Phase II ABT-888 With Cyclophosphamide

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01306032
• Collaborator: (none)
• Enrollment: 124
• Locations: 10
• Arms: 6
• Actual Duration (Months): 71.1
• Patients Per Site: 12.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer; Primary Peritoneal Cancer; Serous Carcinoma Cancer; Triple-Negative Breast Cancer; Fallopian Tube Cancer	Drug: ABT-888; Drug: Cyclophosphamide	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Randomized Trial of ABT-888 in Combination With Metronomic Oral Cyclophosphamide in Refractory BRCA-Positive Ovarian, Primary Peritoneal, Ovarian High-Grade Serous Carcinoma, Fallopian Tube Cancer, or Triple-Negative Breast Cancer
• Actual Study Start Date: Jan 12, 2011
• Actual Primary Completion Date: Dec 31, 2014
• Actual Study Completion Date: Dec 15, 2016

Arms and Interventions

Arm	Intervention/Treatment
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; 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.; Other Names: Veliparib ; Drug: Cyclophosphamide; Other Names: Cytoxan
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; Other Names: Cytoxan
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; 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.; Other Names: Veliparib ; Drug: Cyclophosphamide; Other Names: Cytoxan
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; Other Names: Cytoxan
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; 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.; Other Names: Veliparib ; Drug: Cyclophosphamide; Other Names: Cytoxan
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; Other Names: Cytoxan

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With an Overall Response Rate [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.]

   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.

2. Progression Free Survival [Ovarian cancer patients stayed on study for an average of 126 days and triple-negative breast cancer patients for an average of 71 days.]

   Time to progression for each participant for the initial intervention.

Secondary Outcome Measures

1. Number of Participants With Adverse Events [up to 30 days following the last dose of study drug.]

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

2. Change in Poly-ADP Ribose (PAR) Concentration Levels From Baseline [At baseline (t=0h) and 4h post drug administration (t=4h)]

   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.

3. Change in ϓH2AX- Positive Circulating Tumor Cells (CTCs) in Whole Blood [At baseline (t=0h) and 24h post drug administration (t=24h)]

   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.

4. Number of Participants With Deleterious Mutations in DNA Repair Genes [Optional tumor biopsies were performed prior to start of treatment (baseline) and 6 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Davis	Davis	California	United States	95616
2	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612
3	University of Chicago	Chicago	Illinois	United States	60637
4	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892
5	Mayo Clinic, Rochester	Rochester	Minnesota	United States	55905
6	Montefiore Medical Center	Bronx	New York	United States	10467
7	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10021
8	Ohio State University	Columbus	Ohio	United States	43210-1240
9	MD Anderson Cancer Center	Houston	Texas	United States	77030-4096
10	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Alice Chen, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

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.
• 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.
• 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.

• Responsible Party: Alice Chen, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT01306032
• Other Study ID Numbers: 110080; 11-C-0080
• First Posted: Mar 1, 2011
• Last Update Posted: Apr 26, 2017
• Last Verified: Mar 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Alice Chen, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC): PARP Inhibitor; BRCA Mutations; DNA Damage Repair; Pharmacodynamics; Metronomic Cyclophosphamide; Ovarian Cancer; Breast Cancer; Fallopian Tube Cancer; Peritoneal Cancer
• Additional relevant MeSH terms: Carcinoma; Breast Neoplasms; Ovarian Neoplasms; Triple Negative Breast Neoplasms; Fallopian Tube Neoplasms; Cystadenocarcinoma, Serous; Cyclophosphamide; Veliparib

Study Results

Participant Flow

Pre-assignment Detail	Triple-negative breast cancer participants were enrolled but three did not start the study (two withdrew, 1 progressed).

Arm/Group Title	Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide	Triple-negative Breast Cancer: Cyclophosphamide Alone	BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide	BRCA-positive Ovarian Cancer: Cyclophosphamide Alone	Non-Hodgkin's: ABT-888 + Cyclophosphamide	Non-Hodgkin's: Cyclophosphamide Alone
Arm/Group Description	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	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.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	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.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	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.
Period Title: First Intervention
STARTED	22	20	37	38	2	2
COMPLETED	21	18	35	37	0	0
NOT COMPLETED	1	2	2	1	2	2
Period Title: First Intervention
STARTED	0	16	0	29	0	0
COMPLETED	0	14	0	26	0	0
NOT COMPLETED	0	2	0	3	0	0

