CClinicalTrials.gg
Sign In
CompletedNCT01306032Updated Apr 26, 2017Results posted

Phase II ABT-888 With Cyclophosphamide

A Phase 2 interventional study of ABT-888 and Cyclophosphamide in Ovarian Cancer, Primary Peritoneal Cancer and Serous Carcinoma Cancer, sponsored by National Cancer Institute (NCI). Completed at 10 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-04-26.

Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
124
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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.
Read the detailed description

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 (complete response (CR) + partial response (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/protein 53 (p53)), perform exploratory gene expression profiling to correlate PARP messenger ribonucleic acid (mRNA) levels or BRCA mutation status with response to therapy, count circulating tumor cells (CTCs), and determine H2AX levels in CTCs and tumor biopsies (National Cancer Institute (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.
02

Conditions studied

  • Ovarian Cancer
  • Primary Peritoneal Cancer
  • Serous Carcinoma Cancer
  • Triple-Negative Breast Cancer
  • Fallopian Tube Cancer

Keywords

  • PARP Inhibitor
  • BRCA Mutations
  • DNA Damage Repair
  • Pharmacodynamics
  • Metronomic Cyclophosphamide
  • Ovarian Cancer
  • Breast Cancer
  • Fallopian Tube Cancer
  • Peritoneal Cancer
03

In context

Carcinoma

6,741 studies on the registry are indexed under Carcinoma; 1,163 are open to participants now.

This study's enrollment of 124 is above the median of 45 across 5,174 interventional studies indexed under Carcinoma.

Browse Carcinoma studies →

Lead sponsor

National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.

Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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.

05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Crossover assignment
Masking
None (open label)
Enrollment
124 participants (actual)

Study arms

  • Experimental
    Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide

    Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.

    Drug: ABT-888 · Drug: Cyclophosphamide

  • Experimental
    Triple-negative Breast Cancer: Cyclophosphamide Alone

    Oral cyclophosphamide 50mg by mouth (PO) for 21 days. Participants in the cyclophosphamide alone arm crossed over to the ABT-888 plus cyclophosphamide arm at time of disease progression.

    Drug: Cyclophosphamide

  • Experimental
    BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide

    Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.

    Drug: ABT-888 · Drug: Cyclophosphamide

  • Experimental
    BRCA- positive Ovarian Cancer: Cyclophosphamide Alone

    Oral cyclophosphamide 50mg by mouth (PO) for 21 days. Participants in the cyclophosphamide alone arm crossed over to the ABT-888 plus cyclophosphamide arm at time of disease progression.

    Drug: Cyclophosphamide

  • Experimental
    Non-Hodgkin's: ABT-888 + Cyclophosphamide

    Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.

    Drug: ABT-888 · Drug: Cyclophosphamide

  • Experimental
    Non-Hodgkin's: Cyclophosphamide Alone

    Oral cyclophosphamide 50mg by mouth (PO) for 21 days. Participants in the cyclophosphamide alone arm crossed over to the ABT-888 plus cyclophosphamide arm at time of disease progression.

    Drug: Cyclophosphamide

Interventions

  • DrugABT-888

    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.

    Also known as: Veliparib

  • DrugCyclophosphamide

    Also known as: Cytoxan

06

What researchers measure

Primary outcomes

  1. Percentage of Participants With an Overall Response Rate

    Complete response (CR) + partial response (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. CR + PR was determined by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm). Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

    Time frame: an average of 126 days for ovarian; 71 days for TNBC; for crossover intervention, pts stayed on study for an avg of 134 days for ovarian; 50 days for TNBC.

  2. Progression Free Survival

    Time to progression for each participant for the initial intervention.

    Time frame: Ovarian cancer patients stayed on study for an average of 126 days and triple-negative breast cancer patients for an average of 71 days.

Secondary outcomes

  1. Number of Participants With Adverse Events

    Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

    Time frame: up to 30 days following the last dose of study drug.

  2. Change in Poly-ADP Ribose (PAR) Concentration Levels From Baseline

    PAR levels (in pg/μg protein) were assessed in peripheral blood mononuclear cells (PBMCs) by immunoassay to assess poly (ADP-ribose) polymerase (PARP) activity. Significant inhibition of PARP activity is associated with 50% or greater reduction in PAR levels.

    Time frame: At baseline (t=0h) and 4h post drug administration (t=4h)

  3. Change in ϓH2AX- Positive Circulating Tumor Cells (CTCs) in Whole Blood

    Number of CTCs (evaluable defined as ≥ 6 CTCs) were measured in whole blood during the course of treatment to determine drug-induced deoxyribonucleic acid damage in tumor cells.

