Trial Outcomes & Findings for Phase I-II Study of Vorinostat, Paclitaxel, and Bevacizumab in Metastatic Breast Cancer (NCT NCT00368875)

Results Overview

Dose-limiting toxcities (DLT) were defined as grade 3-4 febrile neutropenia, thrombocytopenia and non-hemtological toxicity attributed to therapy (nausea, vomiting and diarrhea would be considered dose limiting only if not adequately controlled with therapy). Any toxicity occurring during cycle 1 that resulted in dose reduction of vorinostat or paclitaxel or failure to complete all protocol specificed doses in the first cycle was also considered a DLT

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

54 participants

Primary outcome timeframe

28 days

Results posted on

2015-11-05

Participant Flow

Between July 2006 and December 2009 a total of 54 patients were registered on the study.

Participant milestones

Participant milestones
Measure	Phase I Vorinostat dose (200 or 300 mg BID) was assigned at the time of registration. Vorinostat was administered orally twice daily on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose. Vorinostat dose escalation was carried out in the standard 3 + 3 phase I trial design based upon toxicity observed during the first cycle of therapy.	Phase II Vorinostat was administered orally twice daily at the recommended phase II dose of 300 mg on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose.
Overall Study STARTED	6	48
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	6	48

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I Vorinostat dose (200 or 300 mg BID) was assigned at the time of registration. Vorinostat was administered orally twice daily on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose. Vorinostat dose escalation was carried out in the standard 3 + 3 phase I trial design based upon toxicity observed during the first cycle of therapy.	Phase II Vorinostat was administered orally twice daily at the recommended phase II dose of 300 mg on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose.
Overall Study Adverse Event	0	12
Overall Study Progressive disease	3	27
Overall Study Withdrawal by Subject	2	6
Overall Study Other Reason	0	2
Overall Study Alternative Therapy	1	1

Baseline Characteristics

Phase I-II Study of Vorinostat, Paclitaxel, and Bevacizumab in Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I + Phase II n=54 Participants Phase I: Vorinostat dose (200 or 300 mg BID) was assigned at the time of registration. Vorinostat was administered orally twice daily on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose. Vorinostat dose escalation was carried out in the standard 3 + 3 phase I trial design based upon toxicity observed during the first cycle of therapy. Phase II: Vorinostat was administered orally twice daily at the recommended phase II dose of 300 mg on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose.
Age, Continuous	54 years n=99 Participants
Sex: Female, Male Female	54 Participants n=99 Participants
Sex: Female, Male Male	0 Participants n=99 Participants
Race/Ethnicity, Customized White	37 participants n=99 Participants
Race/Ethnicity, Customized Black	11 participants n=99 Participants
Race/Ethnicity, Customized Asian	2 participants n=99 Participants
Race/Ethnicity, Customized Unknown	4 participants n=99 Participants

PRIMARY outcome

Timeframe: 28 days

Population: Three patients were treated at the first vorinostat dose level of 200 mg BID and three additional patients were treated at the second dose level of 300 mg BID

Dose-limiting toxcities (DLT) were defined as grade 3-4 febrile neutropenia, thrombocytopenia and non-hemtological toxicity attributed to therapy (nausea, vomiting and diarrhea would be considered dose limiting only if not adequately controlled with therapy). Any toxicity occurring during cycle 1 that resulted in dose reduction of vorinostat or paclitaxel or failure to complete all protocol specificed doses in the first cycle was also considered a DLT

Outcome measures

Outcome measures
Measure	Phase I n=6 Participants Vorinostat dose (200 or 300 mg BID) was assigned at the time of registration. Vorinostat was administered orally twice daily on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose. Vorinostat dose escalation was carried out in the standard 3 + 3 phase I trial design based upon toxicity observed during the first cycle of therapy.
Recommended Phase II Dose as Assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Phase I)	300 mg

PRIMARY outcome

Timeframe: Up to 12 months

Population: 53 patients in the phase I and phase II portions were evaluated. One patient was not eligible to be evaluated for objective response rate.

Estimated and a 95% confidence interval will be estimated via binomial proportions. Per Response Evaluation Criteria in Solid Tumors (RECIST) for target lesions and assessed by CT scan: Complete response (CR): Disappearance of all target lesions; Partial Response (PR): \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR+PR.

