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Vorinostat, Carboplatin and Gemcitabine in Women With Recurrent, Platinum-Sensitive Ovarian Cancer

This study has been terminated.
(Terminated due to unacceptable toxicity)
Sponsor:
Collaborators:
Brigham and Women's Hospital
Massachusetts General Hospital
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ursula A. Matulonis, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT00910000
First received: May 26, 2009
Last updated: August 10, 2016
Last verified: August 2016
  Purpose
This trial is a Phase Ib/II study of carboplatin/gemcitabine/vorinostat for the treatment of platinum sensitive recurrent ovarian cancer. The carboplatin and gemcitabine combination is an FDA approved regimen for platinum-sensitive recurrent ovarian cancer. Vorinostat is a type of drug called a histone deacetylase inhibitor (HDAC inhibitor). HDAC inhibitors interact with chromosomes in the cancer cell and cause cancer cells to stop growing. Vorinostat has shown a decrease in the amount of ovarian cancer cells growing in the laboratory and also may enhance the anti-cancer effects of carboplatin.The purpose of the Phase Ib study is to determine the highest dose of the drug vorinostat that can be given safely in combination with carboplatin and gemcitabine. Not everyone who participates in this research study will receive the same dose of the study drug, vorinostat, but carboplatin and gemcitabine doses are held constant. Vorinostat doses depend on previous enrollment and tolerability. The expansion Phase II study uses the vorinostat dose found in the Phase Ib study in combination with carboplatin/gemcitabine and as a single agent maintenance therapy to better understand toxicity and efficacy.

Condition Intervention Phase
Ovarian Cancer
Fallopian Tube Cancer
Peritoneal Cancer
Drug: Vorinostat
Drug: Carboplatin
Drug: Gemcitabine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase Ib/II Study of Combination of Vorinostat, Carboplatin and Gemcitabine + Vorinostat Maintenance in Women With Recurrent, Platinum-Sensitive Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer

Resource links provided by NLM:


Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Vorinostat Maximum Tolerated Dose (MTD) [Phase Ib] [ Time Frame: The DLT observation period in determining the MTD was the 21-day cycle 1 length. ] [ Designated as safety issue: Yes ]
    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.

  • Dose Limiting Toxicity (DLT) [Phase Ib] [ Time Frame: The DLT observation period in determining the MTD was the 21-day cycle 1 length. ] [ Designated as safety issue: Yes ]

    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:

    1. Any CTCAE grade 3 or 4 non-hematologic event except manageable gastrointestinal toxicity and fatigue.
    2. 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

    3. Any clinically significant abnormal laboratory value that results in dose delay of >14 days.
    4. <75% of vorinostat dosing taken by the patient during the first cycle due to any toxicity.


Secondary Outcome Measures:
  • Response [ Time Frame: Disease was assessed radiographically (CT or MRI scan) every 2 cycles on treatment; Phase Ib participants received up to 8 cycles of treatment. The median number of cycles started was 2 (range 1-8). ] [ Designated as safety issue: No ]
    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.


Enrollment: 15
Study Start Date: June 2009
Study Completion Date: October 2015
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.

Drug: Vorinostat
Other Name: Zolinza
Drug: Carboplatin
Other Name: paraplatin
Drug: Gemcitabine
Other Name: Gemzar
Experimental: 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.

Drug: Vorinostat
Other Name: Zolinza
Drug: Carboplatin
Other Name: paraplatin
Drug: Gemcitabine
Other Name: Gemzar
Experimental: 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.

Drug: Vorinostat
Other Name: Zolinza
Drug: Carboplatin
Other Name: paraplatin
Drug: Gemcitabine
Other Name: Gemzar
Experimental: 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.

Drug: Vorinostat
Other Name: Zolinza
Drug: Carboplatin
Other Name: paraplatin
Drug: Gemcitabine
Other Name: Gemzar
Experimental: 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.

Drug: Vorinostat
Other Name: Zolinza
Drug: Carboplatin
Other Name: paraplatin
Drug: Gemcitabine
Other Name: Gemzar
Experimental: 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.

Drug: Vorinostat
Other Name: Zolinza
Drug: Carboplatin
Other Name: paraplatin
Drug: Gemcitabine
Other Name: Gemzar

Detailed Description:

OBJECTIVES:

Primary

Phase Ib: Determine the maximally tolerated dose (MTD) of vorinostat when used in combination with standard (fixed) doses of carboplatin/gemcitabine during a 21 day cycle in patients with recurrent platinum-sensitive ovarian cancer

Phase II: Estimate the median progression-free survival (PFS) of patients treated with carboplatin/gemcitabine/vorinostat and vorinostat maintenance

Secondary

  • Estimate the response rate of carboplatin/gemcitabine/vorinostat
  • Assess the toxicities of carboplatin/gemcitabine/vorinostat
  • Assess the toxicities of maintenance vorinostat
  • Measure overall survival (OS) and progression-free survival (PFS)

STATISTICAL DESIGN:

The Phase Ib study was originally design to follow a standard 3+3 dose escalation design and evaluate 4 vorinostat dose levels.The DLT observation period was the 21-day cycle 1 length. Note: Ultimately 6 dose levels were evaluated as the protocol was amended to add dose levels, de-escalating cumulative vorinostat dose per cycle when 2 of 3 participants in dose level cohorts 2A, 1B and 1C experienced DLTs.

In the Phase II study, a median PFS of 13 months would be worthy of further study, representing a 66% improvement compared with the historical median of 8.6 months observed with carboplatin/gemcitabine. With 36 evaluable patients, there is 80% power to reject the null hypothesis in favor of the alternative at a 5% significance level.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00910000

Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Massachusetts General Hospital
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Ursula A. Matulonis, MD Dana-Farber Cancer Institute
  More Information

Publications:
Responsible Party: Ursula A. Matulonis, MD, Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT00910000     History of Changes
Other Study ID Numbers: 09-026 
Study First Received: May 26, 2009
Results First Received: March 29, 2016
Last Updated: August 10, 2016
Health Authority: United States: Food and Drug Administration
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Dana-Farber Cancer Institute:
carboplatin
gemcitabine
vorinostat

Additional relevant MeSH terms:
Ovarian Neoplasms
Fallopian Tube Neoplasms
Peritoneal Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Fallopian Tube Diseases
Abdominal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Peritoneal Diseases
Gemcitabine
Vorinostat
Carboplatin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors

ClinicalTrials.gov processed this record on December 07, 2016