    Time frame: At baseline (t=0h) and 24h post drug administration (t=24h)

  4. Number of Participants With Deleterious Mutations in DNA Repair Genes

    Gene expression profiling was performed in archival tumor tissue for a panel of 211 genes using deoxyribonucleic acid (DNA) array to determine deleterious mutations (i.e. nonsynonymous mutations at coding regions) of genes. Sequences were mapped to human genome reference hg19. Variants were identified with VarScan, annotated with AVIA, and masked to the exonic or exonic:splicing regions of the 211 interrogated DNA repair genes, with nonsynonymous/frameshift/stop-gain/stop-loss variants that have a population frequency of 1% or less in either 1000G (2014_04) or the ExomeSequencingProject (ESP6500si_all) with a minimum variant frequency of 10% and at least 20 reads. Lastly, variants were manually inspected for known platform and mapping errors.

    Time frame: Optional tumor biopsies were performed prior to start of treatment (baseline) and 6 months

07

Results

Posted May 25, 2016

Participant flow

First Intervention
Participant flow — First Intervention
MilestoneTriple-negative Breast Cancer: ABT-888 + CyclophosphamideTriple-negative Breast Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneNon-Hodgkin's: ABT-888 + CyclophosphamideNon-Hodgkin's: Cyclophosphamide Alone
Started2220373822
Completed2118353700
Not completed122122
Withdrew: Adverse event101001
Withdrew: Withdrawal by subject020100
Withdrew: Death001000
Withdrew: Ineligible000001
Withdrew: Progressive disease000020
Disease Progression/Crossover
Participant flow — Disease Progression/Crossover
MilestoneTriple-negative Breast Cancer: ABT-888 + CyclophosphamideTriple-negative Breast Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneNon-Hodgkin's: ABT-888 + CyclophosphamideNon-Hodgkin's: Cyclophosphamide Alone
Started01602900
Completed01402600
Not completed020300
Withdrew: Withdrawal by subject000100
Withdrew: Other/symptomatic progression020200

Outcome measures

PrimaryPercentage of Participants With an Overall Response Rate

Complete response (CR) + partial response (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. CR + PR was determined by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm). Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Time frame:
an average of 126 days for ovarian; 71 days for TNBC; for crossover intervention, pts stayed on study for an avg of 134 days for ovarian; 50 days for TNBC.
Reported as:
Number · percentage of participants
Percentage of Participants With an Overall Response Rate
percentage of participantsTriple-negative Breast Cancer: ABT-888 + CyclophosphamideTriple-negative Breast Cancer: Cyclophosphamide AloneTriple-negative Breast Cancer: CrossoverBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: Crossover
Percentage of Participants With an Overall Response Rate9.55.6011.819.43.4
PrimaryProgression Free Survival

Time to progression for each participant for the initial intervention.

Time frame:
Ovarian cancer patients stayed on study for an average of 126 days and triple-negative breast cancer patients for an average of 71 days.
Reported as:
Median · Cycles of therapy
Progression Free Survival
Cycles of therapyTriple-negative Breast Cancer: ABT-888 + CyclophosphamideTriple-negative Breast Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide Alone
Progression Free Survival3 (1 to 3)2 (1 to 9)3 (1 to 39)3 (1 to 32)
Statistical analysis
  • Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide vs Triple-negative Breast Cancer: Cyclophosphamide Alone · Log Rank · p = 0.034
  • BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide vs BRCA-positive Ovarian Cancer: Cyclophosphamide Alone · Log Rank · p = 0.68
SecondaryNumber of Participants With Adverse Events

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Time frame:
up to 30 days following the last dose of study drug.
Reported as:
Count of participants · Participants
Number of Participants With Adverse Events
ParticipantsBRCA-positive Ovarian Cancer: ABT-888 & CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: CrossoverTriple-negative Breast Cancer: Cyclophosphamide & ABT-888Triple-negative Breast Cancer: Cyclophosphamide AloneTriple-negative Breast Cancer: CrossoverNon-Hodgkin's: ABT-888 & CyclophosphamideNon-Hodgkin's: Cyclophosphamide Alone
Number of Participants With Adverse Events282429144601
SecondaryChange in Poly-ADP Ribose (PAR) Concentration Levels From Baseline

PAR levels (in pg/μg protein) were assessed in peripheral blood mononuclear cells (PBMCs) by immunoassay to assess poly (ADP-ribose) polymerase (PARP) activity. Significant inhibition of PARP activity is associated with 50% or greater reduction in PAR levels.

