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


Phase 1
18 Years
N/A
Not Enrolling
Both
Neoplasms

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Trial Information

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


Background:

The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining
genomic stability by regulating a variety of DNA repair mechanisms. The
carboplatin/paclitaxel combination has demonstrated a wide spectrum of clinical antitumor
activity, making it an ideal platform for evaluation with novel agents, such as the PARP
inhibitor ABT-888.

Objectives:

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

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.

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

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

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.

To evaluate the pharmacodynamic measurement of PAR and platinum adducts in peripheral blood
mononuclear cells (PBMC) and tumor cells associated with the use of this combination

in patients with varying degrees of renal or hepatic dysfunction.

Eligibility:

Patients must have histologically confirmed malignancy that is 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
(e.g., lung, ovarian, breast, and melanoma).

Patients must have adequate bone marrow function.

Patients with normal organ function, patients with all degrees of renal dysfunction, and
patients with mild to severe hepatic dysfunction are allowed.

Study Design:

ABT-888 (80 mg) will be given orally on day -6 ( 1 day) of cycle 1 in all cohorts. ABT-888
in varying doses will then be given on days 1-7 of each cycle, with the dose depending on
each patient's degree of renal or hepatic dysfunction.

Fixed doses of chemotherapy will be given intravenously on day 3 of each cycle. For patients
with renal dysfunction, carboplatin will be given at AUC of 6 and paclitaxel at 175 mg/m2.
For patients with hepatic dysfunction, carboplatin will be given at AUC of 6 and paclitaxel
at doses adjusted to each patient's degree of hepatic dysfunction.

The dose of ABT-888 will be escalated to determine the MTD of the combination.

Inclusion Criteria


- INCLUSION CRITERIA:

- Patients must have histologically confirmed malignancy that is 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 (e.g., lung, ovarian, breast, melanoma).

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of ABT-888 in patients < 18 years of age, children
are excluded from this study, but may be eligible for future pediatric phase 1
combination trials.

- ECOG performance status less than or equal to 2.

- Life expectancy of greater than 12 weeks.

- Patients must have marrow function as defined below:

absolute neutrophil count greater than or equal to 1,500/mcL

platelets greater than or eqaul to 100,000/mcL

hemoglobin greater than or eqaul to 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 less than or eqaul to 5 times ULN AND AST and ALT less than or eqaul
to10 times 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.

-The effects of ABT-888 on the developing human fetus are unknown. For this reason and
because other therapeutic agents or modalities used in this trial are known to be
teratogenic, 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 brain metastasis should have stable disease for at least 4 weeks
following therapy for brain metastasis (such as surgery, radiotherapy or stereotactic
radiosurgery).

- 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 because ABT-888 is PARP inhibitor with
the potential for teratogenic or abortifacient effects. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of
the mother with ABT-888, 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.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for PK interactions with ABT-888 as well as possible interactions with
paclitaxel. In addition, these patients are at increased risk of lethal infections
when treated with marrow-suppressive therapy. However, HIV-positive patients without
an AIDS-defining diagnosis who are not receiving agents with the potential for 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the pharmacokinetics and pharmacodynamics of ABT-888 in patients with varying degrees of renal or hepatic dysfunction. To determine the MTD of ABT-888 with carboplatin and paclitaxel in these patients.

Authority:

United States: Federal Government

Study ID:

110215

NCT ID:

NCT01419548

Start Date:

July 2011

Completion Date:

November 2011

Related Keywords:

  • Neoplasms
  • ABT-888
  • Liver Dysfunction
  • Kidney Dysfunction
  • PARP Inhibitor
  • Pharmacokinetics
  • Cancer
  • Neoplasms

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
University of Pittsburgh Cancer CenterPittsburgh, Pennsylvania  15232