Trial of Decitabine as a Sensitizer to Carboplatin in Platinum Resistant Recurrent Ovarian Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Indiana University
ClinicalTrials.gov Identifier:
NCT00477386
First received: May 21, 2007
Last updated: August 7, 2013
Last verified: April 2013
  Purpose

Based on these pre-clinical data, which were generated by our group, the investigators propose to test in a phase I/II clinical trial the following hypothesis: demethylation induced by decitabine results in re-sensitization to platinum in recurrent ovarian cancer.

To test this hypothesis, the investigators will treat patients with recurrent ovarian cancer platinum resistant (recurrence within 6 months from platinum therapy) or platinum-refractory (no response to platinum) with a combination consisting of decitabine and carboplatin.

This will be an institutional open label phase I/II trial to determine the safety and the biologic activity of the Decitabine/Carboplatin combination.

The investigators will determine whether Carboplatin can be safely combined with Decitabine, the optimal dose schedule and the investigators will define whether at this dosage, the regimen is biologically active (i.e. induces demethylation of target genes).

In the second part of the trial, the investigators will determine the clinical activity of the combination in a population of patients with platinum-resistant ovarian cancer.


Condition Intervention Phase
Ovarian Cancer
Drug: decitabine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Decitabine as a Sensitizer to Carboplatin in Platinum Resistant Recurrent Ovarian Cancer

Resource links provided by NLM:


Further study details as provided by Indiana University:

Primary Outcome Measures:
  • Phase I: Determine the safety & tolerability of decitabine IV qd x 5d ac Carbo on D8 in pts w/ recurrent epithelial Ov Ca, platinum-resistant or refractory. Phase II: Assess the objective response via RECIST in pts trtd w/ Decitabine & Carbo [ Time Frame: 1 yr ] [ Designated as safety issue: Yes ]
    RECIST = Response Evaluation Criteria in Solid Tumors


Secondary Outcome Measures:
  • Determine benefit (# of pts w/obj response)or CA125 response, in the absence of dz progression Measure time to progression in pts trtd Determine the biologic activity of decitabine [ Time Frame: 1 yr ] [ Designated as safety issue: No ]
    CA125 = cancer antigen 125

  • Measure time to progression in patients treated on this protocol [ Time Frame: Baseline until disease progression ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Determine the biologic activity of decitabine by evaluating hypomethylation in PBMC on Day 8, prior to the infusion of Carboplatin. [ Time Frame: Baseline to Day 8 ] [ Designated as safety issue: No ]
    PBMC = peripheral blood mononucleated cells

  • Correlate the methylation pattern of ovarian tumors with clinical outcome. [ Time Frame: Baseline until end of treatment ] [ Designated as safety issue: No ]

Enrollment: 28
Study Start Date: July 2007
Estimated Study Completion Date: October 2013
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Carboplatin combined with Decitabine
Decitabine at escalating dose levels will be given X 5 days followed by Carboplatin given on Day 8.
Drug: decitabine

Decitabine dose will be escalated as follows.

Dose level 1: 10mg/m2 IV QD X 5 days Dose level 2: 20mg/m2 IV QD X 5 days Dose level -1: Carboplatin AUC 4.

Other Names:
  • 5-aza-dCyd
  • deoxyazacytidine
  • dezocitidine
  • Dacogen

Detailed Description:

Decitabine at escalating dose levels will be given IV X 5 days followed by Carboplatin given IV on Day 8 at a dose corresponding to an area under curve (AUC) of 5. The maximum dose of Decitabine (20 mg/m2) is based on the results of the myelodysplastic syndrome (MDS) clinical trial that demonstrated biological and clinical efficacy at this dose (15-17). It is recognized that higher doses of decitabine can be administered, myelotoxicity being the most significant adverse event. This protocol will assess the lower less toxic but biologically active dose.

Decitabine dose will be escalated as follows.

Dose level -1: 5 mg/m2 IV per day (QD) X 5 days Dose level 1: 10mg/m2 IV QD X 5 days Dose level 2: 20mg/m2 IV QD X 5 days

Each cycle will consist of 28 days, with delays to allow blood count recovery. Correlative blood draws will occur on Day1 (baseline) and on Day 8 before Carboplatin for cycle 1 and 2.

The escalation phase will follow the standard 3+3 design. That is, patients will be accrued to each dose level in cohorts of up to 3-6 patients. Escalation will continue until a DLT is observed, the highest dose-level is reached, or medical judgment indicates. The goal of the phase I cohort is to ensure the safety and tolerability of the combination, not to define the maximum tolerated dose.