Time frame:
At baseline (t=0h) and 4h post drug administration (t=4h)
Reported as:
Mean · pg/μg protein
Change in Poly-ADP Ribose (PAR) Concentration Levels From Baseline
pg/μg proteinBRCA-positive Ovarian Cancer: ABT-888 & CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: CrossoverTriple-negative Breast Cancer: Cyclophosphamide & ABT-888Triple-negative Breast Cancer: Cyclophosphamide AloneTriple-negative Breast Cancer: CrossoverNon-Hodgkin's: ABT-888 & CyclophosphamideNon-Hodgkin's: Cyclophosphamide Alone
Change in Poly-ADP Ribose (PAR) Concentration Levels From Baseline-81 (-93 to -48)—-88 (-97 to -68)-74 (-83 to -65)—-85 (-85 to -85)——
SecondaryChange in ϓH2AX- Positive Circulating Tumor Cells (CTCs) in Whole Blood

Number of CTCs (evaluable defined as ≥ 6 CTCs) were measured in whole blood during the course of treatment to determine drug-induced deoxyribonucleic acid damage in tumor cells.

Time frame:
At baseline (t=0h) and 24h post drug administration (t=24h)
Reported as:
Mean · ϓH2AX- Positive CTCs
Change in ϓH2AX- Positive Circulating Tumor Cells (CTCs) in Whole Blood
ϓH2AX- Positive CTCsBRCA-positive Ovarian Cancer: ABT-888 & CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: CrossoverTriple-negative Breast Cancer: Cyclophosphamide & ABT-888Triple-negative Breast Cancer: Cyclophosphamide AloneTriple-negative Breast Cancer: CrossoverNon-Hodgkin's: ABT-888 & CyclophosphamideNon-Hodgkin's: Cyclophosphamide Alone
Change in ϓH2AX- Positive Circulating Tumor Cells (CTCs) in Whole Blood——400 (400 to 400)200 (200 to 200)—9.5 (-38 to 57)——
SecondaryNumber of Participants With Deleterious Mutations in DNA Repair Genes

Gene expression profiling was performed in archival tumor tissue for a panel of 211 genes using deoxyribonucleic acid (DNA) array to determine deleterious mutations (i.e. nonsynonymous mutations at coding regions) of genes. Sequences were mapped to human genome reference hg19. Variants were identified with VarScan, annotated with AVIA, and masked to the exonic or exonic:splicing regions of the 211 interrogated DNA repair genes, with nonsynonymous/frameshift/stop-gain/stop-loss variants that have a population frequency of 1% or less in either 1000G (2014_04) or the ExomeSequencingProject (ESP6500si_all) with a minimum variant frequency of 10% and at least 20 reads. Lastly, variants were manually inspected for known platform and mapping errors.

Time frame:
Optional tumor biopsies were performed prior to start of treatment (baseline) and 6 months
Reported as:
Count of participants · Participants
Number of Participants With Deleterious Mutations in DNA Repair Genes
ParticipantsBRCA-positive Ovarian Cancer: ABT-888 & CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: CrossoverTriple-negative Breast Cancer: Cyclophosphamide & ABT-888Triple-negative Breast Cancer: Cyclophosphamide AloneTriple-negative Breast Cancer: CrossoverNon-Hodgkin's: ABT-888 & CyclophosphamideNon-Hodgkin's: Cyclophosphamide Alone
Number of Participants With Deleterious Mutations in DNA Repair Genes28—27—————

