Vorinostat, Carboplatin and Gemcitabine in Women With Rec... | NCT00910000

NCT00910000

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Brigham and Women's Hospital	OTHER
Massachusetts General Hospital	OTHER
Merck Sharp & Dohme LLC	INDUSTRY

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Dose Level 1A	Experimental	Vorinostat: 200 mg taken orally once a day for the first two weeks of each three-week cycle Carboplatin: AUC 4, given intravenously on day 1 of every three week cycle Gemcitabine: 100 mg/m2, given intravenously on day 1 and day 8 of every three week cycle Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.	Drug: Vorinostat Drug: Carboplatin Drug: Gemcitabine
Dose Level 2A	Experimental	Vorinostat: 300mg, taken orally once a day for the first two weeks of each three-week cycle Carboplatin: AUC 4, given intravenously on day 1 of every three week cycle Gemcitabine: 1000 mg/m2, given intravenously on day 1 and day 8 of every three week cycle Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.	Drug: Vorinostat Drug: Carboplatin Drug: Gemcitabine
Dose Level 1B	Experimental	Vorinostat: 200mg, taken orally twice a day for days 1-3 and days 8-10 of every three week cycle Carboplatin: AUC 4, given intravenously on day 1 of every three week cycle Gemcitabine: 1000 mg/m2, given intravenously on day 1 and day 8 of every three week cycle Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.	Drug: Vorinostat Drug: Carboplatin Drug: Gemcitabine
Dose Level 1C

Name	Type	Description	Arm Group Labels	Other Names
Vorinostat	Drug		Dose Level 1A Dose Level 1B Dose Level 1C Dose Level 1D Dose Level 2A Dose Level 2D

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Vorinostat Maximum Tolerated Dose (MTD) [Phase Ib]	The Vorinostat MTD is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.	The DLT observation period in determining the MTD was the 21-day cycle 1 length.
Dose Limiting Toxicity (DLT) [Phase Ib]	Dose-limiting toxicity was based on the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) and defined as any of the following: Any CTCAE grade 3 or 4 non-hematologic event except manageable gastrointestinal toxicity and fatigue. Any of the following hematologic events (excluding neutropenia lasting < 5 days): i) febrile neutropenia defined as grade 3-4 neutropenia with fever ≥ 38.5°C and/or infection. ii) any grade 4 neutropenia lasting 5 days or more. iii) grade 4 thrombocytopenia (plt count < 25x 109/L) iv) failure of ANC to recover to ≥ 1000/μL or platelets to recover to ≥ 50,000/μL within 14 days of therapy v) grade 4 anemia Any clinically significant abnormal laboratory value that results in dose delay of >14 days. <75% of vorinostat dosing taken by the patient during the first cycle due to any toxicity.	The DLT observation period in determining the MTD was the 21-day cycle 1 length.

Secondary Outcomes

Measure	Description	Time Frame
Response	Response was based on RECIST 1.0 criteria. Per RECIST 1.0 for target lesions, complete response (CR) is complete disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Progressive disease (PD) is at least a 20% increase in sum LD from the smallest LD recorded on treatment. Stable disease (SD) is neither sufficient increase to qualify as PD nor sufficient shrinkage to qualify for PR. For CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed 4 weeks +/- 2 weeks after the response criteria are first met. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. Participants who received therapy but did not have their disease re-evaluated were considered unevaluable.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Histologically confirmed recurrent epithelial ovarian cancer, fallopian tube cancer, or peritoneal cancer
Must have received a platinum-based chemotherapy regimen at initial diagnosis
Patients with primary platinum-sensitive (defined as a cancer initially platinum-sensitive followed by a progression-free interval from first exposure to platinum of 6 months or greater) recurrent ovarian, tubal or peritoneal cancer
Must have an elevated CA125 (twice the ULN) within 2 weeks of enrolling on study (2 pretreatment measurements that are twice the upper limits of institutional normal and are drawn at least 1 day but not more than 14 days apart). At least one of the samples should be checked within one week of starting treatment. Measurable cancer via RECIST criteria via CT or MRI scan is not required but if clinically indicated will be monitored.
For patients who do not have an elevated CA125 (twice the ULN), participants 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 20mm or greater with conventional techniques or as 10mm or greater with spiral CT scan.
18 years of age or older
Life expectancy of greater than 16 weeks
ECOG Performance Status 0, 1, or 2
Participants must have normal organ and marrow function as outlined in the protocol
Patients could have received up to 1 prior non-platinum chemotherapy regimen in the recurrent setting (anti-angiogenic agents and other phase II non-hormonal therapies used to treat recurrent cancer count as a prior non-platinum therapy) but only one prior platinum (used to treat initial diagnosis). Patients may received up to 2 prior hormonal therapies.
Women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation
Must be able and willing to take oral medications
No clinical nor radiographic evidence of an existing or impending bowel obstruction
Should be at least 2 weeks from any surgical procedure, with the exception of minor surgery, such as port placement
Patients who have known carboplatin hypersensitivity reaction can receive carboplatin if they are followed by an allergist, follow a published hypersensitivity desensitization protocol when receiving carboplatin, and agree to receive carboplatin under these circumstances
Patients taking valproic acid for epilepsy may enroll if they discontinue valproic acid 30 days prior to enrolling for washout
Patients must have a normal QTc interval and no history of QTc prolongation on EKG

