Veliparib, Cisplatin, and Vinorelbine Ditartrate in Treating Patients With Recurrent and/or Metastatic Breast Cancer

Tracking Information
First Submitted Date ICMJE	April 13, 2010
First Posted Date ICMJE	April 15, 2010
Last Update Posted Date	August 10, 2017
Actual Study Start Date ICMJE	July 2010
Actual Primary Completion Date	February 2015 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: January 6, 2014)	MTD of veliparib, defined as the highest dose tested in which fewer than 33% of patients experienced dose-limiting toxicity attributable to the study regimen, when at least 6 patients were treated at that dose and were evaluable for toxicity [ Time Frame: Day 21 ]
Original Primary Outcome Measures ICMJE; (submitted: April 13, 2010)	Dose-limiting toxicity and MTD of ABT-888 in combination with cisplatin and vinorelbine ditartrate [ Time Frame: During period of dose escalation, estimated to be 12 to 18 months ]
Change History	Complete list of historical versions of study NCT01104259 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: May 15, 2014)	Toxicity profile, defined by the incidence of toxicity, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days post-treatment ]; Pharmacokinetic (PK) parameters of veliparib in plasma and urine samples [ Time Frame: Baseline and day 1 of courses 1 and 4 ]The PK parameters determined will be: AUC0-t (the area under the concentration-time curve over a dosing interval), Cmax (maximal concentration), Tmax (time to maximal concentration), Vd (volume of distribution), CL/F (oral clearance for veliparib), CL (clearance for cisplatin), and t1/2 (elimination half-life). To improve understanding of systemic bioavailability, the amount of veliparib excreted in the urine for each collection interval will be calculated by the product of urinary drug concentration and urine volume.; Pharmacokinetic (PK) parameters of cisplatin in plasma samples [ Time Frame: Baseline and day 1 of courses 1 and 4 ]The PK parameters determined will be: AUC0-t, Cmax, Tmax, Vd, CL/F, CL, and t1/2 .; Pharmacodynamic parameters of PARP inhibition [ Time Frame: Baseline and day 1 of courses 1 and 4 ]Assessed by measuring changes in PAR levels in peripheral blood mononuclear cells and in tumor tissue (if available).
Original Secondary Outcome Measures ICMJE; (submitted: April 13, 2010)	Toxicity profile as assessed by NCI CTCAE v3.0 [ Time Frame: During period of dose escalation and expanded safety cohort phases, estimated to be 19 months to 2 years ]; Pharmacokinetics of ABT-888 [ Time Frame: Measured at intervals during dose escalation phase ]; Pharmacodynamic parameters of PARP inhibition will be evaluated by measuring changes in PAR levels in PBMCs and in tumor tissue (if available) [ Time Frame: Measured at intervals during dose escalation and expanded safety cohort phases ]; Progression-free survival (Exploratory) [ Time Frame: Measured at median follow-up of 1year ]; Time to disease progression (Exploratory) [ Time Frame: Measured at median follow-up of 1year ]; Response rate as assessed by RECIST version 1.1 [ Time Frame: Measured for individual patient after every 3 courses and for the group at median follow-up of 1 year ]; Duration of overall response (Exploratory) [ Time Frame: Measured at median follow-up of 1year ]; ECOG performance status [ Time Frame: Measured for individual patient at follow-up visits and for the group at median follow-up of 1 year ]
Current Other Outcome Measures ICMJE; (submitted: May 15, 2014)	Progression-free survival [ Time Frame: The number of days from the date the subject started study drug to the date the subject experiences an event of disease progression, or to the date of death if disease progression is not reached, assessed up to 30 days ]Estimated using Kaplan-Meier methodology and 95% confidence interval.; Time to disease progression [ Time Frame: The number of days from the date the subject started study drug to the date of the subject's disease progression, assessed up to 30 days ]Estimated using Kaplan-Meier methodology and 95% confidence interval.; Proportion of patients achieving a complete response (CR) or partial response (PR) (objective response rate) [ Time Frame: Up to 30 days ]Assessed by Response Evaluation Criteria in Solid Tumors version 1.1 and estimated with 95% confidence interval.; Duration of overall response [ Time Frame: The number of days from the day the criteria are met for CR or PR (whichever is recorded first) to the date that progressive disease is objectively documented, assessed up to 30 days ]Estimated using Kaplan-Meier Methodology.; ECOG performance status [ Time Frame: Up to 30 days ]Descriptive statistics will be summarized for each assessment.
