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Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor, in Combination With Cisplatin in People With Refractory Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02723864
Recruitment Status : Completed
First Posted : March 31, 2016
Results First Posted : January 10, 2022
Last Update Posted : February 8, 2022
Sponsor:
Information provided by (Responsible Party):
Alice Chen, M.D., National Cancer Institute (NCI)

Brief Summary:

Background:

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

Objectives:

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

Eligibility:

People ages 18 and older with:

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

Design:

Participants will be screened with:

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

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

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

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

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

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

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

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

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


Condition or disease Intervention/treatment Phase
Neoplasms Drug: Veliparib + VX-970 + Cisplatin Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 53 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor in Combination With Cisplatin in Patients With Refractory Solid Tumors
Actual Study Start Date : August 9, 2017
Actual Primary Completion Date : December 15, 2020
Actual Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Cisplatin

Arm Intervention/treatment
Experimental: M6620 (VX-970)
M6620 will be administered intravenous (IV) on Days 2 and 9 of each 21-day cycle; Veliparib will be administered orally twice a day (BID) Days 1-3 and 8-10 of each cycle; Cisplatin will be administered at 40 mg/m^2 IV Day 1 (and Day 8 from dose level 3 onwards) of each cycle
Drug: Veliparib + VX-970 + Cisplatin
Ataxia-telangiectasia-related (ATR) protein kinase is central to the deoxyribonucleic acid (DNA) damage response and homologous recombination, activating a series of phosphorylation cascades, culminating in cell cycle arrest to allow time for DNA repair. Poly (ADP-ribose) polymerase (PARP) plays a pivotal role in base-excision repair of single strand breaks formed either due to direct genotoxic stress or during the processing of double strand breaks. Preclinical studies show ATR inhibitor M6620 (VX-970) synergizes with cisplatin to induce DNA damage and antitumor activity. The addition of PARP inhibitor veliparib with VX-970 allows for impairment of DNA repair, induction of a breast cancer gene (BRCA) null phenotype, and potentiation of the antitumor activity of cisplatin.
Other Name: ABT-888 + M6620 (berzosertib) + Cisplatinum




Primary Outcome Measures :
  1. Number of Participants With Worst Grade 2 or Higher Adverse Events Occurring in >5% of Participants at Least Possibly Related to Study Drugs [ Time Frame: Cycle 1 (i.e., one cycle = 21 days) ]
    Adverse events were assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 2 is moderate, Grade 3 is severe or medically significant but not immediately life threatening, and Grade 4 is life threatening.


Secondary Outcome Measures :
  1. Number of Participants With RAD51 Recombinase (Rad51), Phosphorylated Histone H2AX (γH2AX), Phosphorylated at Serine 343 (pS343)-Nibrin (Nbs1), and Phosphorylated KRAB-associated Protein 1 (pKAP-1) Induced After Treatment [ Time Frame: Cycle 1 Day 1, and Cycle 1 Day 9 (i.e., one cycle = 21 days) ]
    Biopsies were collected at Cycle 1 Day 1, and Cycle 1 Day 9 and markers Rad51, γH2AX, pS343-Nbs1, and pKAP-1 were measured for deoxyribonucleic acid (DNA) damage and apoptosis by immunofluorescence assays (IFA).

  2. Number of Participants With a Best Response to the Antitumor Activity of Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor, in Combination With Cisplatin [ Time Frame: 4 cycles (i.e., one cycle = 21 days) ]
    Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, and the appearance of one or more new lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.


Other Outcome Measures:
  1. Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) [ Time Frame: Date treatment consent signed to date off study, approximately 6 months and 20 days, 3 months and 17 days, 24 months and 13 days, 9 months and 8 days, 5 months and 18 days, 35 months and 20 days, and 5 months and 22 days for each Arm/Group respectively. ]
    Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients must have histologically confirmed solid tumors for which standard therapy known to prolong survival has failed in the metastatic setting or for which standard therapies do not exist.
  • Tumor amenable to biopsy and willingness to undergo tumor biopsies before and after M6620 (VX-970) treatment during the expansion phase of the trial (biopsies optional during the escalation phase).
  • Patients must have completed any chemotherapy, radiation therapy, surgery, or biologic therapy greater than or equal to 3 weeks (or greater than or equal to 5 half-lives, whichever is shorter) prior to entering the study. Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in an exploratory investigational new drug (IND)/Phase 0 study and greater than or equal to 1 week since any palliative radiation therapy. Patients must have recovered to eligibility levels from prior toxicity or adverse events.
  • Age greater than or equal to 18 years of age.
  • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
  • Life expectancy > 3 months.
  • Patients must have normal organ and marrow function as defined below:

