Veliparib, Paclitaxel, and Carboplatin in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery and Liver or Kidney Dysfunction

An Early Phase 1 Study of ABT-888 in Combination With Carboplatin and Paclitaxel in Patients With Hepatic or Renal Dysfunction and Solid Tumors

This phase I trial studies the side effects and the best dose of veliparib when given together with paclitaxel and carboplatin in treating patients with solid tumors that are metastatic or cannot be removed by surgery and liver or kidney dysfunction. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving veliparib together with paclitaxel and carboplatin may kill more tumor cells.

Study Overview

• Status: Active, not recruiting
• Conditions: Liver Failure; Melanoma; Renal Failure; Breast Carcinoma; Endometrial Carcinoma; Urothelial Carcinoma; Lung Carcinoma; Ovarian Carcinoma; Esophageal Carcinoma; Metastatic Malignant Neoplasm; Unresectable Malignant Neoplasm; Malignant Head and Neck Neoplasm; Carcinoma of Unknown Primary; Malignant Testicular Neoplasm
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Carboplatin; Other: Pharmacological Study; Drug: Paclitaxel; Drug: Veliparib

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the pharmacokinetics and pharmacodynamics of ABT-888 (veliparib) in patients with varying degrees of renal or hepatic dysfunction.

II. To determine the maximum tolerated dose (MTD) of ABT-888 in combination with carboplatin and paclitaxel for patients with varying degrees of liver or kidney dysfunction.

III. To provide dosing recommendations for ABT-888 in combination with carboplatin and paclitaxel based on degree of hepatic and renal impairment.

SECONDARY OBJECTIVES:

I. To define the dose-limiting toxicity (DLT) and other toxicities associated with the use of this combination in patients with varying degrees of renal or hepatic dysfunction.

II. To evaluate the pharmacokinetic parameters of ABT-888, carboplatin, and paclitaxel when administered as a combination in patients with varying degrees of renal or hepatic dysfunction.

III. To evaluate the pharmacodynamic measurement of poly-ADP-ribosylated (PAR) and platinum adducts in tumor cells associated with the use of this combination in patients with varying degrees of renal or hepatic dysfunction.

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive veliparib* orally (PO) twice daily (BID) on days 1-7 and paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30 minutes on day 3. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

NOTE: * All patients receive a single dose of veliparib PO on day -6 before course 1 (except patients with very severe renal dysfunction who receive veliparib on day -5 or -6 to coincide with a dialysis day).

After completion of study treatment, patients are followed up for 4 weeks.

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • South Pasadena, California, United States, 91030
      • City of Hope South Pasadena
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital/Winship Cancer Institute
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center - Moses Campus
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center-Weiler Hospital
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Milton S Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have histologically confirmed malignancy that is radiologically evaluable and metastatic or unresectable, for which standard curative or palliative measures do not exist or are no longer effective, and for which there is expectation of response to the combination of carboplatin/paclitaxel (i.e., lung, ovarian, breast, melanoma, head and neck, endometrial, urothelial, testicular, esophageal, carcinoma of unknown primary); for indications not listed, eligibility based on disease must be verified by the principal investigator before they are considered
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Life expectancy of greater than 12 weeks
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 8.0 g/dL
• Patients with all degrees of renal dysfunction are allowed including patients on hemodialysis; patients with mild to severe hepatic dysfunction are allowed as defined below:
• Total bilirubin =< 5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 10 x ULN
• For patients with a recently placed biliary stent, patients should have consistent results within a hepatic group from two laboratory readings within 3 days apart, taken at least 10 days following biliary stent placement; for patients with a biliary stent placed over 2 months ago, no obstruction or blockage can have occurred within the last 2 months
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those whose adverse event due to agents administered more than 4 weeks earlier have not resolved or stabilized; patients who have been administered ABT-888 as part of a single or combination, phase 0 or I study, should not necessarily be excluded from participating in this study solely because of receiving prior ABT-888
• Patients may not be receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or other agents used in study
• Peripheral neuropathy of severity greater than grade 1
• Inability to take oral medications on a continuous basis
• Evidence of bleeding diathesis
• Patients with central nervous system (CNS) metastases must be stable after therapy for CNS metastases (such as surgery, radiotherapy or stereotactic radiosurgery) for at least 3 months and must be off steroid treatment prior to study enrollment
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888; these potential risks may also apply to other agents used in this study
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; however, HIV-positive patients without an acquired immune deficiency syndrome (AIDS)-defining diagnosis who are not receiving agents with the potential for pharmacokinetic (PK) interactions with ABT-888 may be eligible
• Patients with both hepatic and renal dysfunction will also be excluded
• Patients who received and progressed on the combination of carboplatin/paclitaxel will not be eligible
• Active seizure or history of seizure disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (veliparib, paclitaxel, carboplatin); Patients receive veliparib* PO BID on days 1-7 and paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 3. Courses repeat every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. NOTE: * All patients receive a single dose of veliparib PO on day -6 before course 1 (except patients with very severe renal dysfunction who receive veliparib on day -5 or -6 to coincide with a dialysis day).