Adverse events

Collected over up to 30 days following the last dose of study drug.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide1/37 (2.7%)3/37 (8.1%)28/37 (75.7%)
BRCA-positive Ovarian Cancer: Cyclophosphamide Alone0/38 (0%)0/38 (0%)24/38 (63.2%)
BRCA-positive Ovarian Cancer: Crossover0/29 (0%)0/29 (0%)29/29 (100%)
Triple-negative Breast Cancer: Cyclophosphamide & ABT-8880/21 (0%)2/21 (9.5%)14/21 (66.7%)
Triple-negative Breast Cancer: Cyclophosphamide Alone0/18 (0%)0/18 (0%)4/18 (22.2%)
Triple-negative Breast Cancer: Crossover0/16 (0%)1/16 (6.3%)6/16 (37.5%)
Non-Hodgkin's: ABT-888 + Cyclophosphamide0/2 (0%)0/2 (0%)0/2 (0%)
Non-Hodgkin's: Cyclophosphamide Alone0/1 (0%)1/1 (100%)1/1 (100%)
Most frequent serious events
Most frequent serious events
EventBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: CrossoverTriple-negative Breast Cancer: Cyclophosphamide & ABT-888Triple-negative Breast Cancer: Cyclophosphamide AloneTriple-negative Breast Cancer: CrossoverNon-Hodgkin's: ABT-888 + CyclophosphamideNon-Hodgkin's: Cyclophosphamide Alone
ThrombocytopeniaInvestigations0/370/380/291/210/180/160/21/1
Weight lossMetabolism and nutrition disorders0/370/380/290/210/181/160/20/1
Sinus tachycardiaCardiac disorders0/370/380/291/210/180/160/20/1
Heart failureCardiac disorders0/370/380/291/210/180/160/20/1
LymphopeniaInvestigations1/370/380/290/210/180/160/20/1
NeutropeniaInvestigations1/370/380/290/210/180/160/20/1
DehydrationGastrointestinal disorders1/370/380/290/210/180/160/20/1
HyponatremiaMetabolism and nutrition disorders1/370/380/290/210/180/160/20/1
Death Not Associated with CTCAE: Death NOSGeneral disorders1/370/380/290/210/180/160/20/1
Most frequent other events
Showing 10 of 34
Most frequent other events
EventBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: CrossoverTriple-negative Breast Cancer: Cyclophosphamide & ABT-888Triple-negative Breast Cancer: Cyclophosphamide AloneTriple-negative Breast Cancer: CrossoverNon-Hodgkin's: ABT-888 + CyclophosphamideNon-Hodgkin's: Cyclophosphamide Alone
NeutropeniaInvestigations7/371/384/291/210/180/160/21/1
LymphopeniaInvestigations23/3716/3818/299/213/183/160/20/1
LeucopeniaInvestigations12/376/388/294/210/180/160/20/1
AnemiaBlood and lymphatic system disorders9/372/389/293/213/182/160/20/1
FatigueGeneral disorders4/373/385/290/212/183/160/20/1
HypophosphatemiaMetabolism and nutrition disorders0/371/380/292/210/180/160/20/1
HyperglycemiaMetabolism and nutrition disorders0/370/380/292/210/180/160/20/1
ThrombocytopeniaInvestigations3/370/382/290/210/180/160/20/1
NauseaGastrointestinal disorders1/371/382/290/210/180/160/20/1
AnorexiaMetabolism and nutrition disorders1/372/380/290/210/181/160/20/1

Baseline characteristics

All enrolled participants.

Age, Categorical
Age, Categorical(Participants)Triple-negative Breast Cancer: ABT-888 + CyclophosphamideTriple-negative Breast Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneNon-Hodgkin's: ABT-888 + CyclophosphamideNon-Hodgkin's: Cyclophosphamide AloneTotal
<=18 years0000000
Between 18 and 65 years201628291296
>=65 years54991028
Age, Continuous
Age, Continuous(years)Triple-negative Breast Cancer: ABT-888 + CyclophosphamideTriple-negative Breast Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneNon-Hodgkin's: ABT-888 + CyclophosphamideNon-Hodgkin's: Cyclophosphamide AloneTotal
Mean55 ± 1053 ± 1357 ± 1058 ± 1070 ± 2456 ± 657 ± 11
Sex: Female, Male
Sex: Female, Male(Participants)Triple-negative Breast Cancer: ABT-888 + CyclophosphamideTriple-negative Breast Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneNon-Hodgkin's: ABT-888 + CyclophosphamideNon-Hodgkin's: Cyclophosphamide AloneTotal
Female2520373812123
Male0000101
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Triple-negative Breast Cancer: ABT-888 + CyclophosphamideTriple-negative Breast Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneNon-Hodgkin's: ABT-888 + CyclophosphamideNon-Hodgkin's: Cyclophosphamide AloneTotal
Hispanic or Latino1211005
Not Hispanic or Latino2217363512113
Unknown or Not Reported2102106
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Triple-negative Breast Cancer: ABT-888 + CyclophosphamideTriple-negative Breast Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneNon-Hodgkin's: ABT-888 + CyclophosphamideNon-Hodgkin's: Cyclophosphamide AloneTotal
American Indian or Alaska Native0000000
Asian2221007
Native Hawaiian or Other Pacific Islander0000000
Black or African American73000010
White1615353722107
More than one race0000000
Unknown or Not Reported0000000
Region of Enrollment
Region of Enrollment(Participants)Triple-negative Breast Cancer: ABT-888 + CyclophosphamideTriple-negative Breast Cancer: Cyclophosphamide AloneBRCA-positive Ovarian Cancer: ABT-888 + CyclophosphamideBRCA-positive Ovarian Cancer: Cyclophosphamide AloneNon-Hodgkin's: ABT-888 + CyclophosphamideNon-Hodgkin's: Cyclophosphamide AloneTotal
United States221723232289
Canada3314150035
08

