Investigator. Biopsy samples will be analyzed for γH2AX, Rad51, pNbs1, and pATR as described above; any additional tissue will be flash-frozen and kept for future analysis in the Frederick National Laboratories CR Biorepository in liquid nitrogen freezers. Additional studies, if performed, will be conducted following an amendment to the current protocol.  
- **Restaging follow-up or progression biopsies** should be processed as follows:
o As the first priority, two cores, or equivalent tissue from dermatology or ENT
biopsy, should be flash frozen as described above and transferred on dry ice to Dr. Mickey Williams' laboratory (MoCha) at the Frederick National Laboratory for Cancer Research (FNLCR).
Following processing, one tissue section will be stained with H&E for histopathological examination by a designated pathologist. The remaining biopsy tissue will be extracted for nucleic acids. DNA will be assessed for quantity and quality by spectroscopy (OD 260/280) and a PCR-based amplification quality assessment test. All specimens that meet necessary quantity and quality will be sequenced using a targeted sequencing assay.  
o Any remaining tissue collected (up to 5 cores or equivalent) will be transferred to PADIS on dry ice and stored for analysis of γH2AX, Rad51, pNbs1, and pATR.  
o Note: Per the discretion of the PI, restaging follow-up or progression biopsies may be used for other analyses, including analyses carried out as a part of other DTC clinical trials, providing that the tissue is collected per SOP for those analyses.
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9.1.2.3 optional archival tissue submission

Patients may choose to submit an additional, archival tumor tissue specimen that has been collected within 3 months prior to patient registration if the patient has not received any intervening cancer therapy since collection of the specimen and the tissue was collected and processed according to SOP340507 (https://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507_Bi opsy_Frozen.pdf), including flash-freezing in liquid nitrogen, minimal cold ischemia time (< 5 minutes), and shipment on dry ice. Archival tissue submissions do not fulfill the requirement for a baseline (C1D1) biopsy because the baseline biopsy must be collected after the C1D1 cisplatin administration; however, qualifying archival tissue submissions will be analyzed for the same PD biomarkers as C1D1 and C1D9 biopsies to provide additional context for interpreting PD changes after drug administration. Please send an email to FNLCR PD Specimen Central Receiving (NCI_PD_Support@mail.nih.gov) to advise that archival tissue is being prepared for shipment. State "P9771 PD Specimens Ready for Shipment" in the subject line. If needed, FNLCR PD Central Receiving can be contacted directly at 301846-1951 or 301-846-6747.
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9.1.3 blood collection for ctc

Whole blood (at least 7.5 mL) will be collected aseptically by venipuncture or from a venous port into one 10 mL CellSave preservative tube. Prior to CTC collection, each participating site should e-mail a request for specimen collection and shipping materials from NCIPDSupportPADIS@mail.nih.gov . See Appendix G for the collection procedure for CTC samples for pharmacodynamic studies. At the NCI only, whole blood (at least 7.5 mL) will be collected aseptically by venipuncture or from a venous port into one 10 mL Streck tube (catalog number 218962). One 10 mL RareCyte tube (catalog number 24-1070-005) is also acceptable. Tubes must be inverted 8 times to ensure adequate mixing of the additive. Blood samples for CTCs will be collected at the following times:  
- at baseline - on cycle 1 day 2 prior to administration of M6620 (VX-970) - on cycle 1 day 2, 8 hours (± 30 minutes) after the start of M6620 (VX-970)
administration
- on cycle 1 day 8 prior to administration of veliparib/cisplatin administration
- on cycle 1 day 9 prior to M6620 (VX-970) administration, - on cycle 2 day 1 prior to veliparib/cisplatin administration
- on cycle 2 day 2 prior to M6620 (VX-970) administration
- on cycle 2 day 2, 10 hours (± 2 hours) after the start of M6620 (VX-970)
administration*
- on the first day of every subsequent cycle prior to veliparib/cisplatin administration
- at the time of restaging follow-up biopsy or progression biopsy, if applicable
***At the NCI only:** CTC collection on cycle 2 day 2 is fixed at 7:00pm (± 30 minutes) in order to make the timing of the procedure more feasible and convenient for study participants. The time elapsed between M6620 (VX-970) administration and blood collection will be recorded. Testing and data analysis will be performed by Dr. Bob Kinders (PADIS/FNLCR).
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9.1.4 sample collection and processing

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

As of **Amendment L** (dated 4/22/2019), the MoCha laboratory at FNLCR will investigate the occurrence of tumor genomic alterations potentially associated with acquired drug resistance for only those patients who agree to undergo an optional progression or restaging follow-up biopsy.
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9.2.1 optional restaging follow-up and

With patient consent, tumor tissue collected at the (optional) restaging follow-up or progression biopsy may be analyzed by the CLIA-certified OCAv3 assay and results will be returned to patients in the form of the Oncomine report. If additional tumor tissue is available after the OCAv3 analysis, exploratory, non-CLIA certified genomic analyses such as WES may be conducted but the results will not be returned to patients or used for clinical decision making (Figure 5). Note: Per the discretion of the PI, restaging follow-up or progression biopsies may be used for other analyses, including analyses carried out as a part of other DTC clinical trials, providing that the tissue is collected per SOP for those analyses.
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9.2.2 cycle 1 day 1

For only those patients who have undergone the optional restaging follow-up or progression biopsy and consented to genomic analyses, tumor biopsy tissue collected at C1D1 will be used for exploratory WES analyses if there is sufficient tissue remaining after PD biomarker analyses have been completed ( Figure 5 ).  Remaining C1D9 biopsy tissue may also be used for exploratory WES analysis after PD
biomarker analyses have been completed if there is not sufficient C1D1 tissue available.  Tissue availability will be tracked in real time using Labmatrix.  Although the MoCha Laboratory is CLIA-certified, these sequencing studies will not be done per CLIA specifications and these data will not be returned to the patients or used for clinical decision making.  
Figure 5. Summary of Planned Genomic Analyses.  
  
| Tumor Biopsy:                                                                           | ↑ C1D1                  | ↑ C1D9            |                  |
|-----------------------------------------------------------------------------------------|-------------------------|-------------------|------------------|
| Restaging Follow-up                                                                     |                         |                   |                  |
| Progression or Restaging                                                                |                         |                   |                  |
| C1D1 Tumor                                                                              | C1D9 Tumor              | Follow-up Biopsy* |                  |
| Biopsy                                                                                  | Biopsy                  | (optional)        |                  |
| All tissue flash                                                                        | All tissue flash        |                   |                  |
| Collection Information:                                                                 | All tissue flash frozen |                   |                  |
| frozen                                                                                  | frozen                  |                   |                  |
| First Priority Assay:                                                                   | PD assays               | PD assays         | CLIA OCAv3 assay |
| Second Priority Assay:                                                                  | WES                     | WES               | WES              |
| Third Priority Assay:                                                                   | PD assays               |                   |                  |
| Reporting to Patients:                                                                  | None                    | None              | Oncomine report  |
| *Note: Per the discretion of the PI, restaging follow-up or progression biopsies may be |                         |                   |                  |  
collected per SOP to be used for analyses other than those listed here, including analyses carried out as a part of other DTC clinical trials.
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9.3 human data sharing plan

What data will be shared? We will share human data generated in this research for future research as follows:
X De-identified data in an NIH-funded or approved public repository X Identified data in BTRIS (automatic for activities in the Clinical Center) X De-identified or identified data with approved outside collaborators under appropriate agreements How and where will the data be shared? Data will be shared through: X An NIH-funded or approved public repository: clinicaltrials.gov X BTRIS (automatic for activities in the Clinical Center) X Approved outside collaborators under appropriate individual agreements X Publication and/or public presentations When will the data be shared? X At the time of publication or shortly thereafter
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10 study calendar

Eligibility screening evaluations are to be conducted within 8 days prior to enrollment, with the exception of informed consent and diagnostic imaging, which must be done within 28 days prior to enrollment. Baseline history, physical examination, laboratory evaluations, and ECG are to be conducted within 8 days prior to the start of protocol therapy. If protocol therapy is started within 8 days of the eligibility screening evaluations, values from the screening evaluations may be used as baseline measurements; if > 8 days have passed since the screening evaluations, the medical history, physical examination, laboratory evaluations, and ECG must be repeated prior to starting protocol therapy. Baseline imaging scans must be done within 28 days prior to the start of protocol therapy. Start of next cycle may be changed by 1 day or delayed for up to 1 week to accommodate scheduling conflicts. Treatments within a cycle may be delayed ± 1 day to accommodate scheduling conflicts. History and physical examination and laboratory evaluations can be performed up to 3 days before the start of the next cycle.  
| Study Treatment                                                                                                                                                                      |                        |                                                                                                                        |                                                 |      |      |    |          |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|------|------|----|----------|----|
| Cycle 1                                                                                                                                                                              | Cycle 2 and subsequent | Off                                                                                                                    |                                                 |      |      |    |          |    |
| cycles                                                                                                                                                                               | Treatment              |                                                                                                                        |                                                 |      |      |    |          |    |
| Wk 1                                                                                                                                                                                 | Wk 2                   | Wk 3                                                                                                                   | Wk 1                                            | Wk 2 | Wk 3 |    |          |    |
| M6620 (VX-970)a                                                                                                                                                                      | X                      | X                                                                                                                      | X                                               | X    |      |    |          |    |
| Veliparibb                                                                                                                                                                           | X                      | X                                                                                                                      | X                                               | X    |      |    |          |    |
| Cisplatinc                                                                                                                                                                           | X                      | X                                                                                                                      |                                                 |      |      |    |          |    |
| Informed consent                                                                                                                                                                     | X                      |                                                                                                                        |                                                 |      |      |    |          |    |
| Demographics                                                                                                                                                                         | X                      |                                                                                                                        |                                                 |      |      |    |          |    |
| Medical history                                                                                                                                                                      | X                      | Xl                                                                                                                     |                                                 |      |      |    |          |    |
| Concomitant meds                                                                                                                                                                     | X                      | X---------------------------------------------------------------------X                                                |                                                 |      |      |    |          |    |
| Physical examd                                                                                                                                                                       | X                      | Xl                                                                                                                     | X                                               | X    | X    | X  |          |    |
| Vital signsd                                                                                                                                                                         | X                      | Xl                                                                                                                     | X                                               | X    | X    | X  |          |    |
| Heightd                                                                                                                                                                              | X                      |                                                                                                                        |                                                 |      |      |    |          |    |
| d                                                                                                                                                                                    | X                      | Xl                                                                                                                     | X                                               | X    | X    | X  |          |    |
| Weight Performance statusd                                                                                                                                                           | X                      | Xl                                                                                                                     | X                                               | X    | X    | X  |          |    |
| ECGe                                                                                                                                                                                 | X                      | X                                                                                                                      |                                                 |      |      |    |          |    |
| CBC w/diff, pltsf                                                                                                                                                                    | X                      | Xl                                                                                                                     | X                                               | X    | X    | X  | optional | X  |
| Serum chemistryf                                                                                                                                                                     | X                      | Xl                                                                                                                     | X                                               | X    | X    | X  | optional | X  |
| PT, INR, PTTg                                                                                                                                                                        | X                      | X                                                                                                                      |                                                 |      |      |    |          |    |
| β-HCGh                                                                                                                                                                               | X                      |                                                                                                                        |                                                 |      |      |    |          |    |
| Adverse event  evaluation                                                                                                                                                            | X                      | X-------------------------------------------------------------------X Tumor measurements are repeated per Section 11.1 |                                                 |      |      |    |          |    |
| Tumor  measurementsi                                                                                                                                                                 | X                      | Xl                                                                                                                     | Documentation (radiologic) must be provided for | X    |      |    |          |    |
| patients removed from study for progressive disease.                                                                                                                                 |                        |                                                                                                                        |                                                 |      |      |    |          |    |
| Pre-Study                                                                                                                                                                            |                        |                                                                                                                        |                                                 |      |      |    |          |    |
| Study Procedure                                                                                                                                                                      | Eligibility  Screen    |                                                                                                                        |                                                 |      |      |    |          |    |
| Tumor biopsyj                                                                                                                                                                        | X                      | X                                                                                                                      |                                                 |      |      |    |          |    |
| Circulating Tumor  Cellsk                                                                                                                                                            | X                      | X                                                                                                                      | X                                               | X    |      |    |          |    |
| a. M6620 (VX-970) will be administered intravenously as a 1-hour infusion ± 10 minutes on days  2 and 9 of a 21-day cycle (or on days 1 and 8 of any cycle in which cisplatin is not |                        |                                                                                                                        |                                                 |      |      |    |          |    |  
Tumor biopsyj X X
Circulating Tumor Cellsk **X X X X**
a. M6620 (VX-970) will be administered intravenously as a 1-hour infusion ± 10 minutes on days 2 and 9 of a 21-day cycle (or on days 1 and 8 of any cycle in which cisplatin is not administered).  
b. Veliparib will be administered orally q12 hours ± 1 hour on days 1 through 3 and 8 through 10 of a 21-day cycle. Veliparib should be administered before cisplatin and M6620 (VX-970).  
c. Cisplatin will be administered intravenously as a 1-hour infusion ± 10 minutes on day 1 of a 21day cycle (days 1 and 8 for patients on dose level 3 and higher). As of *Amendment I* (12/7/2017), patients who have been on trial for at least 6 cycles may have cisplatin administration held or discontinued while continuing on trial at the discretion of the PI, Dr.  
d. Physical examination, including vitals, weight, and performance status, will be performed at the Clinical Center at the start of each cycle of treatment (up to 3 days before the start of a new cycle) and on day 8 or 9 (±1 day) of each cycle. Weight will be used to calculate doses per institutional SOP. Height will be performed prior to enrollment and will not need to be repeated prior to each treatment.  
e. ECG for eligibility screening and at baseline (within 8 days prior to enrolling or starting study drug, respectively), within approximately 1 hour after the end of M6620 (VX-970) infusion during cycle 1, and as clinically indicated.  
f. Serum chemistry (albumin, total bilirubin, calcium, creatinine, phosphorus, magnesium, potassium, sodium, SGOT [AST], SGPT [ALT]); CBC w/diff, and platelets should be performed for eligibility screening and at baseline (within 8 days prior to enrollment or starting treatment, respectively), and prior to treatment on days 2, 8, 9, and 15 (±1 day for all) of cycle 1. For all subsequent cycles, these labs should be performed prior to treatment on day 1 (±1 day) and prior to the first IV treatment on week 2 of the cycle (day 8 or 9, ±1 day). C1D1 values need to re-meet eligibility criteria. C1D15 labs may be obtained by the patient's local physician and day 15 labs in subsequent cycles are optional.  
g. PT, INR, PTT required within 1 week prior to all biopsies, and may also be performed as clinically indicated.  
h. Serum or urine pregnancy test (women of childbearing potential) within 8 days prior to enrollment and as clinically indicated.  
i. Radiologic examination (CT scan or MRI) will be performed for eligibility screening and at baseline (within 28 days prior to enrolling or starting study drug, respectively) and then every 2 cycles (every 3 or 4 cycles for patients on study for more than one or three years, respectively).  
j. Tumor biopsies will be obtained after the administration of cisplatin on C1D1 and again on C1D
9 2-5 hours after the day 9 dose of M6620 (VX-970). Tumor biopsies are optional during the escalation phase and mandatory during the expansion phase.  
k. Circulating tumor cells (optional) will be drawn as defined in Section 9.1.3. l: Eligibility screening results may be used for these baseline measurements if conducted within 8 days (for medical history, physical exam, vital signs, weight, performance status ECG, serum chemistry, and CBC) or 28 days (for tumor measurements) prior to the start of protocol therapy.
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11 measurement of effect 11.1

Although response is not the primary endpoint of this trial, patients with measurable disease will be assessed by standard criteria. For the purposes of this study, patients should be re-evaluated for response every 6 weeks (every 2 cycles; every 3 cycles for patients on study for more than one year or every 4 cycles for more than three years). In addition to a baseline scan, confirmatory scans should also be obtained at least 4 weeks following initial documentation of objective response. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [*Eur J Ca* 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
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11.1.1 definitions

Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with the combination of M6620 (VX-970), veliparib, and cisplatin. Evaluable for objective response: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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11.1.2 disease parameters

Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.
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11.1.3 guidelines for evaluation of

All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [*JNCI* 96:487-488, 2004; *J Clin* Oncol 17, 3461-3467, 1999; *J Clin Oncol* 26:1148-1159, 2008]. In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer [*JNCI* 92:1534-1535, 2000].  
Cytology, Histology: These techniques can be used to differentiate between partial responses
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDGPET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.
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11.2response criteria

11.2.1 Evaluation of Target Lesions  
| Complete Response (CR):   | Disappearance of all target lesions. Any pathological  lymph nodes (whether target or non-target) must have  reduction in short axis to <10 mm.                                                                                                                                                                                                                                                     |
|---------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Partial Response (PR):    | At least a 30% decrease in the sum of the diameters of  target lesions, taking as reference the baseline sum  diameters.                                                                                                                                                                                                                                                                            |
| Progressive Disease (PD): | At least a 20% increase in the sum of the diameters of  target lesions, taking as reference the smallest sum on  study (this includes the baseline sum if that is the  smallest on study). In addition to the relative increase  of 20%, the sum must also demonstrate an absolute  increase of at least 5 mm. (Note: the appearance of  one or more new lesions is also considered  progressions). |
| Stable Disease (SD):      | Neither sufficient shrinkage to qualify for PR nor  sufficient increase to qualify for PD, taking as  reference the smallest sum diameters while on study.                                                                                                                                                                                                                                          |  
11.2.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).  
Progressive Disease (PD): Appearance of one or more new lesions and/or  
unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall  
disease status change, not a single lesion increase.  
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response.  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.  
Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).
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11.2.3 evaluation of best overall

