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Ph II Randomized Trial of the Combination of ABT-888 With Metronomic Oral Cyclophosphamide in Refractory BRCA-Pos Ovarian, Primary Peritoneal or Ovarian High-Grade Serous Carcinoma, Fallopian Tube Cancer, Triple-Neg Breast Cancer, and Low-Grade NHL


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Ovarian, Primary Peritoneal, Serous Carcinoma, Triple-Negative Breast, Fallopian Tube

Thank you

Trial Information

Ph II Randomized Trial of the Combination of ABT-888 With Metronomic Oral Cyclophosphamide in Refractory BRCA-Pos Ovarian, Primary Peritoneal or Ovarian High-Grade Serous Carcinoma, Fallopian Tube Cancer, Triple-Neg Breast Cancer, and Low-Grade NHL


Background:

- The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining
genomic stability by regulating a variety of DNA repair mechanisms.

- Individuals with deleterious mutations in the BRCA1 or BRCA2 tumor suppressor genes
have an increased risk of developing breast and ovarian cancers due to impaired or
defective DNA damage repair; these individuals have an increased susceptibility to
DNA-damaging agents and PARP inhibitors. Inhibition of PARP inhibits the repair of DNA
damage caused by alkylating agents such as cyclophosphamide.

- Metronomic cyclophosphamide has demonstrated efficacy in several tumor types. The PARP
inhibitor ABT-888 has been shown to potentiate the action of cyclophosphamide in
xenograft models. This combination is well tolerated in a Phase I study and showing
promising activity.

Objectives:

- Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral
cyclophosphamide to the response rate (CR+PR) of metronomic oral cyclophosphamide in
patients with deleterious BRCA mutations and refractory ovarian cancer or patients with
primary peritoneal or ovarian high-grade serous carcinoma or fallopian tube cancer.

- Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral
cyclophosphamide to the response rate (CR+PR) of single-agent oral cyclophosphamide in
patients with triple-negative metastatic breast cancer, stratified for deleterious BRCA
mutation.

- Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral
cyclophosphamide to the response rate (CR+PR) of single-agent metronomic oral
cyclophosphamide in patients with refractory low-grade lymphomas.

Secondary Objectives:

- Determine PAR levels in tumor biopsies, evaluate in archival tissue whether patients'
tumors have mutations in genes involved in DNA damage repair (e.g., BRCA/Fanconi
anemia/p53), perform exploratory gene expression profiling to correlate PARP mRNA levels or
BRCA mutation status with response to therapy, count CTCs, and determine ??H2AX levels in
CTCs and tumor biopsies (NCI clinical center only).

Eligibility:

-Adults with refractory BRCA-positive ovarian cancer, primary peritoneal or ovarian
high-grade serous carcinoma, fallopian tube cancer, triple-negative breast cancer, or
low-grade lymphoid malignancies (non-Hodgkin's lymphoma) whose disease has progressed
following at least one line of therapy.

Study Design:

- This is a randomized, multi-histology Phase II trial with patients enrolled into 3
cohorts: BRCA-positive ovarian cancer or primary peritoneal or ovarian high-grade
serous carcinoma or fallopian tube cancer (A); triple-negative breast cancer (B); or
low grade non-Hodgkin's lymphoma (C). Patients in cohort A will be randomized to the
combination of ABT-888 with metronomic oral cyclophosphamide or metronomic oral
cyclophosphamide alone. Patients in cohort B will be randomized to the combination of
ABT-888 with metronomic oral cyclophosphamide or metronomic oral cyclophosphamide
alone. Patients in cohort C will be randomized to the combination of ABT-888 with
metronomic oral cyclophosphamide or metronomic oral cyclophosphamide alone.

- Cyclophosphamide (50 mg) and ABT-888 (60 mg) will be administered orally once a day,
continuously in 21-day cycles.

Inclusion Criteria


- INCLUSION CRITERIA:

- Patients with histologically documented:

- BRCA-positive ovarian cancer (documented deleterious BRCA1/2 mutation or a
BRCAPRO score of greater than or equal to 30%)

- primary peritoneal or ovarian high-grade serous carcinoma or fallopian tube
cancer (no requirement for BRCA status)

- triple-negative breast cancer (documented ER negative, PR negative, and Her2/neu
negative from the original pathology report if considered adequate, or per
ASCO/CAP guidelines (47, 48)) with metastasis to distant sites

- Low-grade lymphoid malignancies (NHL), as described below, whose disease has
progressed following at least one line of standard therapy:

- Follicle center lymphoma, follicular or diffuse-recurrent/refractory

- Marginal zone B-cell lymphoma: splenic, nodal, extranodal (this includes
MALT) - recurrent/refractory

- Lymphoplasmacytic lymphoma - recurrent/refractory

- SLL (absolute lymphocytes count below 5,000)

Pathology must be confirmed by the registering institution. For patients who are eligible
for the study due to a history of BRCA1/2 mutation, documented evidence of their mutation
status must be provided prior to enrolling on the study.