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Veliparib, Cisplatin, and Vinorelbine Ditartrate in Treating Patients With Recurrent and/or Metastatic Breast Cancer
Official Title ICMJE	Phase I Study of ABT-888 in Combination With Cisplatin and Vinorelbine for Patients With Advanced Triple Negative Breast Cancer and/or BRCA-Mutation Associated Breast Cancer
Brief Summary	This phase I trial studies the side effects and best dose of veliparib when given together with cisplatin and vinorelbine ditartrate in treating patients with breast cancer that has returned or spread to other parts of the body. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin and vinorelbine ditartrate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving veliparib together with combination chemotherapy may be a better treatment for breast cancer.
Detailed Description	PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of ABT-888 (veliparib) when administered daily for 14 days out of a 21 day cycle in combination with cisplatin and vinorelbine (vinorelbine ditartrate) in subjects with metastatic triple negative breast cancer (TNBC) and breast cancer (BRCA) mutation associated breast cancer. SECONDARY OBJECTIVES: I. Assess the pharmacokinetic profile of ABT-888 when combined with cisplatin and vinorelbine and the safety/tolerability profile of the combination. II. Evaluate the level of poly ADP ribose polymerase (PARP) inhibition at each dose level to determine whether maximal PARP inhibition is achieved. III. Identify the subgroup of triple negative breast cancer patients who will potentially derive the most benefits from PARP inhibition combined with platinum-based chemotherapy. OUTLINE: This is a dose-escalation study of veliparib. Patients receive veliparib orally (PO) twice daily (BID) on days 1-14 (days 0-13 of course 1 only). Patients also receive cisplatin intravenously (IV) over 1 hour on day 1 and vinorelbine ditartrate IV over 10-20 minutes on days 1 and 8. Treatment repeats every 21 days for 6-10 courses in the absence of disease progression or unacceptable toxicity. Treatment with veliparib alone may continue in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for up to 30 days.
Study Type ICMJE	Interventional
Study Phase	Phase 1
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Hereditary Breast/Ovarian Cancer - BRCA1; Hereditary Breast/Ovarian Cancer - BRCA2; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer
Intervention ICMJE	Drug: veliparib Given PO Other Name: ABT-888; Drug: cisplatin Given IV Other Names: CACP CDDP CPDD DDP; Drug: vinorelbine tartrate Given IV Other Names: Eunades navelbine ditartrate NVB VNB; Other: laboratory biomarker analysis Correlative studies; Other: pharmacological study Correlative studies Other Name: pharmacological studies
Study Arms	Experimental: Treatment (veliparib with cisplatin and vinorelbine tartrate); Patients receive veliparib PO BID on days 1-14 (days 0-13 of course 1 only). Patients also receive cisplatin IV over 1 hour on day 1 and vinorelbine ditartrate IV over 10-20 minutes on days 1 and 8. Treatment repeats every 21 days for 6-10 courses in the absence of disease progression or unacceptable toxicity. Treatment with veliparib alone may continue in the absence of disease progression or unacceptable toxicity.; Interventions: Drug: veliparib; Drug: cisplatin; Drug: vinorelbine tartrate; Other: laboratory biomarker analysis; Other: pharmacological study
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: August 8, 2017)	50
Original Estimated Enrollment ICMJE; (submitted: April 13, 2010)	36
Actual Study Completion Date	April 2017
Actual Primary Completion Date	February 2015 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Recurrent and/or metastatic breast cancer; Subjects must meet at least one of the following two criteria: Histologically confirmed primary or metastatic site that is estrogen receptor (ER)-negative (less than 10%), progesterone receptor (PR)-negative (less than 10%), and human epidermal growth factor receptor (HER)2 non-over expressing by immunohistochemistry (IHC) (0, 1) or non-amplified by fluorescence in situ hybridization (FISH) Confirmed BRCA1 or BRCA2 mutation associated breast cancer; Subjects must have measurable disease, defined as at least one lesion that can be measured in at least one dimension with a minimum size of: longest diameter >= 10 mm (computed tomography [CT] scan slice thickness no greater than 5 mm); 10 mm caliper measurement by clinical exam; to be considered pathologically