Study locations

10 sites
  • University of California, Davis
    Davis, California 95616, United States
  • H. Lee Moffitt Cancer Center &amp; Research Institute
    Tampa, Florida 33612, United States
  • University of Chicago
    Chicago, Illinois 60637, United States
  • National Institutes of Health Clinical Center, 9000 Rockville Pike
    Bethesda, Maryland 20892, United States
  • Mayo Clinic, Rochester
    Rochester, Minnesota 55905, United States
  • Montefiore Medical Center
    Bronx, New York 10467, United States
  • Memorial Sloan Kettering Cancer Center
    New York, New York 10021, United States
  • Ohio State University
    Columbus, Ohio 43210-1240, United States
  • MD Anderson Cancer Center
    Houston, Texas 77030-4096, United States
  • Princess Margaret Hospital
    Toronto, Ontario M5G 2M9, Canada
09

References and documents

Publications

  • Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, Bontcheva-Diaz VD, Cox BF, DeWeese TL, Dillehay LE, Ferguson DC, Ghoreishi-Haack NS, Grimm DR, Guan R, Han EK, Holley-Shanks RR, Hristov B, Idler KB, Jarvis K, Johnson EF, Kleinberg LR, Klinghofer V, Lasko LM, Liu X, Marsh KC, McGonigal TP, Meulbroek JA, Olson AM, Palma JP, Rodriguez LE, Shi Y, Stavropoulos JA, Tsurutani AC, Zhu GD, Rosenberg SH, Giranda VL, Frost DJ. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007 May 1;13(9):2728-37. doi: 10.1158/1078-0432.CCR-06-3039. PubMed 17473206 ↗
  • Shiobara M, Miyazaki M, Ito H, Togawa A, Nakajima N, Nomura F, Morinaga N, Noda M. Enhanced polyadenosine diphosphate-ribosylation in cirrhotic liver and carcinoma tissues in patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 2001 Mar;16(3):338-44. doi: 10.1046/j.1440-1746.2001.02378.x. PubMed 11339428 ↗
  • Tomoda T, Kurashige T, Moriki T, Yamamoto H, Fujimoto S, Taniguchi T. Enhanced expression of poly(ADP-ribose) synthetase gene in malignant lymphoma. Am J Hematol. 1991 Aug;37(4):223-7. doi: 10.1002/ajh.2830370402. PubMed 1907096 ↗
  • Kummar S, Oza AM, Fleming GF, Sullivan DM, Gandara DR, Naughton MJ, Villalona-Calero MA, Morgan RJ Jr, Szabo PM, Youn A, Chen AP, Ji J, Allen DE, Lih CJ, Mehaffey MG, Walsh WD, McGregor PM 3rd, Steinberg SM, Williams PM, Kinders RJ, Conley BA, Simon RM, Doroshow JH. Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer. Clin Cancer Res. 2015 Apr 1;21(7):1574-82. doi: 10.1158/1078-0432.CCR-14-2565. Epub 2015 Jan 14. PubMed 25589624 ↗
  • Tattersall A, Ryan N, Wiggans AJ, Rogozinska E, Morrison J. Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Database Syst Rev. 2022 Feb 16;2(2):CD007929. doi: 10.1002/14651858.CD007929.pub4. PubMed 35170751 ↗

Individual participant data

Plan to share: No — Data are being shared with this CT.gov report and two peer-reviewed publications. There is no plan to share individual patient results.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Apr 26, 2017, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01306032
Lead sponsor
National Cancer Institute (NCI)
Responsible party
Alice Chen, M.D. (Principal Investigator, National Institutes of Health Clinical Center (CC)) — Principal investigator
First posted
Mar 1, 2011
Start date
Jan 12, 2011
Primary completion
Dec 31, 2014
Completion
Dec 15, 2016
Results posted
May 25, 2016
Last update
Apr 26, 2017

Study contacts

Alice Chen, M.D.
principal investigator · National Cancer Institute (NCI)

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Mar 2017. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Carcinoma→

Other studies from this sponsor

National Cancer Institute (NCI)

Start the discussion