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Target           | Non-Target                                                                                                           | New     | Overall                                            | Best Overall Response when   |
|------------------|----------------------------------------------------------------------------------------------------------------------|---------|----------------------------------------------------|------------------------------|
| Lesions          | Lesions                                                                                                              | Lesions | Response                                           | Confirmation is Required*    |
| CR               | CR                                                                                                                   | No      | CR                                                 | ≥4 wks. Confirmation**       |
| CR               | Non-CR/Non-PD                                                                                                        | No      | PR                                                 | ≥4 wks. Confirmation**       |
| CR               | Not evaluated                                                                                                        | No      | PR                                                 |                              |
| PR               | Non-CR/Non                                                                                                                      |         |                                                    |                              |
| PD/not evaluated | No                                                                                                                   | PR      |                                                    |                              |
| SD               | Non-CR/Non                                                                                                                      |         |                                                    |                              |
| PD/not evaluated | No                                                                                                                   | SD      | Documented at least once ≥ 4  wks. from baseline** |                              |
| PD               | Any                                                                                                                  | Yes or  | PD                                                 |                              |
| No               |                                                                                                                      |         |                                                    |                              |
| Any              | PD***                                                                                                                | Yes or  | no prior SD, PR or CR                              |                              |
| PD               |                                                                                                                      |         |                                                    |                              |
| No               |                                                                                                                      |         |                                                    |                              |
| Any              | Any                                                                                                                  | Yes     | PD                                                 |                              |
| *                | See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.                                   |         |                                                    |                              |
| **               | Only for non-randomized trials with response as primary endpoint.                                                    |         |                                                    |                              |
| ***              | In exceptional circumstances, unequivocal progression in non-target lesions may be  accepted as disease progression. |         |                                                    |                              |  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "*symptomatic deterioration."* Every effort should be made to document the objective progression even after discontinuation of treatment.  
| Non-Target Lesions                                                                                                                                                                                                                             | New Lesions   | Overall Response   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------------|
| CR                                                                                                                                                                                                                                             | No            | CR                 |
| Non-CR/non-PD                                                                                                                                                                                                                                  | No            | Non-CR/non-PD*     |
| Not all evaluated                                                                                                                                                                                                                              | No            | not evaluated      |
| Unequivocal PD                                                                                                                                                                                                                                 | Yes or No     | PD                 |
| Any                                                                                                                                                                                                                                            | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is  increasingly used as an endpoint for assessment of efficacy in some trials so to assign this  category when no lesions can be measured is not advised |               |                    |
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11.3 duration of response

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

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 (Adverse Events: List and Reporting Requirements).
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12.1 study oversight

This protocol is monitored at several levels, as described in this section. The Protocol Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious adverse events; reporting of expedited adverse events; and accumulation of reported adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and statistician have access to the data at all times through the CTMS web-based reporting portal. All Study Investigators at participating sites who register/enroll patients on a given protocol are responsible for timely submission of data via Medidata Rave and timely reporting of adverse events for that particular study. This includes timely review of data collected on the electronic CRFs submitted via Medidata Rave.
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12.2 data reporting 12.2.1 method

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

Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it is greater than 4 weeks past due. Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as data is received. Queries will be issued by CTMS directly within Rave. Monthly web-based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI policies and procedures with the overarching goal of ensuring the integrity of data generated from NCI-sponsored clinical trials. Guidelines may be found on the CTEP (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.h tm) and CTSU websites. An End of Study CRF is to be completed by the PI, and is to include a summary of study endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended phase 2 dose (RP2D) and a description of any dose-limiting toxicities (DLTs). CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedicalinformatics-resources/interoperability-and-semantics/metadata-and-models).  
Customized eCRFs will be included when appropriate to meet unique study requirements. The PI is encouraged to review the eCRFs, working closely with CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs prior to study activation. CTMS will prepare the eCRFs with built-in edit checks to the extent possible to promote data integrity.
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12.3 ctep multicenter guidelines

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

The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the "Intellectual Property Option to Collaborator" (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms of award, apply to the use of the Agent(s) in this study:  
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s)
be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient's family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from http://ctep.cancer.gov.  
2. For a clinical protocol where there is an investigational Agent used in combination with
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data"):
a. NCI will provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NCI, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol. b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own Agent. c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own Agent.  
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order as described in the IP Option to Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.  
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them.  
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group office for Cooperative Group studies or by the principal investigator for nonCooperative Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in addition to Collaborator(s)'s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: E-mail: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator's confidential/ proprietary information.
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12.5 genomic data sharing plan

The NIH Genomic Data Sharing (GDS) Policy does not apply to this protocol as the genomic analysis will be performed will be for no more than 30 patient samples; therefore, this study does not meet GDS criteria, and a GDS plan is not warranted.
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13 statistical considerations 13.1 study

This Phase I study will use a standard 3+3 design with a slight modification as outlined in Section 5.3. Accrual will not proceed to a higher dose level until all patients have been treated at the current dose level, and the last patient treated has been observed for at least one cycle. The MTD dose for the combination of M6620 (VX-970), veliparib, and cisplatin is defined as the dose level at which no more than 1 of 6 patients experience a DLT during the first cycle of the treatment, and the dose level below that at which at least 2 (of ≤ 6) patients have DLT as a result of the drugs. Patients will receive cisplatin intravenously on day 1 (and day 8 from DL3 onwards; at the discretion of the PI, Dr. after cycle 6), M6620 (VX-970) intravenously on days 1/2 and 8/9, and veliparib orally q12 hours ± 1 hour on days 1-3 and 8-10 of each 21-day cycle. Once the MTD is established, up to 15 additional patients will be enrolled to the expansion phase of the trial at the MTD. Mandatory tumor biopsies will be obtained in the expansion phase to assess for pharmacodynamic endpoints. With up to 15 patients and a tumor biopsy QA criteria failure rate of 50% with respect to paired (pre- and post-dose) biopsies, we have an 85% likelihood of having at least 6 usable PD samples, and 95% likelihood of having at least 5 usable samples.
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13.2 sample size/accrual rate

We plan to accrue up to 55 patients in this study. To allow for some patients who may have only evaluable and not measurable disease, the accrual ceiling is set at 60. It is anticipated that 2-3 patients may be enrolled per month onto this study. It is expected that 12-18 months will be required to accrue the number of patients necessary to complete the trial.
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13.3 secondary endpoints

- To assess the effect of the combination of M6620 (VX-970), veliparib, and cisplatin on markers of DNA damage and apoptosis.  
- To assess the antitumor activity of the combination
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14 human subjects protections 14.1

This study will be open to all individuals regardless of gender, ethnicity, or race, provided that the aforementioned inclusion and exclusion criteria are met. Patients for this study will be recruited through internal referral, our physician referral base, and through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer). To date, there is no information that suggests that differences in drug metabolism or effect on tumor would be expected in one ethnic group compared to another. Efforts will be made to extend accrual to each representative population, but a balance must be struck between participant safety considerations and limitations on the number of individuals exposed to potentially ineffective treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to ethnic identity are noted, a follow-up study may be written to investigate those differences more fully. Due to lack of knowledge of the effects of the combination of M6620 (VX-970), veliparib, and cisplatin on the fetus or infants, as well as the possibility of teratogenic effects, pregnant and nursing women will be excluded from this trial. Patients with unstable or serious medical conditions are excluded due to the possibility that the combination of M6620 (VX-970), veliparib, and cisplatin may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events to M6620 (VX-970), veliparib, and cisplatin. HIVpositive patients are excluded from the study per Section 3.1.9.
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14.1.1 participation of children

This study includes patients 18 years of age and older. Because insufficient dosing or adverse event data are currently available on the use of combination of M6620 (VX970), veliparib, and cisplatin in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials. Studies will be performed in patients <18 years of age when it is appropriate to do so.
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14.2 evaluation of benefits and

There may or may not be any clinical benefit to a patient from participation in this trial. Their participation will benefit future cancer patients. Potential risks include the possible occurrence of any of a range of side effects that are listed in the consent document. The procedure for protecting against or minimizing risks will be to medically evaluate patients as described in Section 5 and Section 6. Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which participants are entitled under applicable regulations.
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14.3 consent and assent process

An associate or principal investigator on the trial will inform patients of the purpose, alternatives, drug administration plan, research objectives, and follow-up of this trial. The patient will be provided an IRB-approved consent for review and signature and his/her questions will be answered. After a decision is made to enroll into the study, a signature will be obtained from the patient. The original signed consent goes to Medical Records; a copy will be placed in the research record. Patients will not be consented by telephone. All patients must have a signed informed consent form and an on-study (confirmation of eligibility) form filled out and signed by a participating investigator before entering on study.  
Adults who are unable to provide initial informed consent are excluded from participation on this study. All patients > 18 years old will be offered the opportunity to assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form, so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired.  
14.3.1 Participation of subjects unable to give consent At the NCI only: Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation, all subjects ≥ age 18 at the NCI only will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team for evaluation. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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14.3.2 informed consent of non-english

If there is an unexpected enrollment of a research participant for whom there is no translated extant IRB approved consent document, the principal investigator and/or those authorized to obtain informed consent will use the Short Form Oral Consent Process as described in MAS Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2). The summary that will be used is the English version of the extant IRB approved consent document. Signed copies of both the English version of the consent and the translated short form will be given to the subject or their legally authorized representative, and the signed original will be filed in the medical record. Unless the PI is fluent in the prospective subject's language, an interpreter will be present to facilitate the conversation (using the Short Form process). Preferably, someone who is independent of the subject (i.e., not a family member) will assist in presenting information and obtaining consent. Whenever possible, interpreters will be provided copies of the relevant consent documents well before the consent conversation with the subject (24 to 48 hours if possible).  
We request prospective IRB approval of the use of the short form process for nonEnglish speaking subjects and will notify the IRB at the time of continuing review of the frequency of use of the Short Form. The Short Form process will be used no more than 5 times per language, after which the full consent document will be translated into that language.
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14.4 procedure for protecting against

All care will be taken to minimize side effects, but they can be unpredictable in nature and severity. This study may involve risks to patients, which are currently unforeseeable. All patients will be monitored for side effects from taking study medication. This research represents a greater than minimal risk to participants, but presents the prospect of direct benefit to individual subjects. The research component of this study required to obtain 3 CT tumor biopsies confers radiation exposure at an effective dose of 2.4 rem. This dose is below NIH RSC guidelines of less than 5.0 rem per year in adults, and represents a slightly greater than minimal risk to patients.
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14.5 patient advocate

The patients' rights representative is available to patients receiving treatment on this protocol at the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical Research Center, Room 1-3521, on the Bethesda NIH campus. Patients will be informed that they can contact the study PI or RN at any time with questions about their medical care, and that the patients' rights representative is also available to answer non-medical questions about the study.
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references

1. Chen, X., et al., *Platinum-based agents for individualized cancer treatment.* Curr Mol Med, 2013. 13(10): p. 1603-12.  
2. Zhu, G., P. Chang, and S.J. Lippard, *Recognition of platinum-DNA damage by poly(ADPribose) polymerase-1.* Biochemistry, 2010. 49(29): p. 6177-83.  
3. Jazayeri, A., et al., ATM- and cell cycle-dependent regulation of ATR in response to DNA
double-strand breaks. Nat Cell Biol, 2006. 8(1): p. 37-45.  
4. Serrano, M.A., et al., *DNA-PK, ATM and ATR collaboratively regulate p53-RPA interaction* to facilitate homologous recombination DNA repair. Oncogene, 2013. 32(19): p. 2452-62.  
5. El-Khamisy, S.F., et al., *A requirement for PARP-1 for the assembly or stability of XRCC1* nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res, 2003. 31(19): p. 5526-33.  
6. Haince, J.F., et al., *PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to* multiple DNA damage sites. J Biol Chem, 2008. 283(2): p. 1197-208.  
7. Huntoon, C.J., et al., *ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy* independent of BRCA status. Cancer Res, 2013. 73(12): p. 3683-91.  
8. Reaper, P.M., et al., Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol, 2011. 7(7): p. 428-30.  
9. Yap, T.A., et al., Abstract PR14: Phase I trial of first-in-class ataxia telangiectasia-mutated and Rad3-related (ATR) inhibitor VX-970 as monotherapy (mono) or in combination with carboplatin (CP) in advanced cancer patients (pts) with preliminary evidence of target modulation and antitumor activity. Molecular Cancer Therapeutics, 2015. 14(12 Supplement 2): p. PR14.  
10. Helleday, T., *The underlying mechanism for the PARP and BRCA synthetic lethality: clearing* up the misunderstandings. Mol Oncol, 2011. 5(4): p. 387-93.  
11. Donawho, C.K., et al., *ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that* potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res, 2007. 13(9): p.  
2728-37. 12. Peralta-Leal, A., M.I. Rodriguez, and F.J. Oliver, Poly(ADP-ribose)polymerase-1 (PARP-1) in carcinogenesis: potential role of PARP inhibitors in cancer treatment. Clin Transl Oncol, 2008.  
10(6): p. 318-23.  
13. Kummar, S., et al., *Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT888 in patients with advanced malignancies.* J Clin Oncol, 2009. 27(16): p. 2705-11.  
14. Rodler, E.T., et al., Phase I: Veliparib with cisplatin (CP) and vinorelbine (VNR) in advanced triple-negative breast cancer (TNBC) and/or BRCA mutation-associated breast cancer. ASCO
Meeting Abstracts, 2014. 32(15_suppl): p. 2569.  
15. Wilsker, D.F., et al., *Pharmacodynamic Responses to DNA Damage from Cancer* Therapeutic Agents. Clin Cancer Res, 2019. **in press**.  
16. Caulfield, T., et al., Research Ethics Recommendations for Whole-Genome Research:
Consensus Statement. PLoS Biol, 2008. 6(3): p. e73.  
17. Berg, J.S., M.J. Khoury, and J.P. Evans, Deploying whole genome sequencing in clinical practice and public health: Meeting the challenge one bin at a time. Genet Med, 2011. 13(6): p. 499504.
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appendix a performance status criteria

| ECOG Performance Status Scale   |                                                                                                                                                                 |
|---------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                           | Descriptions                                                                                                                                                    |
| 0                               | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction.  Symptoms, but ambulatory. Restricted in physically strenuous |
| 1                               | activity, but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light housework, office work).  In bed <50% of the time. Ambulatory and capable of all selfcare, but unable to carry out any work activities. Up and about                                                                                                                                                                 |
| 2                               | more than 50% of waking hours.                                                                                                                                  |
| 3                               | In bed >50% of the time. Capable of only limited self-care,  confined to bed or chair more than 50% of waking hours.                                            |
| 4                               | 100% bedridden. Completely disabled. Cannot carry on any  self-care. Totally confined to bed or chair.                                                          |
| 5                               | Dead.                                                                                                                                                           |
appendix b patient drug interactions
appendix a performance status criteria

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

The study drugs M6620 (VX-970) and veliparib (ABT-888) may interact with other drugs which can cause side effects. For this reason, it is very important to tell your doctors about all your medicines, including: (a) medicines you are taking before this clinical trial, (b) medicines you start or stop taking during this study, (c) medicines you buy without a prescription (over-the-
appendix b patient drug interactions
ctep # p9771

Clinical Center \# 16-C-0087 counter remedy), (d) herbals or supplements (e.g. St. John's Wort). It is helpful to bring your medication bottles or an updated medication list with you.  
Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers to review any medicines and herbal supplements that are considered strong inhibitors or inducers of CYP3A4, P-gp, OCT2, and MATE1/2K, and substrates of P-gp and BCRP.  
- Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to determine if there could be any side effects.  
- Make sure your doctor knows to avoid certain prescription medications.  
- Your regular health care provider should check a frequently updated medical reference or call your study doctor before prescribing any new medicine or discontinuing any medicine.
Version Feb/2019  
| NH ➤ NATIONAL CANCER INSTITUTE                                               | NH 〉 NATIONAL CANCER INSTITUTE                                              | RH 〉 NATIONAL CANCER INSTITUTE                                                | RIH ⟩ NATIONAL CANCER INSTITUTE      |
|------------------------------------------------------------------------------|------------------------------------------------------------------------------|--------------------------------------------------------------------------------|--------------------------------------|
| EMERGENCY INFORMATION                                                        | DRUG INTERACTIONS                                                            |                                                                                |                                      |
| Show this card to all of your                                                | Tell your doctors before you start or                                        | Carry this card with you at all times                                          |                                      |
| stop any medicines                                                           |                                                                              |                                                                                |                                      |
| healthcare providers. Keep it with                                           | M6620 (VX-970) and veliparib (ABT-888) interact with specific enzymes in     |                                                                                |                                      |
| you in case you go to the                                                    | Check with your doctor or pharmacist                                         | your liver or other tissues like the gut and transport proteins that help move |                                      |
| emergency room.                                                              | if you need to use an over-the-counter                                       | drugs in and out of cells and must be used very carefully with other           |                                      |
| medicine or herbal supplement!                                               | medicines.                                                                   |                                                                                |                                      |
| Patient Name:                                                                | Use caution and avoid the                                                    | Your healthcare providers should be aware of any medicines that are strong     |                                      |
| following drugs if possible:                                                 | inhibitors/inducers of CYP3A4, P-gp, OCT2, MATE1/2K or substrates of P-gp or |                                                                                |                                      |
| Diagnosis:                                                                   | - Oxaliplatin, carboplatin,                                                  | BCRP,                                                                          |                                      |
| Study Doctor:                                                                | cisplatin, and topotecan (in                                                 |                                                                                |                                      |
| patients with pre-existing                                                   | - Strong inhibitors or inducers of CYP3A4 should be avoided.                 |                                                                                |                                      |
| kidney impairment)                                                           | - Strong inhibitors of P-gp, BCRP, OCT2, or MATE1/MATE2K should be           |                                                                                |                                      |
| Study Doctor Phone #:                                                        | used with caution.                                                           |                                                                                |                                      |
| - Substrates of P-gp and BCRP should be used with caution.                   |                                                                              |                                                                                |                                      |
| NCI Trial #:                                                                 | Before prescribing new medicines, your health care provider should check a   |                                                                                |                                      |
| frequently-updated medical reference for a list of drugs to avoid or contact |                                                                              |                                                                                |                                      |
| Study Drug(S):                                                               | your study doctor.                                                           | Version Feb/2019                                                               |                                      |
| For more information: 1-800-4-CANCER                                         | For more information: 1-800-4-CANCER                                         | For more information: 1-800-4-CANCER                                           | For more information: 1-800-4-CANCER |
| EGONIC                                                                       |                                                                              |                                                                                |                                      |
| gy I cli                                                                     | FROM LO                                                                      |                                                                                |                                      |
appendix b patient drug interactions
(next page patient drug interaction