Outcome measures

Outcome measures
Measure	Phase I n=53 Participants Vorinostat dose (200 or 300 mg BID) was assigned at the time of registration. Vorinostat was administered orally twice daily on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose. Vorinostat dose escalation was carried out in the standard 3 + 3 phase I trial design based upon toxicity observed during the first cycle of therapy.
Objective Response Rate (CR + PR)	49 percentage of participants Interval 37.0 to 60.0

SECONDARY outcome

Timeframe: From first treatment day until objective or symptomatic progression, assessed up to 12 months

Population: 53 patients in the phase I and phase II portions were evaluated

Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.

Outcome measures

Outcome measures
Measure	Phase I n=53 Participants Vorinostat dose (200 or 300 mg BID) was assigned at the time of registration. Vorinostat was administered orally twice daily on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose. Vorinostat dose escalation was carried out in the standard 3 + 3 phase I trial design based upon toxicity observed during the first cycle of therapy.
Progression-free Survival (PFS),	11.9 months Interval 8.9 to 13.9

SECONDARY outcome

Timeframe: Time from the first treatment day until disease progression or discontinuation of treatment due to toxicity, assessed up to 12 months

Population: Zero participants analyzed because time to treatment failure was not assessed.

Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae. Time to treatment failure was not reported for this study.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Time from first treatment day until death, assessed up to 12 months

Population: 54 patients in the phase I and phase II portion were evaluated

Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.

Outcome measures

Outcome measures
Measure	Phase I n=54 Participants Vorinostat dose (200 or 300 mg BID) was assigned at the time of registration. Vorinostat was administered orally twice daily on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose. Vorinostat dose escalation was carried out in the standard 3 + 3 phase I trial design based upon toxicity observed during the first cycle of therapy.
Overall Survival(OS)	29.4 months Interval 25.6 to 34.7

Adverse Events

Phase I + Phase II

Serious events: 27 serious events

Other events: 40 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Phase I + Phase II n=54 participants at risk Phase I: Vorinostat dose (200 or 300 mg BID) was assigned at the time of registration. Vorinostat was administered orally twice daily on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose. Vorinostat dose escalation was carried out in the standard 3 + 3 phase I trial design based upon toxicity observed during the first cycle of therapy. Phase II: Vorinostat was administered orally twice daily at the recommended phase II dose of 300 mg on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose.
Blood and lymphatic system disorders Neutropenia	27.8% 15/54
Blood and lymphatic system disorders Anemia	5.6% 3/54
Gastrointestinal disorders Diarrhea	5.6% 3/54
Gastrointestinal disorders Vomiting	7.4% 4/54
General disorders Headache	5.6% 3/54
General disorders Fatigue	18.5% 10/54
Nervous system disorders Neuropathy	22.2% 12/54
Renal and urinary disorders Proteinuria	1.9% 1/54

Other adverse events

Other adverse events
Measure	Phase I + Phase II n=54 participants at risk Phase I: Vorinostat dose (200 or 300 mg BID) was assigned at the time of registration. Vorinostat was administered orally twice daily on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose. Vorinostat dose escalation was carried out in the standard 3 + 3 phase I trial design based upon toxicity observed during the first cycle of therapy. Phase II: Vorinostat was administered orally twice daily at the recommended phase II dose of 300 mg on days 1-3, 8-10, and 15-17 of each 28-day cycle. All patients also received paclitaxel at 90 mg/m2 as 1-hour infusion on days 2, 9, and 16 of every 28-day cycle. Bevacizumab was administered on day 2 and day 16 of the 28 day cycle at 10 mg/kg dose.
Blood and lymphatic system disorders Anemia	37.0% 20/54
Blood and lymphatic system disorders Neutropenia	37.0% 20/54
Blood and lymphatic system disorders Thrombocytopenia	33.3% 18/54
Gastrointestinal disorders Vomiting	38.9% 21/54
Gastrointestinal disorders Diarrhea	74.1% 40/54
General disorders Fatigue	64.8% 35/54
Nervous system disorders Neuropathy	46.3% 25/54
Ear and labyrinth disorders Epistaxis	57.4% 31/54

Additional Information

NYCC Regulatory Coordinator

Montefiore Medical Center - New York

Phone: 718-379-6862

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60