    • absolute neutrophil count greater than or equal to 1,500/mcL
    • hemoglobin greater than or equal to 10 g/dL
    • platelets greater than or equal to 100,000/mcL
    • total bilirubin less than or equal to 1.5 X institutional upper limit of normal
    • Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase(SGOT)/alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (SGPT) less than or equal to 1.5 X institutional upper limit of normal (OR < 3X upper limit of normal (ULN) in the setting of liver metastases)
    • creatinine less than or equal to 1.5X institutional upper limit of normal

OR

  • creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

    • The effects of M6620 (VX-970) and veliparib on the developing human fetus are unknown. For this reason and because cisplatin is known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after completing study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months after completion of administration of study agents.
    • Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with M6620 (VX-970). In addition, these subjects are at increased risk of lethal infections when treated with marrow-suppressive therapy.
    • Patients must be able to swallow whole tablets or capsules. Nasogastric or gastric (G)-tube administration is not allowed. Any gastrointestinal disease which would impair ability to swallow, retain, or absorb drug is not allowed.
    • Ability to understand and the willingness to sign a written informed consent document.
    • During the expansion phase of the protocol, patients must have disease amenable to biopsy and be willing to undergo pre- and post-treatment biopsies.
    • Patients must have greater than or equal to 10.0 g/dL hemoglobin (Hb) and no blood transfusion in the past 28 days to receive Veliparib.

EXCLUSION CRITERIA:

  • Patients who are receiving any other investigational agents.
  • Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients whose brain metastatic disease status has remained stable for greater than or equal to 4 weeks following treatment of brain metastases are eligible to participate at the discretion of the principal investigator.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active untreated infection, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients required to be on any of the concomitant medications are excluded.
  • Pregnant women and women who are breastfeeding are excluded from this study because the effects of the study drugs on the developing fetus are unknown.
  • Patients who have had prior platinum-based therapy who have > Grade 1 neurotoxicity or ototoxicity at the time of enrollment will not be permitted on study.
  • Patients with a seizure history will not be permitted on protocol due to association of veliparib with seizure activity in animal toxicology studies at higher doses. Patients on anticonvulsant medications will not be permitted on study due to the potential to lower plasma levels of anticonvulsants and risk for seizure activity.
  • Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/Myelodysplastic syndromes (MDS), or with features suggestive of AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation, should not receive Veliparib due to reports of MDS and leukemia secondary to oncology therapy on Cancer Therapy Evaluation Program (CTEP)-sponsored studies utilizing Veliparib.

INCLUSION of WOMEN and MINORITIES

Both men and women of all races and ethnic groups are eligible for this trial.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02723864


Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030-4096
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Alice P Chen, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by Alice Chen, M.D., National Cancer Institute (NCI):
Informed Consent Form  [PDF] January 11, 2021

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Alice Chen, M.D., Principal Investigator, National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02723864    
Other Study ID Numbers: 160087
16-C-0087
First Posted: March 31, 2016    Key Record Dates
Results First Posted: January 10, 2022
Last Update Posted: February 8, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: We will share IPD (clinical data) during the study and indefinitely via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: During the study and indefinitely via subscription to Biomedical Translational Research Information System (BTRIS).
Access Criteria: IPD will be shared with NIH Intramural investigators who provide a methodologically sound proposal and whose proposed use of the data has been approved by the study PI, for the purpose of achieving the aims in the approved proposals. Proposals should be submitted via subscription to Biomedical Translational Research Information System (BTRIS).
URL: http://btris.nih.gov/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alice Chen, M.D., National Cancer Institute (NCI):
Pharmacodynamic
DNA Damage Repair
BRCA Null
Apoptosis
Combination Therapy
Additional relevant MeSH terms:
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Veliparib
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action