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as
greater than or equal to 20 mm with conventional techniques or as greater than or
equal to 10 mm with spiral CT scan.

- Any prior therapy or radiotherapy must have been completed greater than or equal to 4
weeks (greater than 6 weeks for nitrosoureas or mitomycin C) prior to enrollment on
protocol, and the participant must have recovered to eligibility levels from prior
toxicity. Patients must be greater than or equal to 2 weeks since any investigational
agent administered as part of a Phase 0 study, and should have recovered to
eligibility levels from any toxicities.

- Patients who have had prior treatment with any PARP inhibitors are eligible unless
the PARP inhibitor was administered in combination with cyclophosphamide.

- Patients with bone metastases or hypercalcemia on bisphosphonate treatment are
eligible to participate

- 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 less than 18 years of age,
children are excluded from this study, but may be eligible for future pediatric Phase
I combination trials.

- Karnofsky performance status greater than or equal to 70%.

- Life expectancy greater than 3 months.

- Patients must have adequate organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,500/microL (mcL)

- platelets greater than or equal to 100,000/microL (mcL)

- total bilirubin less than 1.5 times institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal

- creatinine less than 1.5 times institutional upper limit of normal

OR

--creatinine clearance greater than or equal to 60 mL/min for patients with creatinine

levels greater than or equal to 1.5 times institutional upper limit of normal.

- The effects of ABT-888 on the developing human fetus are unknown. For this reason and
because cyclophosphamide hydrochloride is known to be teratogenic, women of
childbearing potential and men must agree to use adequate contraception (abstinence;
female use of hormonal methods, or barrier methods of birth control; male use of a
condom) prior to study entry, for the duration of study participation, and for 3
months after completion of study. Because there is a risk for adverse events in
nursing infants secondary to treatment of the mother with cyclophosphamide,
breastfeeding should be discontinued while the patient is on this trial and for 30
days after completion of treatment on this trial. 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:

- Women who are pregnant or breastfeeding.

- Patients with 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.

- Patients with germ cell and borderline ovarian epithelial tumors.

- Patients who have received prior cyclophosphamide should not be excluded solely
because of receiving prior cyclophosphamide.

- Patients with history of CNS metastases who have received treatment and who have been
on stable doses of anti-seizure medicine and had no seizures x 3 months will be
eligible.

- Patients with gastrointestinal conditions that might predispose for drug
intolerability or poor drug absorption (e.g., inability to take oral medication or a
requirement for IV alimentation, prior surgical procedures affecting absorption,
malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with
ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel
obstruction are also excluded, as are any patients who cannot swallow the capsule
whole. Capsules must not be crushed or chewed; nasogastric or G-tube administration
is not allowed.

INCLUSION OF WOMEN AND MINORITIES:

-Men and women of all races and ethnic groups are eligible for this trial.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Compare the CR+PR of ABT-888 with metronomic cyclophosphamide to the CR+PR of metronomic cyclophosphamide in patients with deleterious BRCA mutations/ ovarian cancer or patient's with peritoneal /ovarian high-grade serous cancer or fallopian tub...

Outcome Time Frame:

2 years

Safety Issue:

Yes

Principal Investigator

Shivaani Kummar, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110080

NCT ID:

NCT01306032

Start Date:

January 2011

Completion Date:

October 2013

Related Keywords:

  • Ovarian
  • Primary Peritoneal
  • Serous Carcinoma
  • Triple-Negative Breast
  • Fallopian Tube
  • PARP Inhibitor
  • BRCA Mutations
  • DNA Damage Repair
  • Pharmacodynamics
  • Metronomic Cyclophosphamide
  • Ovarian Cancer
  • Breast Cancer
  • Fallopian Tube Cancer
  • Peritoneal Cancer
  • Breast Neoplasms
  • Carcinoma
  • Lymphoma, Non-Hodgkin
  • Fallopian Tube Neoplasms
  • Cystadenocarcinoma, Serous

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
Memorial Sloan Kettering Cancer CenterNew York, New York  10021
MD Anderson Cancer CenterHouston, Texas  77030-4096
Montefiore Medical CenterBronx, New York  10467-2490
H. Lee Moffitt Cancer Center & Research InstituteTampa, Florida  33612
Ohio State UniversityColumbus, Ohio  43210
University of ChicagoChicago, Illinois  60637
Mayo Clinic, RochesterRochester, Minnesota  55905
University of California, DavisSacramento, California  95818