The study drugs are given over a 21-day period of time called cycles. The 21-day treatment cycle will be repeated as long as you are tolerating the medications and your cancer is either stable or getting better. The chart below shows what will happen to you during cycle 1 and future cycles after you sign the consent form and start the study. Each cycle is numbered. The left-hand column shows the day in the cycle, and the right-hand column tells you what will happen on that day.  
| Day                           | What to do and what will happen to you                                                                |                                                                              |
|-------------------------------|-------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|
| Before  starting  study  drug | -                                                                                                     | Check in at ________________ [name of outpatient clinic]                     |
| -                             | Get routine blood tests                                                                               |                                                                              |
| -                             | Pregnancy test for women who are able to become pregnant                                              |                                                                              |
| -                             | Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider    |                                                                              |
| -                             | CT or MRI scan will be done                                                                           |                                                                              |
| -                             | Research blood samples will be drawn                                                                  |                                                                              |
| Cycle 1,                      | -                                                                                                     | Admitted to ________________ [name of clinical center]                       |
| Day 1                         | -                                                                                                     | Get routine blood tests                                                      |
| -                             | Research blood samples will be drawn                                                                  |                                                                              |
| -                             | Receive the first dose of veliparib (ABT-888) by mouth                                                |                                                                              |
| -                             | Receive the first dose of cisplatin through a vein                                                    |                                                                              |
| -                             | Tumor biopsies will be taken for some patients                                                        |                                                                              |
| Cycle 1,                      | -                                                                                                     | Get routine blood tests                                                      |
| Day 2                         | -                                                                                                     | Receive the first dose of M6620 (VX-970) through a vein                      |
| -                             | Tumor biopsies will be taken for some patients 2 to 5 hours after receiving M6620  (VX-970)           |                                                                              |
| -                             | Research blood samples will be drawn                                                                  |                                                                              |
| -                             | Continue to take veliparib (ABT-888) by mouth twice a day about 12 hours apart  for a total of 3 days |                                                                              |
| Cycle 1,                      | -                                                                                                     | Have a history taken of how you feel and undergo a physical examination by a |
| Days 8-10                     | Health Care Provider                                                                                  |                                                                              |
| -                             | Get routine blood tests                                                                               |                                                                              |
| -                             | Research blood samples will be drawn                                                                  |                                                                              |
| -                             | Take veliparib (ABT-888) by mouth twice a day about 12 hours apart for 3 days                         |                                                                              |
| -                             | Receive cisplatin through a vein on day 8                                                             |                                                                              |
| -                             | Receive M6620 (VX-970) through a vein on day 9                                                        |                                                                              |
| -                             | Tumor biopsies will be taken for some patients 2 to 5 hours after receiving M6620  (VX-970)           |                                                                              |  
| Clinical Center # 16-C-0087 Day What to do and what will happen to you Cycle 1,  - Get routine blood tests at your clinical center or by your home physician Day 15  Cycle 2,  - Have a history taken of how you feel and undergo a physical examination by a  Day 1  Health Care Provider  - Get routine blood tests  - Research blood samples will be drawn - Start taking veliparib (ABT-888) by mouth twice a day about 12 hours apart for  days 1 through 3  - Receive cisplatin through a vein Cycle 2,  - Research blood samples will be drawn Day 2  - Receive M6620 (VX-970) through a vein  Cycle 2,  - Check in at ________________ [name of outpatient clinic] Days 8-10  - Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider  - Get routine blood tests  - Continue taking veliparib (ABT-888) by mouth twice a day about 12 hours apart on  days 8 through 10  - Receive cisplatin through a vein on day 8  - Receive M6620 (VX-970) through a vein on day 9  Cycle 2,  - Get routine blood tests at your clinical center or by your home physician (optional) Day 15  Cycle 3,  and  onward  - Check in at ________________ [name of outpatient clinic] - Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider - Get routine blood tests  - CT scan to determine how your tumor is responding to the treatment will be done  every 6 weeks (every 2 cycles, or every 3 cycles if you have been on study for more  than one year, every 4 cycles if on study for more than 3 years)  - Research blood samples will be drawn before Cycle 3 treatment - Cisplatin will be given through a vein on Day 1 and 8 of each cycle - M6620 (VX-970) will be given through a vein on Day 2 and 9 of each cycle  - veliparib (ABT-888) will be taken orally twice a day about 12 hours apart on  days 1 through 3 and 8 through 10 of each cycle   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
study diary
patient name instructions

Please complete this form and return to the research nurse or doctor every cycle (21 days) Dose of veliparib (ABT-888) (number of capsules): Time of dosing: Take veliparib (ABT-888) capsules twice each day (morning and evening, about 12 hours apart) on days 1 to 3 and 8-10 Cycle number: _________ Start date: _________ Patient Signature: _____________________________________  
| Time taken   | Comments:   |    |    |                          |
|--------------|-------------|----|----|--------------------------|
| Date         | Day         | AM | PM | Side effects/missed dose |
| 1  2  3  4   | No veliparib (ABT888) taken today             |    |    |                          |
| 5            | No veliparib (ABT888) taken today             |    |    |                          |
| 6            | No veliparib (ABT888) taken today             |    |    |                          |
| 7            | No veliparib (ABT888) taken today             |    |    |                          |
| 8            |             |    |    |                          |  
| Clinical Center # 16-C-0087 9  10  11 No veliparib (ABT888) taken today 12 No veliparib (ABT888) taken today 13 No veliparib (ABT888) taken today 14 No veliparib (ABT888) taken today 15 No veliparib (ABT888) taken today 16 No veliparib (ABT888) taken today 17 No veliparib (ABT888) taken today 18 No veliparib (ABT888) taken today 19 No veliparib (ABT888) taken today 20 No veliparib (ABT888) taken today 21 No veliparib (ABT888) taken today   |
|---|  
CTEP \# P9771 Clinical Center \# 16-C-0087
appendix d pd sample collection
patient name instructions

| Date:                | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 1 DAY 1   |         |
|----------------------|---------------------------------------------------|---------|
| CTEP Protocol P9771  | Page 102-12798 for Sample                         |         |
| Dose level:          | Veliparib Dose:                                   | Pick-up |
| M6620 (VX-970) Dose: | Lab phone: 301-451-1169                           |         |
| Patient ID:          | Cisplatin Dose:                                   |         |  
Research Nurse:
Phone:
PI:  
  
  
  
