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Sequential Phase I - Randomized Phase II, Double-Blind, Placebo-Controlled Trial of Cyclophosphamide Alone or in Combination With Veliparib (ABT-888) in ER and/or PR-Positive and HER2/Neu-Negative Metastatic Breast Cancer


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Male Breast Cancer, Progesterone Receptor-positive Breast Cancer, Recurrent Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

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Trial Information

Sequential Phase I - Randomized Phase II, Double-Blind, Placebo-Controlled Trial of Cyclophosphamide Alone or in Combination With Veliparib (ABT-888) in ER and/or PR-Positive and HER2/Neu-Negative Metastatic Breast Cancer


PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of veliparib (ABT-888) that can be combined
with metronomic dose cyclophosphamide in patients with metastatic breast cancer. (Phase I)
II. To determine if the addition of veliparib (ABT-888) to metronomic dose cyclophosphamide
improves median progression free survival (PFS) compared with cyclophosphamide alone in
patients with estrogen receptor (ER) and/or progesterone receptor (PR)-positive, human
epidermal growth factor receptor 2 (Her2)-negative metastatic breast cancer who progressed
on at least two lines of prior chemotherapy and one line of prior endocrine therapy. (Phase
II)

SECONDARY OBJECTIVES:

I. To determine if the addition veliparib (ABT-888) to cyclophosphamide chemotherapy
improves the response rate.

II. To determine if the addition veliparib (ABT-888) to cyclophosphamide chemotherapy
improves the clinical benefit rate (defined as objective response plus stable disease for at
least 24 weeks from day +1) III. To determine the survival in patients treated with
cyclophosphamide alone and cyclophosphamide plus veliparib (ABT-888).

IV. To determine the adverse event profile in patients treated with cyclophosphamide alone
and cyclophosphamide plus veliparib (ABT-888).

TERTIARY OBJECTIVES:

I. To determine whether the macroH2A1.1 and poly (ADP-ribose) polymerase 1 (PARP1)
expression status in archival paraffin embedded tumor specimens from either the primary
tumor or metastatic disease is predictive of clinical benefit with veliparib (ABT-888) plus
cyclophosphamide.

OUTLINE: This is a multicenter study. Patients are stratified according to measurable
disease (yes vs no) and ECOG performance status (0 vs 1 or 2). Patients are randomized to 1
of 2 treatment arms.

ARM I: Patients receive cyclophosphamide orally (PO) once daily (QD) and veliparib PO QD on
days 1-21. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

ARM II: Patients receive placebo PO QD on days 1-21 and cyclophosphamide as in arm I.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients may undergo peripheral blood mononuclear cells sample collection for correlative
studies. Archived tissue from primary tumor or a biopsy sample from metastatic disease may
also be collected.


Inclusion Criteria:



- Phase I: Patients must have histologically confirmed breast cancer (MBC) that is
HER2/neu negative (as determined by local pathology or reference laboratory), and
have disease that is metastatic (stage IV [TxNxM1]) or locally advanced and not
amenable to potentially curative surgical resection (eg, clinical stage IIIB-C) Phase
II: Patients must have histologically confirmed breast cancer (MBC) that is ER
positive and/or PR positive, and HER2/neu negative (as determined by local pathology
or reference laboratory), and have disease that is metastatic (stage IV [TxNxM1]) or
locally advanced and not amenable to potentially curative surgical resection (eg,
clinical stage IIIB-C)

- HER2/neu negative disease (performed on primary tumor and/or metastatic lesion using
commercially available/approved assay in local institutional or reference
laboratory), according to American Society of Clinical Oncology (ASCO)/College of
American Pathologists (CAP) guidelines

- ER/PR expression (by standard immunohistochemical assay) on primary tumor and/or
metastatic lesion known, and classified as ER and/or PR-positive according to
ASCO/CAP guidelines (including 1-9%expression)

- National Comprehensive Cancer Network (NCCN) guidelines recommend for metastatic
breast cancer "…biopsy documentation of first recurrence, if possible, and
determination of hormone receptor status (ER and PR) and HER2 status…."; therefore,
histologic and/or cytologic confirmation of metastatic disease is encouraged whenever
feasible, but not required; in some circumstances, histologic confirmation may not be
feasible (eg, bone metastases not amenable to biopsy and elevated CA27-29 tumor
marker); for patients who have had histologic confirmation of metastatic disease, it
is required that the biopsy confirm that the metastatic tumor is ER and/or PR
positive, and HER2/neu negative; for patients in whom biopsy confirmation of
metastatic disease is not feasible, it is required that the primary tumor be ER
and/or PR-positive and HER2/neu negative

- Measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) or
non-measurable disease, with measurement obtained within 4 weeks of registration

- Phase I: Patients must have received at least one prior chemotherapy regimen for
metastatic disease Phase II: Patients must have received two or more prior
chemotherapy regimens for metastatic disease, which must have included an antitubulin
agent (eg, paclitaxel, docetaxel, vinorelbine, ixabepilone) and capecitabine; there
should be at least a 4 week interval between the last chemotherapy dose and
registration (one week for capecitabine, 2 weeks for weekly paclitaxel in the
presence of disease progression), and the patient should have recovered from acute
toxicity related to prior therapy; no prior treatment with veliparib or other PARP
inhibitors (eg, BSI 201)

- Patients must have had progressive disease after at least one line of endocrine
therapy for metastatic disease (includes relapse while receiving endocrine therapy);
there should be at least 1 week interval between the last endocrine treatment for an
aromatase inhibitor and at least 2 weeks for tamoxifen or fulvestrant

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (Karnofsky >=
60%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin > 9g/dl (per manufacturer recommendation)

- Total bilirubin within normal institutional limits (unless isolated indirect
hyperbilirubinemia due to Gilbert's disease)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 × institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Patients with a history of brain metastases are eligible if they have been treated
with radiation and have stable brain metastases at least 3 months after radiation and
must also be off steroids

- Patients must be able to swallow whole capsules and tolerate oral medications

- 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; being not of childbearing potential is
defined as: (1) prior hysterectomy, or (2) no menstrual period for at least 24 months

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

Exclusion Criteria:

- Patients who have radiotherapy within 3 weeks prior to entering the study or those
who have not recovered from adverse events due to systemic agents administered more
than 3 weeks earlier

- Patients may not be receiving any other investigational agents

- Patients with known brain metastases with active symptoms or requiring anticonvulsive
medications, or steroids should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to veliparib (ABT-888) or cyclophosphamide used in the study

- Evidence of complete or partial bowel obstruction or other unable to take oral
medications

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption

- Patients unable to swallow whole capsules

- 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 (positive pregnancy test) or lactating women will be excluded from the
study; also, unwillingness to use effective means of contraception in subjects with
child-bearing potential will be excluded from the study; women of child-bearing
potential must use two forms of contraception (i.e., barrier contraception and one
other method of contraception) at least 4 weeks prior to study entry, for the
duration of study participation

- Patients with active severe infection; known infection with human immunodeficiency
virus (HIV), hepatitis B virus, hepatitis C virus, or severe concurrent illness will
be excluded from the study; HIV-positive patients on combination antiretroviral
therapy are ineligible

- Patients with a history of seizure disorder requiring antiepileptics who have had a
seizure episode within the last 6 months

- Prior treatment with veliparib (ABT-888) or other PARP inhibitors (e.g., olaparib)

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Recommended phase II dose of veliparib that may be used with metronomic cyclophosphamide

Outcome Description:

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.

Outcome Time Frame:

21 days

Safety Issue:

Yes

Principal Investigator

Eleni Andreopoulou

Investigator Role:

Principal Investigator

Investigator Affiliation:

Montefiore Medical Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02590

NCT ID:

NCT01351909

Start Date:

May 2011

Completion Date:

Related Keywords:

  • Estrogen Receptor-positive Breast Cancer
  • HER2-negative Breast Cancer
  • Male Breast Cancer
  • Progesterone Receptor-positive Breast Cancer
  • Recurrent Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male

Name

Location

Weill Medical College of Cornell UniversityNew York, New York  10021
Maimonides Medical CenterBrooklyn, New York  11219
Mount Sinai Medical CenterNew York, New York  10029
Montefiore Medical CenterBronx, New York  10467-2490
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical CenterColumbus, Ohio  43210-1240
University of ConnecticutFarmington, Connecticut  06032
New York University Langone Medical CenterNew York, New York  10016
Columbia University Medical CenterNew York, New York  10032