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Carboplatin; Given IV; Other Names: Blastocarb; Carboplat; Carboplatin Hexal; Carboplatino; Carboplatinum; Carbosin; Carbosol; Carbotec; CBDCA; Displata; Ercar; JM-8; Nealorin; Novoplatinum; Paraplatin; Paraplatin AQ; Paraplatine; Platinwas; Ribocarbo; JM8; Other: Pharmacological Study; Correlative studies; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Drug: Veliparib; Given PO; Other Names: ABT-888; PARP-1 inhibitor ABT-888

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK parameters of veliparib	Standard quantitative and graphical statistical summaries of the derived PK parameters (e.g. area under curve and clearance) will be produced for each organ function cohort. The effect of dysfunction on pharmacokinetics will be explored by comparing each pharmacokinetic parameter across all cohorts using one-way analysis (analysis of variance) or Kruskal-Wallis test. The level of each protein will be compared between responders and non-responders using the Wilcoxon signed rank test.	Day -6 and 3 of course 1 after veliparib dosing
MTD of veliparib in combination with carboplatin and paclitaxel, determined according to incidence of DLT as graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.0		21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of toxicities as assessed by NCI CTCAE v4.0	The maximum grade of toxicity for each category of interest will be recorded for each patient and the summary results will be tabulated by category, grade and dose level. Severe and life-threatening toxicities and adverse event-related deaths (>= grade 3) will be described on a patient-by-patient basis and will include any relevant baseline data.	Up to 4 weeks after completion of study treatment
Response rate as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1	Responses will be tabulated by disease diagnosis and by dose level. 95% confidence limits will also be reported on the response rates.	Up to 4 weeks after completion of study treatment
Incidence of stable disease as assessed by RECIST version 1.1	Incidence of stable disease will be tabulated by disease diagnosis and by dose level.	Up to 4 weeks after completion of study treatment
Time to progression	Displayed for all patients and for patients who have responded; no formal statistical analysis is planned.	Up to 4 weeks after completion of study treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PAR levels	Descriptive statistics (mean, standard deviation, median, range) for measurements of PAR levels will provided with 95% confidence intervals (CIs). When sample size permits, a formal statistical test using the Wilcoxon signed rank test will be used to compare the post treatment PAR levels to the baseline levels. When feasible, the level will be compared between responders and non-responders using the Wilcoxon signed rank test.	Baseline to up to 4 weeks
Change in gamma-H2AX levels	Descriptive statistics (mean, standard deviation, median, range) for measurements of gamma-H2AX levels will provided with 95% CIs. When sample size permits, a formal statistical test using the Wilcoxon signed rank test will be used to compare the post treatment PAR levels to the baseline levels. When feasible, the level will be compared between responders and non-responders using the Wilcoxon signed rank test.	Baseline to up to 4 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: Abbott
• Investigators: Principal Investigator: Hussein A Tawbi, University of Pittsburgh Cancer Institute (UPCI)

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2011
• Primary Completion (Actual): November 10, 2017
• Study Completion (Estimated): March 5, 2025

Study Registration Dates

• First Submitted: June 2, 2011
• First Submitted That Met QC Criteria: June 2, 2011
• First Posted (Estimated): June 3, 2011

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Skin Diseases; Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Endocrine System Diseases; Gonadal Disorders; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Endocrine Gland Neoplasms; Genital Neoplasms, Male; Testicular Diseases; Breast Diseases; Liver Diseases; Esophageal Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Genital Diseases, Female; Neoplasms; Testicular Neoplasms; Breast Neoplasms; Head and Neck Neoplasms; Liver Failure; Carcinoma; Endometrial Neoplasms; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Poly(ADP-ribose) Polymerase Inhibitors; Carboplatin; Paclitaxel; Albumin-Bound Paclitaxel; Veliparib
• Other Study ID Numbers: NCI-2011-02500 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U01CA070095 (U.S. NIH Grant/Contract); UM1CA186691 (U.S. NIH Grant/Contract); UM1CA186716 (U.S. NIH Grant/Contract); U01CA099168 (U.S. NIH Grant/Contract); U01CA062502 (U.S. NIH Grant/Contract); U01CA062505 (U.S. NIH Grant/Contract); U01CA062490 (U.S. NIH Grant/Contract); U01CA069856 (U.S. NIH Grant/Contract); UM1CA186690 (U.S. NIH Grant/Contract); UM1CA186717 (U.S. NIH Grant/Contract); UM1CA186709 (U.S. NIH Grant/Contract); N01CM00100 (U.S. NIH Grant/Contract); P30CA047904 (U.S. NIH Grant/Contract); CDR0000700997; UPCI 10-115; UPCI-10-115; 8808 (Other Identifier: CTEP)