Baseline Characteristics

Arm/Group Title	Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide	Triple-negative Breast Cancer: Cyclophosphamide Alone	BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide	BRCA-positive Ovarian Cancer: Cyclophosphamide Alone	Non-Hodgkin's: ABT-888 + Cyclophosphamide	Non-Hodgkin's: Cyclophosphamide Alone	Total
Arm/Group Description	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO).	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO).	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO).	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Total of all reporting groups
Overall Participants	25	20	37	38	2	2	124
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	20 80%	16 80%	28 75.7%	29 76.3%	1 50%	2 100%	96 77.4%
>=65 years	5 20%	4 20%	9 24.3%	9 23.7%	1 50%	0 0%	28 22.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55 (10)	53 (13)	57 (10)	58 (10)	70 (24)	56 (6)	57 (11)
Sex: Female, Male (Count of Participants)
Female	25 100%	20 100%	37 100%	38 100%	1 50%	2 100%	123 99.2%
Male	0 0%	0 0%	0 0%	0 0%	1 50%	0 0%	1 0.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4%	2 10%	1 2.7%	1 2.6%	0 0%	0 0%	5 4%
Not Hispanic or Latino	22 88%	17 85%	36 97.3%	35 92.1%	1 50%	2 100%	113 91.1%
Unknown or Not Reported	2 8%	1 5%	0 0%	2 5.3%	1 50%	0 0%	6 4.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	2 8%	2 10%	2 5.4%	1 2.6%	0 0%	0 0%	7 5.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	7 28%	3 15%	0 0%	0 0%	0 0%	0 0%	10 8.1%
White	16 64%	15 75%	35 94.6%	37 97.4%	2 100%	2 100%	107 86.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	22 88%	17 85%	23 62.2%	23 60.5%	2 100%	2 100%	89 71.8%
Canada	3 12%	3 15%	14 37.8%	15 39.5%	0 0%	0 0%	35 28.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With an Overall Response Rate
Description	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.

Outcome Measure Data

Analysis Population Description

Participants evaluable for response.

Arm/Group Title	Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide	Triple-negative Breast Cancer: Cyclophosphamide Alone	Triple-negative Breast Cancer: Crossover	BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide	BRCA-positive Ovarian Cancer: Cyclophosphamide Alone	BRCA-positive Ovarian Cancer: Crossover
Arm/Group Description	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.
Measure Participants	21	18	16	34	36	29
Number [percentage of participants]	9.5 38%	5.6 28%	0 0%	11.8 31.1%	19.4 970%	3.4 170%

2. Primary Outcome

Title	Progression Free Survival
Description	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.

Outcome Measure Data

Analysis Population Description

Participants evaluable for response.

Arm/Group Title	Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide	Triple-negative Breast Cancer: Cyclophosphamide Alone	BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide	BRCA-positive Ovarian Cancer: Cyclophosphamide Alone
Arm/Group Description	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.
Measure Participants	21	18	34	36
Median (Full Range) [Cycles of therapy]	3	2	3	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide, Triple-negative Breast Cancer: Cyclophosphamide Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Triple-negative Breast Cancer: Crossover, BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.68
	Comments
	Method	Log Rank
	Comments

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BRCA-positive Ovarian Cancer: ABT-888 & Cyclophosphamide	BRCA-positive Ovarian Cancer: Cyclophosphamide Alone	BRCA-positive Ovarian Cancer: Crossover	Triple-negative Breast Cancer: Cyclophosphamide & ABT-888	Triple-negative Breast Cancer: Cyclophosphamide Alone	Triple-negative Breast Cancer: Crossover	Non-Hodgkin's: ABT-888 & Cyclophosphamide	Non-Hodgkin's: Cyclophosphamide Alone
Arm/Group Description	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.
Measure Participants	37	38	29	21	18	16	2	1
Count of Participants [Participants]	28 112%	24 120%	29 78.4%	14 36.8%	4 200%	6 300%	0 0%	1 NaN

4. Secondary Outcome

Title	Change in Poly-ADP Ribose (PAR) Concentration Levels From Baseline
Description	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)

Outcome Measure Data

Analysis Population Description

Patients with PBMCs data pre- and post-drug administration, and with PAR levels above the lower limit of quantitation (LLOQ) of 23 pg/μg protein were analyzed.

