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

NCT00477386 | Completed Phase 1 Results DMC

• 1 other identifier: 0704-07 IUCRO-0185
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Ovarian Cancer

Keywords

recurrent ovarian cancer; platinum resistant; decitabine

Outcome Measures

Primary Outcomes (2)

• Phase I: Maximum Tolerated Dose (MTD) for Use in Phase II

  The definition of MTD will follow the standard definition of the phase I 3+3 trial concept. Dose Limiting Toxicities (DLTs) will be scored in the first cycle. Patients will be monitored for 28 days (a cycle) to determine whether a DLT is experienced for the specific dose level.

  28 days

• Phase II: Percent of Patients With Objective Response

  The percent of patients having an objective response (Complete Response or Partial Response) will be estimated with a 95% exact binomial confidence interval for the percent of patients receiving drug.

  screening until end of study (approx 12-18 months)

Secondary Outcomes (2)

• Phase II: Percent of Patients With Objective Response, CA125 Response or Stable Disease > 3 Months

  screening until end of study (approx 12-18 months)

• Phase II: Progression Free Survival

  Baseline until disease progression or last visit

Study Arms (1)

Carboplatin combined with Decitabine

EXPERIMENTAL

Decitabine at escalating dose levels will be given X 5 days followed by Carboplatin given on Day 8.

Drug: decitabine

Interventions

decitabine DRUG

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.

Also known as: 5-aza-dCyd, deoxyazacytidine, dezocitidine, Dacogen

Carboplatin combined with Decitabine

Eligibility Criteria

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

You may qualify if:

• \- 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

You may not qualify if:

• \- 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.

Sponsors & Collaborators

• Indiana University: lead
• Eisai Inc.: collaborator

Study Sites (1)

Indiana University Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Related Publications (2)

• Matei D, Fang F, Shen C, Schilder J, Arnold A, Zeng Y, Berry WA, Huang T, Nephew KP. Epigenetic resensitization to platinum in ovarian cancer. Cancer Res. 2012 May 1;72(9):2197-205. doi: 10.1158/0008-5472.CAN-11-3909.

  PMID: 22549947 RESULT

• Fang F, Balch C, Schilder J, Breen T, Zhang S, Shen C, Li L, Kulesavage C, Snyder AJ, Nephew KP, Matei DE. A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer. Cancer. 2010 Sep 1;116(17):4043-53. doi: 10.1002/cncr.25204.

  PMID: 20564122 RESULT

MeSH Terms

Conditions

Ovarian Neoplasms

Interventions

Decitabine

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

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Daniela Matai, MD
• Organization: IndianaU

dmatai@iupui.edu

317-944-0920

Study Officials

• Daniela Matei, MD

  Indiana University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2007
• First Posted: May 23, 2007
• Study Start: July 1, 2007
• Primary Completion: May 1, 2011
• Study Completion: September 1, 2013
• Last Updated: September 25, 2014
• Results First Posted: September 25, 2014

Record last verified: 2014-09

Locations

US (1)