Phone:  
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION   | Record comments (i.e., if collection missed),   |                                          |                |             |                                         |
|-------------------------------------------------------------------------|-------------------------------------------------|------------------------------------------|----------------|-------------|-----------------------------------------|
| Day                                                                     | Time                                            | Instructions                             | ldeal Time     | Actual Time | and sign each time you collect a sample |
| Prior to drug                                                           | PD 400 10 mL Streck x1                          | Morning of drug                          |                |             |                                         |
| Day 1                                                                   | aministration                                   | Label tube: sample number, date and time | administration |             |                                         |  
| Date:                                                                 | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 1 DAY 2   |                                          |            |             |                                         |
|-----------------------------------------------------------------------|---------------------------------------------------|------------------------------------------|------------|-------------|-----------------------------------------|
| CTEP Protocol P9771                                                   | Research Nurse:                                   |                                          |            |             |                                         |
| Page 102-12798 for Sample                                             | Phone:                                            |                                          |            |             |                                         |
| Dose level:                                                           | Veliparib Dose:                                   | Pick-up                                  |            |             |                                         |
| M6620 (VX-970) Dose:                                                  | Lab phone: 301-451-1169                           |                                          |            |             |                                         |
| Patient ID:                                                           | Cisplatin Dose:                                   | PI:                                      |            |             |                                         |
| Phone:                                                                |                                                   |                                          |            |             |                                         |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION | Record comments (i.e., if collection missed),     |                                          |            |             |                                         |
| Day                                                                   | Time                                              | Instructions                             | ldeal Time | Actual Time | and sign each time you collect a sample |
| Prior to M6620                                                        | PD 401 10 mL Streck x1                            |                                          |            |             |                                         |
| Day 2                                                                 | (VX-970)                                          | Label tube: sample number, date and time |            |             |                                         |
| administration                                                        |                                                   |                                          |            |             |                                         |
| Start time of M6620 (VX-970) administration:                          |                                                   |                                          |            |             |                                         |
| 8 hr (± 30 min)                                                       |                                                   |                                          |            |             |                                         |
| after start of                                                        | PD 402 10 mL Streck x1                            |                                          |            |             |                                         |
| Day 2                                                                 | M6620 (VX-970)                                    | Label tube: sample number, date and time |            |             |                                         |
| administration                                                        |                                                   |                                          |            |             |                                         |  
CTEP \# P9771 Clinical Center \# 16-C-0087  
| Date:                                                                 | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 1 DAY 8   |                                          |             |                                         |
|-----------------------------------------------------------------------|---------------------------------------------------|------------------------------------------|-------------|-----------------------------------------|
| CTEP Protocol P9771                                                   | Research Nurse:                                   |                                          |             |                                         |
| Page 102-12798 for Sample                                             |                                                   |                                          |             |                                         |
| Dose level:                                                           | Veliparib Dose:                                   | Phone:                                   |             |                                         |
| Pick-up                                                               |                                                   |                                          |             |                                         |
| M6620 (VX-970) Dose:                                                  | Lab phone: 301-451-1169                           |                                          |             |                                         |
| Patient ID:                                                           | Cisplatin Dose:                                   | PI:                                      |             |                                         |
| Phone:                                                                |                                                   |                                          |             |                                         |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION | Record comments (i.e., if collection missed),     |                                          |             |                                         |
| ldeal Time                                                            |                                                   |                                          |             |                                         |
| Day                                                                   | Time                                              | Instructions                             | Actual Time | and sign each time you collect a sample |
| Prior to                                                              |                                                   |                                          |             |                                         |
| veliparib +                                                           | PD 403 10 mL Streck x1                            |                                          |             |                                         |
| Day 8                                                                 | cisplatin                                         | Label tube: sample number, date and time |             |                                         |
| aministration                                                         |                                                   |                                          |             |                                         |  
| Date:                                                                 | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 1 DAY 9   |                                          |            |             |                                         |
|-----------------------------------------------------------------------|---------------------------------------------------|------------------------------------------|------------|-------------|-----------------------------------------|
| CTEP Protocol P9771                                                   | Research Nurse:                                   |                                          |            |             |                                         |
| Page 102-12798 for Sample                                             | Phone:                                            |                                          |            |             |                                         |
| Dose level:                                                           | Veliparib Dose:                                   | Pick-up                                  |            |             |                                         |
| M6620 (VX-970) Dose:                                                  | Lab phone: 301-451-1169                           |                                          |            |             |                                         |
| Patient ID:                                                           | Cisplatin Dose:                                   | PI:                                      |            |             |                                         |
| Phone:                                                                |                                                   |                                          |            |             |                                         |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION | Record comments (i.e., if collection missed),     |                                          |            |             |                                         |
| Day                                                                   | Time                                              | Instructions                             | ldeal Time | Actual Time | and sign each time you collect a sample |
| Prior to M6620                                                        | PD 404 10 mL Streck x1                            |                                          |            |             |                                         |
| Day 9                                                                 | (VX-970)                                          | Label tube: sample number, date and time |            |             |                                         |
| administration                                                        |                                                   |                                          |            |             |                                         |  
CTEP \# P9771 Clinical Center \# 16-C-0087  
| Date:                                                                 | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 2 DAY 1   |                                          |            |             |                                         |
|-----------------------------------------------------------------------|---------------------------------------------------|------------------------------------------|------------|-------------|-----------------------------------------|
| CTEP Protocol P9771                                                   | Research Nurse:                                   |                                          |            |             |                                         |
| Page 102-12798 for Sample                                             | Phone:                                            |                                          |            |             |                                         |
| Dose level:                                                           | Veliparib Dose:                                   | Pick-up                                  |            |             |                                         |
| M6620 (VX-970) Dose:                                                  | Lab phone: 301-451-1169                           |                                          |            |             |                                         |
| Patient ID:                                                           | Cisplatin Dose:                                   | PI:                                      |            |             |                                         |
| Phone:                                                                |                                                   |                                          |            |             |                                         |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION | Record comments (i.e., if collection missed),     |                                          |            |             |                                         |
| Day                                                                   | Time                                              | Instructions                             | ldeal Time | Actual Time | and sign each time you collect a sample |
| Prior to                                                              |                                                   |                                          |            |             |                                         |
| veliparib +                                                           | PD 405 10 mL Streck x1                            |                                          |            |             |                                         |
| Day 1                                                                 | cisplatin                                         | Label tube: sample number, date and time |            |             |                                         |
| administration                                                        |                                                   |                                          |            |             |                                         |  
| Date:                                                                 | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 2 DAY 2   |                                 |            |             |                                         |
|-----------------------------------------------------------------------|---------------------------------------------------|---------------------------------|------------|-------------|-----------------------------------------|
| CTEP Protocol P9771                                                   | Research Nurse:                                   |                                 |            |             |                                         |
| Page 102-12798 for Sample                                             |                                                   |                                 |            |             |                                         |
| Dose level:                                                           | Veliparib Dose:                                   | Phone:                          |            |             |                                         |
| Pick-up                                                               |                                                   |                                 |            |             |                                         |
| M6620 (VX-970) Dose:                                                  | Lab phone: 301-451-1169                           |                                 |            |             |                                         |
| Cisplatin Dose:                                                       | PI:                                               |                                 |            |             |                                         |
| Patient ID:                                                           | Phone:                                            |                                 |            |             |                                         |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION | Record comments (i.e., if collection missed),     |                                 |            |             |                                         |
| Day                                                                   | Time                                              | Instructions                    | ldeal Time | Actual Time | and sign each time you collect a sample |
| Prior to M6620                                                        | PD 406 10 mL Streck x1                            |                                 |            |             |                                         |
| Day 2                                                                 | (VX-970)                                          | Label tube: sample number, date |            |             |                                         |
| administration                                                        | and time                                          |                                 |            |             |                                         |
| Start time of M6620 (VX-970) administration:                          |                                                   |                                 |            |             |                                         |
| 10 hr (± 2 hr)                                                        |                                                   |                                 |            |             |                                         |
| Day 2 (at                                                             | after start of                                    | PD 407 10 mL Streck x1          |            |             |                                         |
| participating                                                         | M6620 (VX-                                        | Label tube: sample number, date |            |             |                                         |
| sites                                                                 | 970)                                              | and time                        |            |             |                                         |
| administration                                                        | PD 407 10 mL Streck x1                            |                                 |            |             |                                         |
| Day 2 (at                                                             | 7:00 pm                                           | Label tube: sample number, date |            |             |                                         |
| NCI only)                                                             | ( ≥ 30 min)                                       | and time                        |            |             |                                         |  
CTEP \# P9771 Clinical Center \# 16-C-0087  
| Date:                     | PD BLOOD SAMPLE COLLECTION SHEET: EACH SUBSEQUENT CYCLE DAY 1   |         |
|---------------------------|-----------------------------------------------------------------|---------|
| CTEP Protocol P9771       | Research Nurse:                                                 |         |
| Page 102-12798 for Sample | Phone:                                                          |         |
| Dose level:               | Veliparib Dose:                                                 | Pick-up |
| M6620 (VX-970) Dose:      | Lab phone: 301-451-1169                                         |         |
| Patient ID:               | Cisplatin Dose:                                                 | PI:     |  
Cycle number:
Phone:  
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION   | Record comments (i.e., if collection missed),   |                                          |            |             |                                         |
|-------------------------------------------------------------------------|-------------------------------------------------|------------------------------------------|------------|-------------|-----------------------------------------|
| Day                                                                     | Time                                            | Instructions                             | ldeal Time | Actual Time | and sign each time you collect a sample |
| Prior to                                                                |                                                 |                                          |            |             |                                         |
| veliparib +                                                             | PD 40X 10 mL Streck x1                          |                                          |            |             |                                         |
| Day 1                                                                   | cisplatin                                       | Label tube: sample number, date and time |            |             |                                         |
| aministration                                                           |                                                 |                                          |            |             |                                         |  
| Date:                     | PD BLOOD SAMPLE COLLECTION SHEET: ON THE DAY OF RESTAGING FOLLOW_UP OR PROGRESSION BIOPSY   |         |
|---------------------------|---------------------------------------------------------------------------------------------|---------|
| CTEP Protocol P9771       | Research Nurse:                                                                             |         |
| Page 102-12798 for Sample | Phone:                                                                                      |         |
| Dose level:               | Veliparib Dose:                                                                             | Pick-up |
| M6620 (VX-970) Dose:      | Lab phone: 301-451-1169                                                                     |         |
| Patient ID:               | Cisplatin Dose:                                                                             | PI:     |
| Cycle number:             | Phone:                                                                                      |         |  
Phone:  
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION   | Record comments (i.e., if collection missed),   |                                          |            |             |                                         |
|-------------------------------------------------------------------------|-------------------------------------------------|------------------------------------------|------------|-------------|-----------------------------------------|
| Day                                                                     | Time                                            | Instructions                             | ldeal Time | Actual Time | and sign each time you collect a sample |
| Prior to                                                                |                                                 |                                          |            |             |                                         |
| veliparib +                                                             | PD 40X 10 mL Streck x1                          |                                          |            |             |                                         |
| Day 1                                                                   | cisplatin                                       | Label tube: sample number, date and time |            |             |                                         |
| aministration                                                           |                                                 |                                          |            |             |                                         |
appendix d pd sample collection
appendix e informed consent form

Study Title: Phase I Study of Veliparib (ABT-888), an Oral PARP Inhibitor, and M6620 (VX970), an ATR Inhibitor, in Combination with Cisplatin in Patients with Refractory Solid Tumors
appendix d pd sample collection
introduction

We invite you to take part in this research study. First, we want you to know that:
Taking part in this research study is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not lose any benefits to which you are otherwise entitled. You may receive no benefit from taking part. The research may give us knowledge that may help people in the future.  
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your doctors or research team before you agree to the study. Now we will describe this research study. Before you decide to take part, please take as much time as you need to ask any questions and discuss this study with family, friends or your personal physician or other health professional.
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why is this study being

The purpose of this study is to test the safety of a combination of 3 drugs (M6620 (VX-970), veliparib (ABT-888), and cisplatin) to find out the doses of these drugs that can be safely given to humans and to learn if these drugs have activity against tumors. Although we hope this experimental therapy will decrease the size of your tumor, we cannot promise or predict the benefits of the treatment at this time. The drugs used in this study have known side effects that will be reviewed with you by your medical team before you sign this consent form. Cisplatin is currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with bladder, ovarian, and testicular cancers in combination with other chemotherapy agents. Veliparib (ABT-888) and M6620 (VX-970) are not approved by the FDA. Combining veliparib (ABT-888) and M6620 (VX-970) with cisplatin is thought to block proteins that are known to be important for cancer cell growth. We are also studying the genes in your tumor to help us understand how your tumor responds to these 3 drugs. Blood, tissue, and tumor cells contain genes that are made up of DNA and serve as the "instruction book" for each cell in the body. We know that variations in some tumor genes play an important role in how cancers respond to drugs. Determining whether different tumor gene variations affect how veliparib (ABT-888), M6620 (VX-970), and cisplatin work against tumors will help scientists understand why some patients might stop responding to these drugs.
appendix d pd sample collection
why are you being asked