enlarged and measurable, a lymph node must be >= 15 mm in short axis when assessed by CT scan; Subjects may have had any number of prior chemotherapy, endocrine therapy, immunologic, or biologic regimens for metastatic breast cancer; Performance status >= 60% on the Karnofsky scale (Eastern Cooperative Oncology Group [ECOG] =< 2); Absolute neutrophil count (ANC) >= 1,500/mm^3 (1.5 x 10^9/L); Platelets >= 100,000/mm^3 (100 x 10^9/L); Hemoglobin >= 9.0 g/dL; Serum creatinine =< 1.5 x upper normal limit of institution's normal range OR creatinine clearance >= 50 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal; Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2.5 x the upper normal limit of institution's normal range; for subjects with liver metastases, AST and/or ALT < 5 x the upper normal limit of institution's normal range; Bilirubin =< 1.5 x the upper normal limit of institution's normal range; subjects with Gilbert's syndrome may have a bilirubin > 1.5 x the upper normal limit of institution's normal range; Partial thromboplastin time (PTT) must be =< 1.5 x the upper normal limit of institution's normal range and international normalized ratio (INR) < 1.5; subjects on anticoagulant (such as Coumadin) will have PTT and INR as determined by the investigator; Women of childbearing potential must agree to use adequate contraception (one of the following listed below) prior to study entry, for the duration of study participation and for 90 days following completion of therapy; women of childbearing potential must have a negative serum pregnancy test within 21 days prior to initiation of treatment and/or be confirmed as having postmenopausal status; criteria for determining menopause include any of the following: prior bilateral oophorectomy; age >= 60 years; age < 60 years and amenorrheic for at least 12 months in the absence of chemotherapy, endocrine therapy, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range; Total abstinence from sexual intercourse (minimum one complete menstrual cycle) Vasectomized partner of female subjects Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug administration Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream) Intra-uterine device (IUD); Male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and for 90 days following completion of therapy; Radiation therapy of a non-target lesion must have been completed at least 2 weeks prior to the enrollment date; Subjects with known brain metastases must have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 14 days of stable neurologic function prior to the first dose of study drug; Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, biologic or any investigational therapy within either 28 days or 5 half-lives of a targeted therapy (whichever is shorter), prior to study drug administration; subjects receiving hormone therapy, bisphosphonates, denosumab or luteinizing-hormone-releasing hormone (LHRH)-agonists are eligible; subjects who have not recovered to within one grade level (not to exceed grade 2) of their baseline following a significant adverse event or toxicity attributed to prior anti-cancer treatment are excluded; Subjects with a known hypersensitivity to platinum compounds or vinorelbine; Subjects with baseline peripheral neuropathy that exceeds grade 1; Clinically significant and uncontrolled major medical condition(s) including but not limited to: Active uncontrolled infection Symptomatic congestive heart failure Unstable angina pectoris or cardiac arrhythmia Psychiatric illness/social situation that would limit compliance with study requirements Any medical condition, which in the opinion of the study investigator, places the subject at an unacceptably high risk for toxicities Subjects with significant fluid retention, including ascites or pleural effusion, may be allowed at the discretion of the principal investigator; Subject is pregnant or lactating
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01104259
Other Study ID Numbers ICMJE	7161; NCI-2010-00356 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); P30CA015704 ( U.S. NIH Grant/Contract ); 7161 ( Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	University of Washington
Study Sponsor ICMJE	University of Washington
Collaborators ICMJE	National Cancer Institute (NCI)
Investigators ICMJE	Principal Investigator: Jennifer Specht Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
PRS Account	University of Washington
Verification Date	August 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP