ABT-888 and Gemcitabine Hydrochloride in Treating Patients With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT01154426
• Recruitment Status: Completed
• First Posted: June 30, 2010
• Last Update Posted: July 2, 2015
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: June 29, 2010
• First Posted Date: June 30, 2010
• Last Update Posted Date: July 2, 2015
• Study Start Date: May 2010
• Actual Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 5, 2013): MTD of ABT-888 and gemcitabine hydrochloride, determined according to incidence of DLT graded using the NCI CTCAE version 4.0 [ Time Frame: 3 weeks ]

Original Primary Outcome Measures (submitted: June 29, 2010)

• Maximum-tolerated dose
• Dose-limiting toxicity

Current Secondary Outcome Measures (submitted: April 9, 2015)

• Adverse events as assessed by NCI CTCAE v 4.0 [ Time Frame: Up to 4 weeks after completion of study treatment ]
  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 and grade. We will describe all DLTs and other serious (≥ grade 3) on a patient-by-patient basis; descriptions will include dose level and any relevant baseline data. Statistics on the number of cycles received by patients and any dose reductions will be tabulated.
• Plasma concentrations of gemcitabine hydrochloride and ABT-888 [ Time Frame: Pre-drug, 25, 60, and 90 min, 2, 3, 4, 6, and 8 hours post-ABT-888 on day -2; pre-drug, 15, 25 (before end of gemcitabine infusion), 60, and 90 min, 2, 3, 4, 6, 8, 24, and 48 h after the start of gemcitabine hydrochloride infusion on day 1 of course 1 ]
  Plasma concentration versus time data will be analyzed non-compartmentally using PK Solutions 2.0. Data may also be analyzed using compartmental methods as implemented by the ADAPT computer program or a suitable commercially available software package. Relationships between pharmacokinetic and pharmacodynamic data will be explored and evaluated using the ADAPT computer program or a suitable commercially available software packages.
• Response (complete or partial response) [ Time Frame: Up to 4 weeks after completion of study treatment ]
  Responses and incidence of stable disease will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.

Original Secondary Outcome Measures (submitted: June 29, 2010)

• Adverse events as assessed by NCI CTCAE v. 4.0
• Response (complete or partial response)
• Pharmacokinetics

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: ABT-888 and Gemcitabine Hydrochloride in Treating Patients With Advanced Solid Tumors
• Official Title: Phase I Study of ABT-888 in Combination With Gemcitabine in Patients With Advanced Malignancies
• Brief Summary: This phase I trial is studying the side effects and best dose of giving ABT-888 together with gemcitabine hydrochloride in treating patients with advanced solid tumors. ABT-888 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving ABT-888 together with gemcitabine hydrochloride may kill more tumor cells.

Detailed Description

PRIMARY OBJECTIVES:

I. Establish the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the combination of ABT-888 and gemcitabine (gemcitabine hydrochloride) in patients with advanced solid tumors.

SECONDARY OBJECTIVES:

I. Establish the safety and tolerability of the combination of ABT-888 and gemcitabine in patients with solid tumors.

II. Determine the effects of ABT-888 and gemcitabine treatment on DNA damage response by analysis of markers such as Ataxia telangiectasia mutated (ATM) in peripheral blood mononuclear cells (PBMCs).

III. Determine the pharmacokinetics of ABT-888 and gemcitabine when administered in combination.

IV. Determine the generation of gemcitabine triphosphate in PBMCs. V. Document any evidence of antitumor response.

OUTLINE: This is a dose-escalation study.

Patients receive oral ABT-888 twice daily on days 1-14 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 21* days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up for at least 4 weeks.

NOTE: *Patients previously enrolled on a 4-week schedule (ABT-888 twice daily on days 1-21 with gemcitabine IV over 30 minutes once weekly on days 1, 8, and 15, and courses repeating every 28 days) will continue on the 4-week schedule.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Adult Solid Neoplasm
• BRCA1 Mutation Carrier
• BRCA2 Mutation Carrier

Intervention

• Other: Diagnostic Laboratory Biomarker Analysis
  Correlative studies
• Drug: Gemcitabine Hydrochloride
  Given IV
  Other Names:

  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemzar
  • LY-188011
• Other: Pharmacological Study
  Correlative studies
• Drug: Veliparib
  Given orally
  Other Names:

  • ABT-888
  • PARP-1 inhibitor ABT-888

Study Arms

Experimental: Treatment (gemcitabine hydrochloride and ABT-888)

Patients receive oral ABT-888 twice daily on days 1-14 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 21* days in the absence of disease progression or unacceptable toxicity.

Interventions:

• Other: Diagnostic Laboratory Biomarker Analysis
• Drug: Gemcitabine Hydrochloride
• Other: Pharmacological Study
• Drug: Veliparib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 18, 2014): 31
• Original Estimated Enrollment (submitted: June 29, 2010): 84
• Actual Study Completion Date: October 2013
• Actual Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed solid tumors meeting 1 of the following criteria:

  • Progressive disease following standard therapy
  • Disease for which acceptable standard treatment options do not exist
• May have received 0-2 prior chemotherapeutic regimens (single-agent or combination chemotherapies)

• Willing to undergo BRCA mutation analysis

  • Known BRCA mutations allowed
  • All patients, at any dose level, without a known BRCA mutation undergo screening with the BRCAPRO program to assess the likelihood of having a BRCA mutation

  • Patients with a BRCAPRO likelihood of gene mutation of ≥ 20% must undergo BRCA gene testing by the Myriad Genetic Laboratories in order to participate in the study

    • Patients are eligible whether they have a known deleterious BRCA 1 or 2 mutation or a mutation of uncertain significance
• No CNS disease (e.g., brain metastases or glioma)
• No active seizure or history of seizure disorder
• ECOG performance status 0-2 (Karnofsky 60-100%)
• Life expectancy > 3 months
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Bilirubin < 2.0 mg/dL
• AST and ALT < 3 times upper limit of normal
• Creatinine normal OR creatinine clearance > 50 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to swallow pills
• HIV-positive patients allowed provided that CD4 counts are < 500 and not on protease inhibitors
• No uncontrolled diarrhea

• No uncontrolled intercurrent illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situations that would limit compliance with study requirements
• No other concurrent anticancer therapies or agents
• More than 4 weeks since prior major surgery, radiotherapy, or chemotherapy (6 weeks for mitomycin C or nitrosoureas) and recovered

• Prior gemcitabine hydrochloride or PARP inhibition therapy, including ABT-888, allowed

  • No prior combination of gemcitabine hydrochloride and any PARP inhibitor
• Concurrent bisphosphonate IV allowed provided treatment was initiated before study therapy (for patients with bone metastases or hypercalcemia)
• Patients with prostate cancer must continue luteinizing-hormone releasing-hormone agonist therapy and discontinue antiandrogens (≥ 6 weeks since bicalutamide and ≥ 4 weeks since flutamide)
• No other concurrent investigational agents

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01154426
• Other Study ID Numbers: NCI-2011-01473; NCI-2011-01473 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000673613; 09-012 ( Other Identifier: University of Pittsburgh Cancer Institute (UPCI) ); 8324 ( Other Identifier: CTEP ); P30CA047904 ( U.S. NIH Grant/Contract ); U01CA099168 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ronald Stoller; University of Pittsburgh Cancer Institute (UPCI)

• PRS Account: National Cancer Institute (NCI)
• Verification Date: December 2014