Combination of Decitabine and Temozolomide in the Treatment of Patients With Metastatic Melanoma

Phase 1

Completed

Conditions: Malignant Melanoma

Interventions: Drug: Decitabine
Drug: Temozolomide
Procedure: biopsy

Registration Number: NCT00715793

Lead Sponsor: Hussein Tawbi

Brief Summary: The combination of TMZ and DAC may effect dual modulation of DNA repair genes resulting in improved clinical response.

Detailed Description: Primary Objectives:

* Phase I: To determine the safety, tolerability, and Phase II recommended dose of the combination of extended schedule TMZ and DAC.

* Phase II: To determine the efficacy, as measured by overall response rate, of the combination of extended schedule TMZ and DAC given at the Phase II recommended dose to patients with metastatic melanoma.

Secondary Objectives:

* To determine pharmacokinetics of the combination of TMZ and DAC in patients with metastatic melanoma.

* To determine, in peripheral blood mononuclear cells (PBMC) and tumor tissue, the pharmacodynamic effects of the combination of TMZ and DAC on promoter methylation and expression of selected genes and correlate these with response.

* To determine the progression-free survival of patients treated with the combination of TMZ and DAC.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 39

Inclusion Criteria

Patients who have non-resectable Stage IIIB or stage IV metastatic melanoma that have progressed despite prior therapies.
Life expectancy of at least 12 weeks.
ECOG performance status of 0, 1 and 2.
≥18 years of age.
Patients who have not received any other chemotherapeutic, biological or investigational agent within 28 days of study drug administration.
First line and active brain metastases (metastatic lesions to the brain that have been adequately treated with surgery and/or appropriate radiation therapy and that have documented stability for >4 weeks or >2 weeks if treated with stereotactic radiosurgery, remain eligible)

Exclusion Criteria

Any evidence of renal dysfunction (proteinuria, estimated creatinine clearance from serum creatinine test of <60 ml/min).
Impaired hepatic function (liver enzymes greater than twice the upper limit of normal or bilirubin > 2.0 except in patients with Gilbert's syndrome).
Prior treatment with alkylating agents (including TMZ and DTIC).
Active brain metastases (metastatic lesions to the brain that have been adequately treated with surgery and/or appropriate radiation therapy and that have documented stability for >4 weeks remain eligible).
Active infections or serious general medical conditions.
Female patients of child-bearing age who are not on adequate contraception, or are pregnant or breast-feeding.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single Arm	Temozolomide	-
Single Arm	biopsy	-
Single Arm	Decitabine	-

Primary Outcome Measures

Name	Time	Method
Percentage of Participants That Experienced a Dose Limiting Toxicity (DLT)	Up to 26 months	Dose-limiting toxicities (DLTs) were defined as grade 4 neutropenia or thrombocytopenia which lasts \>7 days; grade 3 or 4 febrile neutropenia; grade 3 or greater non-hematological toxic effects.
Overall Response Rate (ORR)	Up to 30 months	Using RECIST v1.0 criteria, overall response rate (ORR) was determined by the number of participants with complete response (CR) + the number of participants with partial response (PR) / the number of participants with complete response (CR) + the number of participants with partial response (PR) + the number of participants with stable disease (SD) + the number of participants with progressive disease (PD), multiplied by 100. Per RECIST v1.0 criteria (assessed by MRI or CT): Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response (PR) nor sufficient increase to to qualify for Progressive Disease (PD); PD, 20% increase in the sum if target lesion or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions.
Recommended Phase 2 Dose (RP2D) of DAC + TMZ	Up to 26 months	Toxicity assessments used CTCAE v3.0. Two dose levels were explored in the phase I portion of the study. A modified 3 + 3 'up and down' design was used. Given the knowledge that DAC exhibits its epigenetic effects at 30-fold lower doses than at its maximum-tolerated dose (MTD), escalation of DAC to the MTD was not done.

Secondary Outcome Measures

Name	Time	Method
Disease Control Rate (DCR)	Up to 30 months	Using RECIST v1.0 criteria, disease control rate (DCR) was determined by the number of participants with complete response (CR) + the number of participants with partial response (PR) + the number of participants with stable disease (SD) / the number of participants with complete response (CR) + the number of participants with partial response (PR) + the number of participants with stable disease (SD) + the number of participants with progressive disease (PD). Per RECIST v1.0 criteria (assessed by MRI or CT): Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response (PR) nor sufficient increase to to qualify for Progressive Disease (PD); PD, 20% increase in the sum if target lesion or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions.
Progression-free Survival (PFS)	Up to 42 months	PFS was defined as the time from study entry until the documented radiological or symptomatic progression. Per RECIST v1.0 criteria (assessed by MRI or CT): Progressive Disease (PD); PD, 20% increase in the sum if target lesion or the appearance of new lesions.
6-month Progression-free Survival (PFS) Rate	6 months
Overall Survival (OS)	Up to 42 months	OS was defined as the time from study entry until the death or date of last contract.
1-year Overall Survival (OS) Rate	12 months	Percentage of patients alive at one year (number of patients alive / total number of evaluable (analyzed) patients).