Arm/Group Title	BRCA-positive Ovarian Cancer: ABT-888 & Cyclophosphamide	BRCA-positive Ovarian Cancer: Cyclophosphamide Alone	BRCA-positive Ovarian Cancer: Crossover	Triple-negative Breast Cancer: Cyclophosphamide & ABT-888	Triple-negative Breast Cancer: Cyclophosphamide Alone	Triple-negative Breast Cancer: Crossover	Non-Hodgkin's: ABT-888 & Cyclophosphamide	Non-Hodgkin's: Cyclophosphamide Alone
Arm/Group Description	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.
Measure Participants	10	0	11	4	0	2	0	0
Mean (Full Range) [pg/μg protein]	-81	-88	-74	-85

5. Secondary Outcome

Title	Change in ϓH2AX- Positive Circulating Tumor Cells (CTCs) in Whole Blood
Description	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)

Outcome Measure Data

Analysis Population Description

Patients with sufficient CTC counts (defined as ≥6 total CTCs) pre- and post-drug administration were analyzed.

Arm/Group Title	BRCA-positive Ovarian Cancer: ABT-888 & Cyclophosphamide	BRCA-positive Ovarian Cancer: Cyclophosphamide Alone	BRCA-positive Ovarian Cancer: Crossover	Triple-negative Breast Cancer: Cyclophosphamide & ABT-888	Triple-negative Breast Cancer: Cyclophosphamide Alone	Triple-negative Breast Cancer: Crossover	Non-Hodgkin's: ABT-888 & Cyclophosphamide	Non-Hodgkin's: Cyclophosphamide Alone
Arm/Group Description	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.
Measure Participants	0	0	1	1	0	2	0	0
Mean (Full Range) [ϓH2AX- Positive CTCs]	400	200	9.5

6. Secondary Outcome

Title	Number of Participants With Deleterious Mutations in DNA Repair Genes
Description	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

Outcome Measure Data

Analysis Population Description

Patients with sufficient tumor content in archival tissue (defined as ≥70% tumor after macrodissection) were analyzed for genetic alterations in DNA repair genes by whole-exome sequencing.

Arm/Group Title	BRCA-positive Ovarian Cancer: ABT-888 & Cyclophosphamide	BRCA-positive Ovarian Cancer: Cyclophosphamide Alone	BRCA-positive Ovarian Cancer: Crossover	Triple-negative Breast Cancer: Cyclophosphamide & ABT-888	Triple-negative Breast Cancer: Cyclophosphamide Alone	Triple-negative Breast Cancer: Crossover	Non-Hodgkin's: ABT-888 & Cyclophosphamide	Non-Hodgkin's: Cyclophosphamide Alone
Arm/Group Description	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.	Oral cyclophosphamide 50mg by mouth (PO) for 21 days.
Measure Participants	28	0	27	0	0	0	0	0
Count of Participants [Participants]	28 112%	27 135%

