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Phase I Study of ABT-888 in Combination With Cisplatin and Vinorelbine for Patients With Advanced Triple Negative Breast Cancer and/or BRCA-Mutation Associated Breast Cancer


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Estrogen Receptor-negative Breast Cancer, Hereditary Breast/Ovarian Cancer - BRCA1, Hereditary Breast/Ovarian Cancer - BRCA2, Male Breast Cancer, Progesterone Receptor-negative Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer, Triple-negative Breast Cancer

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Trial Information

Phase I Study of ABT-888 in Combination With Cisplatin and Vinorelbine for Patients With Advanced Triple Negative Breast Cancer and/or BRCA-Mutation Associated Breast Cancer


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of ABT-888 (veliparib) when administered
daily for 14 days out of a 21 day cycle in combination with cisplatin and vinorelbine
(vinorelbine ditartrate) in subjects with metastatic triple negative breast cancer (TNBC)
and breast cancer (BRCA) mutation associated breast cancer.

SECONDARY OBJECTIVES:

I. Assess the pharmacokinetic profile of ABT-888 when combined with cisplatin and
vinorelbine and the safety/tolerability profile of the combination.

II. Evaluate the level of poly ADP ribose polymerase (PARP) inhibition at each dose level to
determine whether maximal PARP inhibition is achieved.

III. Identify the subgroup of triple negative breast cancer patients who will potentially
derive the most benefits from PARP inhibition combined with platinum-based chemotherapy.

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

Patients receive veliparib orally (PO) twice daily (BID) on days 1-14 (days 0-13 of course 1
only). Patients also receive cisplatin intravenously (IV) over 1 hour on day 1 and
vinorelbine ditartrate IV over 10-20 minutes on days 1 and 8. Treatment repeats every 21
days for 6-10 courses in the absence of disease progression or unacceptable toxicity.
Treatment with veliparib alone may continue in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed for up to 30 days.


Inclusion Criteria:



- Recurrent and/or metastatic breast cancer

- Subjects must meet at least one of the following two criteria:

- Histologically confirmed primary or metastatic site that is estrogen receptor
(ER)-negative (less than 10%), progesterone receptor (PR)-negative (less than
10%), and human epidermal growth factor receptor (HER)2 non-over expressing by
immunohistochemistry (IHC) (0, 1) or non-amplified by fluorescence in situ
hybridization (FISH)

- Confirmed BRCA1 or BRCA2 mutation associated breast cancer

- Subjects must have measurable disease, defined as at least one lesion that can be
measured in at least one dimension with a minimum size of: longest diameter >= 10 mm
(computed tomography [CT] scan slice thickness no greater than 5 mm); 10 mm caliper
measurement by clinical exam; to be considered pathologically enlarged and
measurable, a lymph node must be >= 15mm in short axis when assessed by CT scan

- Subjects may have had any number of prior chemotherapy, endocrine therapy,
immunologic, or biologic regimens for metastatic breast cancer

- Performance status >= 60% on the Karnofsky scale (Eastern Cooperative Oncology Group
[ECOG] =< 2)

- Absolute neutrophil count (ANC) >= 1,500/mm^3 (1.5 x 10^9/L)

- Platelets >= 100,000/mm^3 (100 x 10^9/L)

- Hemoglobin >= 9.0 g/dL

- Serum creatinine =< 1.5 x upper normal limit of institution's normal range OR
creatinine clearance >= 50 mL/min/1.73m^2 for subjects with creatinine levels above
institutional normal

- Hepatic function: Aspartate aminotransferase (AST) and/or alanine aminotransferase
(ALT) =< 2.5 x the upper normal limit of institution's normal range; for subjects
with liver metastases, AST and/or ALT < 5 x the upper normal limit of institution's
normal range

- Bilirubin =< 1.5 x the upper normal limit of institution's normal range; subjects
with Gilbert's Syndrome may have a bilirubin > 1.5 x the upper normal limit of
institution's normal range

- Partial thromboplastin time (PTT) must be =< 1.5 x the upper normal limit of
institution's normal range and International Normalized Ratio (INR) < 1.5; subjects
on anticoagulant (such as coumadin) will have PTT and INR as determined by the
Investigator

- Women of childbearing potential must agree to use adequate contraception (one of the
following listed below) prior to study entry, for the duration of study participation
and for 90 days following completion of therapy; women of childbearing potential must
have a negative serum pregnancy test within 21 days prior to initiation of treatment
and/or be confirmed as having postmenopausal status; criteria for determining
menopause include any of the following: prior bilateral oophorectomy; age >= 60
years; age < 60 years and amenorrheic for at least 12 months in the absence of
chemotherapy, endocrine therapy, or ovarian suppression and follicle-stimulating
hormone (FSH) and estradiol in the postmenopausal range;

- Total abstinence from sexual intercourse (minimum one complete menstrual cycle)

- Vasectomized partner of female subjects

- Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months
prior to study drug administration

- Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring
with spermicidal jellies or cream)

- Intra-Uterine Device (IUD)

- Male subjects (including those who are vasectomized) whose partners are pregnant or
might be pregnant must agree to use condoms for the duration of the study and for 90
days following completions of therapy

- Radiation therapy of a non-target lesion must have been completed at least 2 weeks
prior to the enrollment date

- Subjects with known brain metastases must have clinically controlled neurologic
symptoms, defined as surgical excision and/or radiation therapy followed by 14 days
of stable neurologic function prior to the first dose of study drug

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Subject has received any anti-cancer therapy including chemotherapy, immunotherapy,
biologic or any investigational therapy within either 28 days or 5 half lives of a
targeted therapy (whichever is shorter), prior to study drug administration; subjects
receiving hormone therapy, bisphosphonates, denosumab or
luteinizing-hormone-releasing hormone (LHRH)-agonists are eligible; subjects who have
not recovered to within one grade level (not to exceed Grade 2) of their baseline
following a significant adverse event or toxicity attributed to prior anti-cancer
treatment are excluded

- Subjects with a known hypersensitivity to platinum compounds or vinorelbine

- Subjects with baseline peripheral neuropathy that exceeds Grade 1

- Clinically significant and uncontrolled major medical condition(s) including but not
limited to:

- Active uncontrolled infection

- Symptomatic congestive heart failure

- Unstable angina pectoris or cardiac arrhythmia

- Psychiatric illness/social situation that would limit compliance with study
requirements

- Any medical condition, which in the opinion of the study investigator, places
the subject at an unacceptably high risk for toxicities

- Subject's with significant fluid retention, including ascites or pleural
effusion, may be allowed at the discretion of the Principal Investigator

- Subject is pregnant or lactating

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose-limiting toxicity (DLT) and MTD of veliparib in combination with cisplatin and vinorelbine ditartrate

Outcome Description:

Defined as the highest dose tested in which fewer than 33% of patients experienced DLT attributable to the study regimen, when at least 6 patients were treated at that dose and were evaluable for toxicity.

Outcome Time Frame:

Course 1

Safety Issue:

Yes

Principal Investigator

John Thompson

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Food and Drug Administration

Study ID:

7161

NCT ID:

NCT01104259

Start Date:

July 2010

Completion Date:

Related Keywords:

  • Estrogen Receptor-negative Breast Cancer
  • Hereditary Breast/Ovarian Cancer - BRCA1
  • Hereditary Breast/Ovarian Cancer - BRCA2
  • Male Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Triple-negative Breast Cancer
  • Breast Neoplasms
  • Ovarian Neoplasms
  • Breast Neoplasms, Male

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109