Exclusion Criteria:

Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
May not be receiving any other investigational agent
Participants with known brain metastases should be excluded from this clinical trial
History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat
Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, pulmonary disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant or breastfeeding women
Individuals with a history of different malignancy are ineligible except for the following circumstances: disease-free for at least 5 years and are deemed by the investigator to be a low risk for recurrence of that malignancy; cervical cancer in situ, concurrent stage IA and grade I endometrial cancer, and basal cell or squamous cell carcinoma of the skin
Patients taking valproic acid unless valproic acid is stopped at least 30 days prior to enrollment
Receipt in the past of any other HDAC inhibitor for treatment of any malignancy
Receipt of radiation therapy to >25% of bone marrow-bearing areas
Patients who have gastrointestinal disorders likely to interfere with absorption of vorinostat
Known active HIV or hepatitis viral infection

Name	Affiliation	Role
Ursula A. Matulonis, MD	Dana-Farber Cancer Institute	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Massachusetts General Hospital		Boston	Massachusetts	02114	United States
Dana-Farber Cancer Institute

PubMed Identifier	Type	Citation	Retractions
26119093	Result	Matulonis U, Berlin S, Lee H, Whalen C, Obermayer E, Penson R, Liu J, Campos S, Krasner C, Horowitz N. Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer. Cancer Chemother Pharmacol. 2015 Aug;76(2):417-23. doi: 10.1007/s00280-015-2813-9. Epub 2015 Jun 29.

Arm/Group Information

ID	Title	Description
FG000	Dose Level 1A	Vorinostat: 200 mg taken orally once a day for the first two weeks of each three-week cycle Carboplatin: AUC 4, given intravenously on day 1 of every three week cycle Gemcitabine: 100 mg/m2, given intravenously on day 1 and day 8 of every three week cycle Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.
FG001	Dose Level 2A	Vorinostat: 300mg, taken orally once a day for the first two weeks of each three-week cycle Carboplatin: AUC 4, given intravenously on day 1 of every three week cycle Gemcitabine: 1000 mg/m2, given intravenously on day 1 and day 8 of every three week cycle Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.
FG002	Dose Level 1B	Vorinostat: 200mg, taken orally twice a day for days 1-3 and days 8-10 of every three week cycle Carboplatin: AUC 4, given intravenously on day 1 of every three week cycle Gemcitabine: 1000 mg/m2, given intravenously on day 1 and day 8 of every three week cycle Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.
FG003	Dose Level 1C	Vorinostat: 200mg, taken orally twice a day for days 1, 2, 8 and 9 of every three week cycle Carboplatin: AUC 4, given intravenously on day 2 of every three week cycle Gemcitabine: 1000 mg/m2, given intravenously on day 2 and day 9 of every three week cycle Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.
FG004	Dose Level 1D	Vorinostat: 300mg, taken orally once a day for days 1 and 2 of every three week cycle Carboplatin: AUC 4, given intravenously on day 2 of every three week cycle Gemcitabine: 1000 mg/m2, given intravenously on day 2 and day 9 of every three week cycle Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.
FG005	Dose Level 2D	Vorinostat: 400mg, taken orally once a day for days 1 and 2 of every three week cycle Carboplatin: AUC 4, given intravenously on day 2 of every three week cycle Gemcitabine: 1000 mg/m2, given intravenously on day 2 and day 9 of every three week cycle Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Dose Level 1A	Vorinostat: 200 mg taken orally once a day for the first two weeks of each three-week cycle Carboplatin: AUC 4, given intravenously on day 1 of every three week cycle Gemcitabine: 100 mg/m2, given intravenously on day 1 and day 8 of every three week cycle Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Customized			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Vorinostat Maximum Tolerated Dose (MTD) [Phase Ib]

The Vorinostat MTD is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.

Per protocol, MTD evaluable participants received day 1 of treatment, were not taken off study during cycle 1 due to disease progression, showed proof via pill diary that all doses of vorinostat were taken or attempted to be taken and were compliant with study procedures. The final MTD dataset was comprised of all enrolled and treated participants.

Posted

Number

mg/day

The DLT observation period in determining the MTD was the 21-day cycle 1 length.

ID	Title	Description
OG000	All Phase Ib Participants	All Phase Ib participants received Vorinostat according to the established dose escalation schedule during a 3-week cycle in combination with IV carboplatin AUC 4 (day 2) and IV gemcitabine 1000 mg/m2 (days 2 and 9). Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	All Phase Ib Participants	All Phase Ib participants received Vorinostat according to the established dose escalation schedule during a 3-week cycle in combination with IV carboplatin AUC 4 (day 2) and IV gemcitabine 1000 mg/m2 (days 2 and 9). Participants received up to 8 cycles of therapy without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.

ID	Term
D010051	Ovarian Neoplasms
D005185	Fallopian Tube Neoplasms

ID	Term
D004701	Endocrine Gland Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D010049	Ovarian Diseases

ID	Term
D000813	Anilides
D000577	Amides
D009930	Organic Chemicals
D000814	Aniline Compounds