Adverse Events

Time Frame	up to 30 days following the last dose of study drug.
Adverse Event Reporting Description	Adverse events were categorized by treatment (initial vs. crossover treatment arms) rather than indication as this was how we analyzed the data.
Arm/Group Title	BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide		BRCA-positive Ovarian Cancer: Cyclophosphamide Alone		BRCA-positive Ovarian Cancer: Crossover		Triple-negative Breast Cancer: Cyclophosphamide & ABT-888		Triple-negative Breast Cancer: Cyclophosphamide Alone		Triple-negative Breast Cancer: Crossover		Non-Hodgkin's: ABT-888 + Cyclophosphamide		Non-Hodgkin's: Cyclophosphamide Alone
Arm/Group Description	Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.		Oral cyclophosphamide 50mg by mouth (PO) for 21 days.		Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.		Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.		Oral cyclophosphamide 50mg by mouth (PO) for 21 days.		Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.		Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.		Oral cyclophosphamide 50mg by mouth (PO) for 21 days.
All Cause Mortality
	BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide		BRCA-positive Ovarian Cancer: Cyclophosphamide Alone		BRCA-positive Ovarian Cancer: Crossover		Triple-negative Breast Cancer: Cyclophosphamide & ABT-888		Triple-negative Breast Cancer: Cyclophosphamide Alone		Triple-negative Breast Cancer: Crossover		Non-Hodgkin's: ABT-888 + Cyclophosphamide		Non-Hodgkin's: Cyclophosphamide Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/37 (2.7%)		0/38 (0%)		0/29 (0%)		0/21 (0%)		0/18 (0%)		0/16 (0%)		0/2 (0%)		0/1 (0%)
Serious Adverse Events
	BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide		BRCA-positive Ovarian Cancer: Cyclophosphamide Alone		BRCA-positive Ovarian Cancer: Crossover		Triple-negative Breast Cancer: Cyclophosphamide & ABT-888		Triple-negative Breast Cancer: Cyclophosphamide Alone		Triple-negative Breast Cancer: Crossover		Non-Hodgkin's: ABT-888 + Cyclophosphamide		Non-Hodgkin's: Cyclophosphamide Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/37 (8.1%)		0/38 (0%)		0/29 (0%)		2/21 (9.5%)		0/18 (0%)		1/16 (6.3%)		0/2 (0%)		1/1 (100%)
Cardiac disorders
Sinus tachycardia	0/37 (0%)	0	0/38 (0%)	0	0/29 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/16 (0%)	0	0/2 (0%)	0	0/1 (0%)	0
Heart failure	0/37 (0%)	0	0/38 (0%)	0	0/29 (0%)	0	1/21 (4.8%)	1	0/18 (0%)	0	0/16 (0%)	0	0/2 (0%)	0	0/1 (0%)	0
Gastrointestinal disorders
Dehydration	1/37 (2.7%)	1	0/38 (0%)	0	0/29 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/16 (0%)	0	0/2 (0%)	0	0/1 (0%)	0
General disorders
Death Not Associated with CTCAE: Death NOS	1/37 (2.7%)	1	0/38 (0%)	0	0/29 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/16 (0%)	0	0/2 (0%)	0	0/1 (0%)	0
Investigations
Lymphopenia	1/37 (2.7%)	1	0/38 (0%)	0	0/29 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/16 (0%)	0	0/2 (0%)	0	0/1 (0%)	0
Neutropenia	1/37 (2.7%)	1	0/38 (0%)	0	0/29 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/16 (0%)	0	0/2 (0%)	0	0/1 (0%)	0
Thrombocytopenia	0/37 (0%)	0	0/38 (0%)	0	0/29 (0%)	0	1/21 (4.8%)	2	0/18 (0%)	0	0/16 (0%)	0	0/2 (0%)	0	1/1 (100%)	1
Metabolism and nutrition disorders
Hyponatremia	1/37 (2.7%)	1	0/38 (0%)	0	0/29 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	0/16 (0%)	0	0/2 (0%)	0	0/1 (0%)	0
Weight loss	0/37 (0%)	0	0/38 (0%)	0	0/29 (0%)	0	0/21 (0%)	0	0/18 (0%)	0	1/16 (6.3%)	2	0/2 (0%)	0	0/1 (0%)	0
Other (Not Including Serious) Adverse Events
	BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide		BRCA-positive Ovarian Cancer: Cyclophosphamide Alone		BRCA-positive Ovarian Cancer: Crossover		Triple-negative Breast Cancer: Cyclophosphamide & ABT-888		Triple-negative Breast Cancer: Cyclophosphamide Alone		Triple-negative Breast Cancer: Crossover		Non-Hodgkin's: ABT-888 + Cyclophosphamide		Non-Hodgkin's: Cyclophosphamide Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/37 (75.7%)		24/38 (63.2%)		29/29 (100%)		14/21 (66.7%)		4/18 (22.2%)		6/16 (37.5%)		0/2 (0%)		1/1 (100%)
