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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01154426
First received: June 29, 2010
Last updated: July 28, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
BRCA1 Mutation Carrier
BRCA2 Mutation Carrier
Unspecified Adult Solid Tumor, Protocol Specific
Drug: gemcitabine hydrochloride
Drug: veliparib
Other: diagnostic laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of ABT-888 in Combination With Gemcitabine in Patients With Advanced Malignancies

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Adverse events as assessed by NCI CTCAE v 4.0 [ Time Frame: Up to 4 weeks after completion of study treatment ] [ Designated as safety issue: Yes ]
    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.

  • Response (complete or partial response) [ Time Frame: Up to 4 weeks after completion of study treatment ] [ Designated as safety issue: No ]
    Responses and incidence of stable disease will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.

  • 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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 31
Study Start Date: May 2010
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar
Drug: veliparib
Given orally
Other Name: ABT-888
Other: diagnostic laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01154426

Locations
United States, Pennsylvania
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania, United States, 17033-0850
Magee-Womens Hospital of UPMC
Pittsburgh, Pennsylvania, United States, 15213
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States, 15232
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
Investigators
Principal Investigator: Ronald Stoller University of Pittsburgh
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01154426     History of Changes
Other Study ID Numbers: NCI-2011-01473, NCI-2011-01473, CDR0000673613, 09-012, 8324, P30CA047904, U01CA099168
Study First Received: June 29, 2010
Last Updated: July 28, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Gemcitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on August 01, 2014