An initial 3 patients will be enrolled at dose level 1. If all 3 patients in dose level 1 complete 4 weeks of therapy without dose limiting toxicity (DLT), the study will proceed to enroll 3 patients at dose level 2. If all 3 patients in dose level 2 complete 4 weeks of therapy without DLT, we will accrue 3 more to ensure that only 0 or 1 of 6 have a DLT and then proceed to the phase II cohort. As dose level 2 represents full doses of both agents, there will be no further dose escalation beyond dose level 2.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

- Have recurrent epithelial ovarian cancer, primary peritoneal carcinomatosis or fallopian tube cancer. - Have platinum-resistant (recurrence within 6 months of a platinum-containing regimen) or platinum refractory (progression while on platinum) disease - Have measurable disease according to RECIST or detectable disease. o Measurable disease is defined as the presence of at least one uni-dimensionally measurable lesion greater than or equal to 20 mm by conventional techniques, including palpation, plain x-ray, CT scan or MRI, or greater than or equal to 10 mm by spiral CT scan. o Detectable disease is defined in a patient as one who does not have measurable disease but has at least one of the following conditions: 1) Baseline values of cancer antigen 125 (CA-125) at least twice the upper limit of normal; 2) Ascites and/or pleural effusion attributed to tumor; 3) solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST definitions for target lesions. - >/= 18 years of age. - Give written, informed consent for participation in the protocol. - Be at least 4 weeks from last treatment to allow recovery from prior toxicity (with the exception of hormonal therapy, where a 1-week wash-out period and radiation therapy where a 3-week wash-out period are sufficient). Patients coming off experimental therapy with biological agents not expected to cause myelotoxicity should have been off treatment for at least 3 weeks as wash-out period. - Have had disease that has progressed within 6 months platinum-based chemotherapeutic regimen. - Have no history of platinum allergy. - Have a negative serum pregnancy test prior to the study entry and be practicing an effective form of contraception if hysterectomy and/or oophorectomy were not part of the prior treatment. It is expected that the overwhelming majority of ovarian cancer patients would have had hysterectomy and oophorectomy as part of the original surgery. - Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. - Have acceptable organ function, as evidenced by laboratory data: o Aspartate aminotransferase and alanine aminotransferase less than 2.5 times upper limit of normal (ULN) o Direct bilirubin less than 1.5 times ULN o Alkaline phosphatase less than 2.5 times ULN o Absolute neutrophil count greater than or equal to 1500 cells/mm3 o White cell blood count greater than 3000cells/mm3 o Hemoglobin greater than or equal to 9.0 g/dL (can be post-transfusion) o Platelets greater than 100,000/mm3 (can not be post-transfusion) o Creatinine levels less than 1.5 times ULN

Exclusion Criteria:

- Not have participated in any clinical trial involving conventional or investigational drugs or devices within the previous 3 weeks. - Not have grade 2 or greater neuropathy. - Have no additional active cancer in addition to the epithelial ovarian cancer within the last 5 years, with the exception of superficial skin cancer (basal cell or squamous cell skin carcinoma), carcinoma in situ of the cervix, Stage I endometrial cancer with less than 50% invasion of the myometrium, or other adequately treated Stage I or II cancer in complete remission. - Be free of active infection requiring antibiotic treatment. - Not have an additional uncontrolled serious medical condition or psychiatric illness. - Not have an immune deficiency and be receiving combination anti-retroviral therapy - Not have known brain metastases, as progressive neurologic dysfunction may develop, that would confound the evaluation of neurologic and other adverse events. - Absence of uncontrolled hypertension, arrhythmia, congestive heart failure or angina. Patients who have had a myocardial infarction or cardiac surgery should be at lease 6 months from the event and free of active symptoms.

  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00477386

Locations
United States, Indiana
Indiana University Cancer Center
Indianapolis, Indiana, United States, 46202
Sponsors and Collaborators
Indiana University
Eisai Inc.
Investigators
Principal Investigator: Daniela Matei, MD Indiana University
  More Information

Additional Information:
Publications:
Responsible Party: Indiana University
ClinicalTrials.gov Identifier: NCT00477386     History of Changes
Other Study ID Numbers: 0704-07 IUCRO-0185
Study First Received: May 21, 2007
Last Updated: August 7, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Indiana University:
recurrent ovarian cancer
platinum resistant
decitabine

Additional relevant MeSH terms:
Ovarian Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Adnexal Diseases
Genital Diseases, Female
Endocrine System Diseases
Gonadal Disorders
Decitabine
Carboplatin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 26, 2014