You are being asked to take part in this research study because you have advanced cancer that has progressed after receiving standard treatment, or for which no effective therapy exists. We hope that this combination of study drugs will slow down the growth of your cancer.
appendix d pd sample collection
how many people will take

Up to 60 patients will take part in this study at multiple sites around the US.
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what will happen if i

If you are accepted and you choose to take part, you will begin receiving veliparib (ABT-888) and cisplatin on the first day, followed by M6620 (VX-970) on the second day. Cisplatin and M6620 (VX-970) are given as an infusion through a vein. The drugs are given in cycles, and each cycle is 21 days (3 weeks) long.  
- Cisplatin is given the first day of each cycle and on day 8 for some patients, for at least the first 6 cycles
- M6620 (VX-970) is given on day 2 and day 9 of each cycle (or day 1 and day 8 if no cisplatin is given during that cycle)
- Veliparib (ABT-888) is given orally twice a day on days 1 through 3 and days 8 through 10 of each cycle
Each patient may receive a different dose based on when he or she entered the study. Your dose of study drugs may be decreased by the study doctor if you are not tolerating it well, or increased if you are tolerating it well. Most of the exams, tests, and procedures you will have are part of your regular care such as a complete medical history, blood tests, and scans to measure your tumors. We would also do a pregnancy test in women who are able to become pregnant. The team will also give you a chart describing the tests and procedures that will be done each day during the study.  
Standard procedures being done because you are in this study; these may be done more often because you are in the study:
- **Clinic visit:** to ask how you are feeling and to evaluate you with a physical examination during week 1 and 2 of each cycle before you receive treatment.  
- **Vital signs and physical examinations:** will be performed during the clinic visits.  
- **Blood tests:** Measurement of your white blood cells, red blood cells, platelets, blood sugar, electrolytes, and of how your liver and kidneys work will be done during the first two days of the first week of each cycle, the second week before you receive treatment every cycle, and the third week of the first cycle (this third week visit can be done with your home physician). About 1 tablespoon (15 mL) of blood will be drawn per visit.  
- **CT scans** or other imaging tests such as MRI (an examination using magnetic field and radio waves) that detect your tumor will be done before the study and every 6 weeks while you are receiving study drugs. This is done so that any benefit of the treatment can be determined, and if your cancer is not responding to the treatment, the study team can tell you and discuss other treatment options (discussed further below).  
- **EKGs** (a recording of the heart's electrical activity) to check for signs of possible damage to your heart.
You will also have tests and procedures done because you are in the study to see how the study drugs are affecting your body. If you develop any side effects, you may be asked to visit more often. You will be asked to keep a diary to record the exact time you took veliparib (ABT-888), and to report any side effects you may have. If you miss a dose or vomit the dose, please make a note of this in your diary and contact your team immediately to receive further instructions. Please bring the study diary with you to each clinic visit.
appendix d pd sample collection
tests and procedures being done

- **Research blood tests:** We will also be collecting blood samples from some patients to find out the effects of the drug on any tumor cells in the blood. Blood samples will be collected from patients at the beginning of the study, and prior to receiving study drugs on days 1, 2, and 9 of cycle 1, days 1 and 2 of cycle 2, and on day 1 of cycle 3 and every subsequent cycle. The total blood for all these tests will be up to 2 tablespoons (about 30 mL).  
- **Tumor Biopsy:** You may be asked to undergo imaging-directed biopsy of your tumor
(removal of a small bit of tissue for microscopic examination) once on day 1 and again on day 9 in the first cycle only. We are collecting biopsy samples to study the effects of study drugs on your tumor and to search for any gene variations in your tumor that may help us understand how it responds to these drugs. Biopsies are an important part of this trial and are done for research purposes. Biopsies are optional in the early part of this study (called the dose escalation phase) but mandatory at a certain point in the study called the expansion phase. If you decide not to have biopsies collected, you will still receive study drugs and other tests that are part of the study and detailed above. However, at the expansion phase, willingness to undergo tumor biopsies will be required for taking part in this study. We will tell you if biopsies are required before you decide to take part in the study. No more than three biopsy procedures will be performed during the study. After the first biopsy, if you decide not to have further biopsies, you will still receive study drugs and have other tests that are part of the study. You will be asked to sign a separate consent form for each biopsy procedure. Tumor biopsies are only collected by trained personnel. Biopsies are collected using a small needle under imaging guidance (CT, MRI, or ultrasound as deemed appropriate by the interventional radiologist performing the biopsy). Imaging helps the specialized radiologist know that the needle has been placed into the tumor mass. Typical risks of biopsy collection include, but are not limited to, bleeding, infection, pain, and scarring. If you experience any complications from the biopsy, medical care will be offered to you. You will be counseled in more detail about biopsies, and you will be asked to sign a separate consent form that will describe the procedures and risks at that time. Your safety is the most important thing at all times. If upon attempting the first biopsy, no tissue can be obtained or it has caused you harm, further biopsies will not be done. After you are enrolled in this study, if for any reason the biopsies cannot be done safely, you may still receive the study drugs but the biopsies will not be done. The biopsies are for research purposes and will not benefit you. They might help other people in the future. Even if you sign "yes" to have biopsies, you can change your mind at any time. Please read each sentence below and think about your choice. After reading the sentence, circle the initial answer that is right for you:
appendix d pd sample collection
have you been informed regarding

Escalation phase_______ Expansion phase________ Initials __________ I agree to have the tumor biopsies for the escalation phase of the research study (optional).  
Yes No Initials_________
I agree to have the tumor biopsies for the expansion phase of the research study (mandatory).  
Yes No N/A ______ Initials_________
appendix d pd sample collection
optional tumor genomic sequencing

Targeted Sequencing—If your cancer looks like it is getting worse, you may choose to have another, optional tumor biopsy before leaving the study and have a targeted genomic sequencing test done on this tumor tissue in a clinically approved laboratory. You and your doctor will receive the results of this test, and the results will be in your electronic medical record. Your doctor will discuss these results with you and tell you about any gene variations that might make you able to take part in targeted therapy clinical trials in the future, such as the NCI MATCH (NCT02465060) and MPACT (NCT01827384) trials.  
Exome Sequencing—If you choose to have the optional, third tumor biopsy, we are also requesting your permission to perform exome sequencing on your tumor biopsies and link this information to information from your medical history. You are not required to agree to exome sequencing to take part in this trial. Your tumor tissue contains genes, which are made up of DNA (deoxyribonucleic acid) and serve as the "instruction book" for the cells that make up our bodies. Exome sequencing will determine the exact order of the base pairs (DNA building blocks) in your tumor. We know that variations in the base pairs of some tumor genes play an important role in how cancers respond to drugs. Information about your gene variations combined with information from your medical history may help us understand how your tumor responds to the study drugs and why it has stopped responding. If you agree, we will identify gene variants in your tumor biopsy samples collected at the beginning and end of treatment with exome sequencing, but this information will be for research purposes only and we will not give you any individual results from this sequencing or add this information to your medical records. This is because it will probably take a long time for this project to produce health-related information that we will know how to interpret accurately. However, we will tell you if we find that you have a communicable disease that we are required by law to report.  
I agree to allow genomic sequencing for research purposes:  
$$\mathbf{N_{0}}$$  
Yes No Initials_________
appendix d pd sample collection
how long will i be

You will stay in the study as long as you are tolerating the drugs and your tumors are either stable or getting better, but you can choose to leave the study at any time. For some study procedures, we will need you to come to ________________ *[name of center]*.
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stopping therapy

You can decide to stop at any time. If you decide to stop for any reason, it is important to let your study doctor know as soon as possible so you can stop safely. If you stop, you can decide whether or not to let the study doctor continue to include your medical information in the study. Your study doctor will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study.  
Your study doctor may take you out of the study:
- If your health changes and the study is no longer in your best interest
- If new information becomes available
- If you do not follow the study rules - If the study is stopped by the sponsor, IRB, or FDA
appendix d pd sample collection
follow-up

You will be followed for 30 days after taking the last dose of study drugs. We will call you between days 27- 30 to ask about any side effects that were ongoing when you stopped therapy, or any new side effects that might be related to the study therapy. If you have side effects that might be related to the study drugs that have not gotten better after 30 days, we will call you every 2 weeks until the side effects have become stable or gotten better. The follow-up period will end if you enroll in another study or start receiving standard therapy.
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alternative approaches or treatments what

Instead of being in this study, you have these options:
- you may choose to have the usual approaches described above  
- you may choose to take part in a different study, if one is available
- you may continue your standard care as usual (see table below), and not take part in this study
- or you may choose not to be treated, but you may want to receive comfort care to relieve symptoms
Please talk to your doctor about these and other options. Your doctor may decide that it is not safe for you to receive a particular treatment or you have the right to refuse a treatment, but before you decide to take part in this study you should discuss all available treatment options with your local doctor.
appendix d pd sample collection
risks or discomforts of participation

