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

NCT00910000 | Terminated Phase 1 Results DMC

• 1 other identifier: 09-026
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer

Keywords

carboplatin; gemcitabine; vorinostat

Outcome Measures

Primary Outcomes (2)

• 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: 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.

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

Secondary Outcomes (1)

• Response

  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).

Study Arms (6)

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

EXPERIMENTAL

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; Drug: Carboplatin; Drug: Gemcitabine

Dose Level 1D

EXPERIMENTAL

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; Drug: Carboplatin; Drug: Gemcitabine

Dose Level 2D

EXPERIMENTAL

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; Drug: Carboplatin; Drug: Gemcitabine

Interventions

Vorinostat DRUG

Also known as: Zolinza

Dose Level 1A; Dose Level 1B; Dose Level 1C; Dose Level 1D; Dose Level 2A; Dose Level 2D

Carboplatin DRUG

Also known as: paraplatin

Dose Level 1A; Dose Level 1B; Dose Level 1C; Dose Level 1D; Dose Level 2A; Dose Level 2D

Gemcitabine DRUG

Also known as: Gemzar

Dose Level 1A; Dose Level 1B; Dose Level 1C; Dose Level 1D; Dose Level 2A; Dose Level 2D

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Brigham and Women's Hospital: collaborator
• Massachusetts General Hospital: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Related Publications (1)

• 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.

  PMID: 26119093 RESULT

MeSH Terms

Conditions

Ovarian Neoplasms; Fallopian Tube Neoplasms

Interventions

Vorinostat; Carboplatin; Gemcitabine

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Fallopian Tube Diseases

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Coordination Complexes; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Limitations and Caveats

The study was terminated early for toxicities and the emergence of better tolerated and more promising biologic agents added to platinum-based chemotherapy and/or use as maintenance.

Results Point of Contact

• Title: Ursula Matulonis, MD
• Organization: Dana-Farber Cancer Institute

umatulonis@partners.org

617-632-2334

Study Officials

• Ursula A. Matulonis, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Director, Gynecologic Oncology

Study Record Dates

• First Submitted: May 26, 2009
• First Posted: May 29, 2009
• Study Start: June 1, 2009
• Primary Completion: January 1, 2013
• Study Completion: October 1, 2015
• Last Updated: September 10, 2018
• Results First Posted: October 4, 2016

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)