Phase II ABT-888 With Cyclophosphamide
Condition: Ovarian Cancer; Primary Peritoneal Cancer; Serous Carcinoma Cancer; Triple-Negative Breast Cancer; Fallopian Tube Cancer
MeSH terms: Carcinoma; Breast Neoplasms; Ovarian Neoplasms; Triple Negative Breast Neoplasms; Fallopian Tube Neoplasms; Cystadenocarcinoma, Serous
Intervention: ABT-888; Cyclophosphamide
Intervention description: PARP enzymes are 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.
Intervention MeSH terms: Cyclophosphamide; Veliparib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 124.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PARP Inhibitor; BRCA Mutations; DNA Damage Repair; Pharmacodynamics; Metronomic Cyclophosphamide; Ovarian Cancer; Breast Cancer; Fallopian Tube Cancer; Peritoneal Cancer

Summary:

      Background:

      - The experimental cancer treatment drug ABT-888 (Veliparib) works by preventing
      deoxyribonucleic acid (DNA) repair in tumor cells. Cyclophosphamide is a cancer treatment
      drug that works by causing DNA damage in cells, including cancer cells, resulting in cell
      death. However, because cyclophosphamide has strong and unpleasant side effects, researchers
      are interested in finding drugs that can be given in combination with cyclophosphamide that
      will allow a lower dose of cyclophosphamide to be given with similar effects. The combination
      of ABT-88 and cyclophosphamide may be an effective treatment for some types of cancer, such
      as certain kinds of breast or ovarian cancer and non-Hodgkin's lymphoma that often do not
      respond to standard therapies.

      Objectives:

      - To evaluate the safety and effectiveness of ABT-888 and cyclophosphamide in ovarian and
      breast cancer and in non-Hodgkin's lymphoma that have not responded to standard treatments.

      Eligibility:

      - Individuals at least 18 years of age who have been diagnosed with (1) (Breast cancer 1/2)
      BRCA1/2 ovarian cancer, primary peritoneal or ovarian high-grade carcinoma, or fallopian tube
      cancer; (2) triple-negative breast cancer (not responsive to hormone-related therapy); or (3)
      low grade non-Hodgkin's lymphoma.

      Design:

        -  Participants will be screened with a full medical history and physical examination,
           blood and urine tests, and tumor imaging studies. Participants will be divided into two
           groups with different treatment subgroups.

        -  Group 1: Participants who have BRCA-positive ovarian cancer, primary peritoneal or
           ovarian high-grade serous carcinoma, or fallopian tube cancer

        -  Participants will receive either the combination of ABT-888 and cyclophosphamide, or
           cyclophosphamide alone.

        -  Participants will take the study drug by mouth once a day for 21-day cycles of
           treatment, and will keep a diary to record drug doses and any side effects.

        -  Participants will have clinic visits with blood and urine tests, imaging studies, and
           other examinations on days 1, 2, 7, and 14 of cycle 1, and on the first day of all other
           cycles.

        -  Group 2: Participants who have triple-negative breast cancer or non-Hodgkin's lymphoma

        -  Participants will receive either the combination of ABT-888 and cyclophosphamide, or
           cyclophosphamide alone.

        -  Participants will take the study drug by mouth once a day for 21-day cycles of
           treatment, and will keep a diary to record drug doses and any side effects.

        -  Participants will have clinic visits with blood and urine tests, imaging studies, and
           other examinations on days 1, 2, 7, and 14 of cycle 1, and on the first day of all other
           cycles.

        -  Participants receiving only cyclophosphamide who show signs of disease progression after
           tumor imaging studies can receive the combination of ABT-888 with cyclophosphamide.

        -  Treatment will continue as long as participants tolerate the drugs and the disease does
           not progress.
    

Eligibility 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 estrogen receptor (ER) negative,
                  progesterone receptor (PR) negative, and human epidermal growth factor receptor 2
                  (Her2/neu) negative from the original pathology report if considered adequate, or
                  per The American Society of Clinical Oncology/College of American Pathologists
                  (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
                       mucosa-associated lymphoid tissue (MALT)) - recurrent/refractory

                    -  Lymphoplasmacytic lymphoma - recurrent/refractory

                    -  Small lymphocytic lymphoma (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 computed tomography (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

               -  Aspartate aminotransaminase (AST) serum glutamic oxaloacetic transaminase
                  (SGOT)/alanine aminotransaminase (ALT) serum glutamic pyruvic transaminase (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 central nervous system (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 intravenous (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 gastrostomy tube
             (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.