If you choose to take part in this study, there is a risk that the treatment may not be as good as the usual approach for your cancer or condition at shrinking or stabilizing your cancer.  
You also may have the following discomforts:
- Spend more time in the hospital or doctor's office. - Be asked sensitive or private questions about things you normally do not discuss. - May not be able to take part in future studies.
The agents used in this study may affect how different parts of your body work such as your liver, kidneys, heart, and blood. The study doctor will test your blood and will let you know if changes occur that may affect your health. There is also a risk that you could have side effects from the study drug(s)/study approach.  
Here are important things to know about side effects:
- The study doctors do not know who will or will not have side effects.  
- Some side effects may go away soon, some may last a long time, and some may never go away.  
- Some side effects may make it hard for you to have children. - Some side effects may be mild. Other side effects may be very serious and even result in death.  
You can ask your study doctor questions about side effects at any time. Here are important ways to make side effects less of a problem:
- If you notice or feel anything different, tell your study doctor. He or she can check to see if it is a side effect.  
- Your study doctor will work with you to treat your side effects. - Your study doctor may adjust the study drugs to try to reduce side effects.  
- Your study doctor will give you a drug interactions handout and wallet card that lists possible interactions.
The tables below show the most common and the most serious side effects doctors know about. Keep in mind that there might be other side effects doctors do not yet know about. If important new side effects are found, the study doctor will discuss these with you.  
- Some patients on this study have had low platelet counts and low red and white blood cell counts in their blood, possibly due to this drug combination. These conditions can cause bruising, bleeding, slow blood clotting after an injury, tiredness, weakness, shortness of breath, and can keep your body from fighting off infections.  
Risks and side effects related to **veliparib (ABT-888)** may include:
appendix d pd sample collection
common some may be serious

In 100 people receiving ABT-888 (veliparib), more than 20 and up to 100 may have:
- Nausea
- Tiredness
- Bruising, bleeding  
RARE, AND SERIOUS  
  
  
In 100 people receiving ABT-888 (veliparib), 3 or fewer may have:  
- Cancer of bone marrow caused by chemotherapy  
- Damage to the bone marrow (irreversible) which may cause infection, bleeding, may  
require transfusions  
- A new cancer resulting from treatment of earlier cancer  
- Seizure  
- Blood clot which may cause swelling, pain, shortness of breath
appendix d pd sample collection
risks and side effects related

OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving ABT-888 (veliparib), from 4 to 20 may have:
- Anemia which may require blood transfusion - Infection, especially when white blood cell count is low
- Belly pain  
  
- Dehydration
- Dizziness, headache
- Changes in taste
- Rash
While taking M6620 (VX-970), you should take protective measures to minimize sun exposure.  
Risks and side effects related to **cisplatin** may include:
appendix d pd sample collection
common some may be serious

In 100 people receiving cisplatin, more than 20 and up to 100 may have:
- Nausea, vomiting
- Infection, especially when white blood cell count is low - Anemia which may cause tiredness, or may require blood transfusions - Bruising, bleeding - Kidney damage which may cause swelling, may require dialysis - Hearing loss including ringing in ears
appendix d pd sample collection
occasional some may be serious

In 100 people receiving cisplatin, from 4 to 20 may have:
- Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the face or throat
- Confusion
- Difficulty with balance
appendix d pd sample collection
rare and serious

In 100 people receiving cisplatin, 3 or fewer may have:
- Cancer of bone marrow caused by chemotherapy later in life
- Seizure
appendix d pd sample collection
risks associated with genomic sequencing

- Anemia which may require blood transfusion - Diarrhea, nausea, vomiting - Tiredness - Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the face or throat
- Infection, especially when white blood cell count is low which may cause painful and frequent urination
- Bruising, bleeding - Pain in tumor - Dizziness, headache
- Itching, rash
- Flushing
appendix d pd sample collection
privacy risks

Your privacy is very important to us and we will use many safety measures to protect your privacy. Your research samples will be stored with a coded identifier, not your name. Any personal data about you will also be stored in a sequence computer database with that code identifier. All information that can directly link you to the tissue or personal information will not be shared with investigators using your specimens for research. This includes information that contains your name, medical record number, date of birth, or address. There are protections in place that restrict who can see the results of your genetic tests. However, there remains a risk someone could get unauthorized access or break into the system that stores information about you. Every precaution will be taken to minimize this risk. There also may be other privacy risks that we have not foreseen. Genetic variant results that we return to you will become part of your medical record at the NIH. In spite of all of the safety measures that we will use, we cannot guarantee that your identity will ever become known. For instance, if you or a family member releases information about you or your involvement in this study, or an insurer, employer, or other person obtains your written consent to receive information from your NIH medical record, your identity, information about your enrollment in this study and genetic variant results may be included in a release of your medical records.
appendix d pd sample collection
protections against misuse of genetic

Since some genetic variations can help to predict the future health problems of you and your relatives, this information might be of interest to health providers, life insurance companies, and others. Patterns of genetic variation also can be used by law enforcement agencies to identify a person or his/her blood relatives. There are state and federal laws that protect against genetic discrimination. There is a federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this law makes it illegal for health insurance companies, group health plans, and most employers to discriminate against you based on your genetic information. GINA also does not apply to members of the United States military, to veterans obtaining health care through the Veteran's Administration or the Indian Health Service. GINA does not forbid insurance medical underwriting based on your current health status, including your cancer. GINA also does not protect you against discrimination by companies that sell life insurance, disability insurance, or long-term care insurance. However, your cancer diagnosis will often be considered more important that genetic information about risk for developing another condition when evaluating you during medical underwriting.
appendix d pd sample collection
emotional and psychological risks

As part of the research study, it is possible that you could learn that you have genetic risks for another disease or disability. This may be upsetting and, depending on what you learn, might create a need to make challenging decisions about how to respond. Although your genomic information is unique to you, you share some genomic similarities with your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your testing results could mean something about your family members and might cause you or your family distress. Before joining the study, it may be beneficial to talk with your family members about whether and how they want you to share your results with them.
appendix d pd sample collection
birth control

If you are a woman who is breast feeding or pregnant, you may not take part in the study because we don't know how this medicine would affect your baby or your unborn child. If you are a woman who can become pregnant, or are the partner of a woman who can become pregnant, you and your partner will need to practice an effective form of birth control before starting study treatment, during study treatment, and for 6 months after you finish study treatment. If you think that you or your partner is pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include using at least two of the following:
- abstinence - intrauterine device (IUD)
- tubal ligation - vasectomy
- barrier methods (condoms)
- hormonal (birth control pills, injections, or implants)
Also, if you are a woman taking hormonal birth control, please tell your study doctor or nurse. Some patients on this study may be given medication to control the side effects of nausea and vomiting that can make some forms of hormonal birth control stop working or work less well. You may need to use an alternative form of birth control during this time.
appendix d pd sample collection
potential risks related to blood

Possible side effects from drawing the blood sample include mild pain, bleeding, bruising, and infection at the site of the needle insertion. Fainting or light-headedness can sometimes occur, but usually last only a few minutes.
appendix d pd sample collection
potential benefits of participation are

The aim of this study is to see if this experimental treatment will cause your tumors to shrink. We do not know if you will receive personal, medical benefit from taking part in this study. These potential benefits could include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by the cancer. Because there is not much information about the drugs' effect on your cancer, we do not know if you will benefit from taking part in this study, although the knowledge gained from this study may help others in the future who have cancer.
appendix d pd sample collection
research subject's rights what are

Taking part in this study is your choice. You may choose either to take part or not to take part in this study. If you decide to take part, you may leave the study at any time. No matter what decision you make, there will be no penalty to you, and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution if you are eligible and choose to participate in another trial. We will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form.
appendix d pd sample collection
will my medical information be

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

You and/or your health plan/insurance company will need to pay for some or all of the costs of treating your cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment.  
The NCI will supply the study agents veliparib (ABT-888) and M6620 (VX-970) at no charge while you take part in this study. Even though it is unlikely, there is a possibility that at some point the supply of study agents may run out, necessitating taking you off-study. The NCI will not provide cisplatin free-of-charge, so you or your health plan may need to pay for cisplatin and the personnel who give it to you. [If applicable, inform the patient of any tests, procedures or agents for which there is no charge. The explanation, when applicable, should clearly state that there are charges resulting from performance of the test or drug administration that will be billed to the patient and/or health plan. For example, "The NCI is supplying (drug) at no cost to you. However, you or your health plan may need to pay for costs of the supplies and personnel who give you the (drug)."]
appendix d pd sample collection
you will not be paid

For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.
appendix d pd sample collection
what happens if i am

It is important that you tell your study doctor, __________________ *[investigator's name(s)],* if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at __________________ *[telephone number].* You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment.
appendix d pd sample collection
who can answer my questions

You can talk to your study doctor about any questions or concerns you have about this study. Contact your study doctor __________________ *[name(s)]* at __________________ [telephone number]. For questions about your rights while taking part in this study, call the ________________________ *[name of center]* Institutional Review Board (a group of people who review the research to protect your rights) at __________________ (telephone number). [Note to Local Investigator: Contact information for patient representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.]
appendix d pd sample collection
where can i get more

You may call the National Cancer Institute's Cancer Information Service at: 1-800-4-CANCER (1-800-422-6237). You may also visit the NCI Web site at http://cancer.gov/.  
- For NCI's clinical trials information, go to: http://cancer.gov/clinicaltrials/
- For NCI's general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form. If you want more information about this study, ask your study doctor.
appendix d pd sample collection
signature

I have been given a copy of all _____ *[insert total of number of pages]* pages of this form. I
have read it or it has been read to me. I understand the information and have had my questions answered. I agree to take part in this study.