Blood and lymphatic system disorders
Anemia	9/37 (24.3%)	16	2/38 (5.3%)	6	9/29 (31%)	9	3/21 (14.3%)	3	3/18 (16.7%)	5	2/16 (12.5%)	4	0/2 (0%)	4	0/1 (0%)	4
Cardiac disorders
Sinus tachycardia	0/37 (0%)		0/38 (0%)		0/29 (0%)		1/21 (4.8%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Heart failure	0/37 (0%)		0/38 (0%)		0/29 (0%)		0/21 (0%)		0/18 (0%)		0/16 (0%)		0/2 (0%)		0/1 (0%)
Gastrointestinal disorders
Abdominal pain	1/37 (2.7%)	1	1/38 (2.6%)	1	0/29 (0%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Nausea	1/37 (2.7%)	1	1/38 (2.6%)	2	2/29 (6.9%)	2	0/21 (0%)	2	0/18 (0%)	2	0/16 (0%)	2	0/2 (0%)	2	0/1 (0%)	2
Oral mucositis	0/37 (0%)		1/38 (2.6%)	1	0/29 (0%)	1	0/21 (0%)	1	1/18 (5.6%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Bloating	1/37 (2.7%)	1	0/38 (0%)	1	0/29 (0%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Vomiting	1/37 (2.7%)	1	0/38 (0%)	1	1/29 (3.4%)	1	0/21 (0%)	1	0/18 (0%)	1	1/16 (6.3%)	1	0/2 (0%)	1	0/1 (0%)	1
Weight loss	0/37 (0%)		0/38 (0%)		0/29 (0%)		0/21 (0%)		0/18 (0%)		1/16 (6.3%)	2	0/2 (0%)	2	0/1 (0%)	2
Diarrhea	1/37 (2.7%)	2	0/38 (0%)	2	0/29 (0%)	2	0/21 (0%)	2	0/18 (0%)	2	0/16 (0%)	2	0/2 (0%)	2	0/1 (0%)	2
General disorders
Fatigue	4/37 (10.8%)	4	3/38 (7.9%)	3	5/29 (17.2%)	5	0/21 (0%)	5	2/18 (11.1%)	2	3/16 (18.8%)	3	0/2 (0%)	3	0/1 (0%)	3
Infections and infestations
Pelvic infection	0/37 (0%)		1/38 (2.6%)	1	0/29 (0%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Tooth infection	1/37 (2.7%)	1	0/38 (0%)	1	0/29 (0%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Urinary tract infection	0/37 (0%)		0/38 (0%)		1/29 (3.4%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Investigations
Leucopenia	12/37 (32.4%)	27	6/38 (15.8%)	14	8/29 (27.6%)	9	4/21 (19%)	8	0/18 (0%)	8	0/16 (0%)	8	0/2 (0%)	8	0/1 (0%)	8
Neutropenia	7/37 (18.9%)	22	1/38 (2.6%)	2	4/29 (13.8%)	4	1/21 (4.8%)	6	0/18 (0%)	6	0/16 (0%)	6	0/2 (0%)	6	1/1 (100%)	1
Lymphopenia	23/37 (62.2%)	62	16/38 (42.1%)	33	18/29 (62.1%)	36	9/21 (42.9%)	21	3/18 (16.7%)	3	3/16 (18.8%)	4	0/2 (0%)	4	0/1 (0%)	4
AST increased	0/37 (0%)		0/38 (0%)		0/29 (0%)		1/21 (4.8%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
PTT prolonged	0/37 (0%)		0/38 (0%)		0/29 (0%)		1/21 (4.8%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
ALP increased	0/37 (0%)		0/38 (0%)		0/29 (0%)		1/21 (4.8%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Thrombocytopenia	3/37 (8.1%)	5	0/38 (0%)	5	2/29 (6.9%)	2	0/21 (0%)	2	0/18 (0%)	2	0/16 (0%)	2	0/2 (0%)	2	0/1 (0%)	2
Metabolism and nutrition disorders
Anorexia	1/37 (2.7%)	1	2/38 (5.3%)	2	0/29 (0%)	2	0/21 (0%)	2	0/18 (0%)	2	1/16 (6.3%)	2	0/2 (0%)	2	0/1 (0%)	2
Hypophosphatemia	0/37 (0%)		1/38 (2.6%)	1	0/29 (0%)	1	2/21 (9.5%)	2	0/18 (0%)	2	0/16 (0%)	2	0/2 (0%)	2	0/1 (0%)	2
Hyperchloremia	1/37 (2.7%)	1	0/38 (0%)	1	0/29 (0%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Hyponatremia	0/37 (0%)		0/38 (0%)		0/29 (0%)		1/21 (4.8%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Hypoalbuminemia	1/37 (2.7%)	1	0/38 (0%)	1	0/29 (0%)	1	1/21 (4.8%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
ALT increased	0/37 (0%)		0/38 (0%)		1/29 (3.4%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Hyperglycemia	0/37 (0%)		0/38 (0%)		0/29 (0%)		2/21 (9.5%)	2	0/18 (0%)	2	0/16 (0%)	2	0/2 (0%)	2	0/1 (0%)	2
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	0/37 (0%)		0/38 (0%)		1/29 (3.4%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Psychiatric disorders
Psychiatric disorders, other (tearfulness)	0/37 (0%)		0/38 (0%)		1/29 (3.4%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Renal and urinary disorders
Hematuria	0/37 (0%)		1/38 (2.6%)	1	0/29 (0%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/37 (0%)		0/38 (0%)		0/29 (0%)		1/21 (4.8%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Vascular disorders
Hot flashes	0/37 (0%)		1/38 (2.6%)	1	0/29 (0%)	1	0/21 (0%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1
Thromboembolic event	0/37 (0%)		0/38 (0%)		0/29 (0%)		1/21 (4.8%)	1	0/18 (0%)	1	0/16 (0%)	1	0/2 (0%)	1	0/1 (0%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.