Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Skin Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Decitabine

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Antimetabolites

Enzyme Inhibitors

In Part I patients will be treated on a standard "3+3" phase I dose-escalation design starting at 0.075 mg/kg until a decitabine dose level of 0.15 mg/kg is reached, or, in case unacceptable toxicities are observed, at the maximum tolerated dose (Phase II recommended dose). Decitabine will be administered at the specified dose level, intravenously, daily 5 days a week for the first 2 weeks of a 6-week cycle.

Temozolomide is available in 25 mg and 100 mg tablets that will be administered orally; doses will be rounded to the nearest 25 mg. Temozolomide will be administered orally at 75 mg/m2 daily for 4 weeks starting on week 2 of a 6-week cycle.

Fine needle aspirates (FNA) and/or core biopsies of tumor samples will be obtained from consenting patients with accessible, evaluable disease, on days 1, 8, 15, and 29 of the first cycle and when patients go off study. Biopsies are optional in Phase I and required for all consenting subjects in Phase II.

biopsy

Hussein Tawbi, MD

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

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.

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

Phase I/II Trial of the Combination of Decitabine and Temozolomide in the Treatment of Patients With Metastatic Melanoma

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.

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.

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.

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.

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.

OS was defined as the time from study entry until the death or date of last contract.

Percentage of patients alive at one year (number of patients alive / total number of evaluable (analyzed) patients).

Eisai Inc.

Schering-Plough

Hussein Tawbi

Principal Investigator

Comprehensive listing of adverse events are presented in total (includes events from both Phase 1 and and Phase 2 of study).

DAC (Decitabine) + TMZ (Temozolomide)

Patients with non-resectable stage IIIB/C or stage IV metastatic melanoma with either no prior therapy, or, have progressed despite prior therapies, who were treated with DAC 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks + TMZ orally 75 mg/m\^2 qd for weeks 2-5 of a 6-week cycle).

All Study Participants DAC (Decitabine) + TMZ (Temozolomide)

Age, Continuous

Sex: Female, Male

Hussein Tawbi, MD, PhD

Patients with non-resectable stage IIIB/C or stage IV metastatic melanoma with either no prior therapy or have progressed despite prior therapies, who were treated with DAC 0.075 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m\^2 qd for weeks 2-5 of a 6-week cycle.

Dose Level 1:DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide)

Patients with non-resectable stage IIIB/C or stage IV metastatic melanoma with either no prior therapy or have progressed despite prior therapies, who were treated with DAC 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m\^2 qd for weeks 2-5 of a 6-week cycle.

Dose Level 2:DAC (Decitabine) 0.15 mg/kg + TMZ (Temozolomide)

Patients participating in the Phase 1 portion of the study that were treated on a standard "3+3" phase I dose-escalation design who were observed for unacceptable toxicities.

Percentage of Participants That Experienced a Dose Limiting Toxicity (DLT)

Patients with non-resectable stage IIIB/C or stage IV metastatic melanoma with either no prior therapy or have progressed despite prior therapies, who were treated with Intravenous DAC of 0.15 mg/kg daily for 5 days a week for the first 2 weeks of a 6-week cycle who received TMZ orally at 75 mg/m\^2 daily for 4 weeks (weeks 2-5) of a 6-week cycle.

Overall Response Rate (ORR)

Decitabine: In Part I patients will be treated on a standard "3+3" phase I dose-escalation design starting at 0.075 mg/kg until a decitabine dose level of 0.15 mg/kg is reached, or, in case unacceptable toxicities are observed, at the maximum tolerated dose (Phase II recommended dose). Decitabine will be administered at the specified dose level, intravenously, daily 5 days a week for the first 2 weeks of a 6-week cycle.

Temozolomide: Temozolomide is available in 25 mg and 100 mg tablets that will be administered orally; doses will be rounded to the nearest 25 mg. Temozolomide will be administered orally at 75 mg/m2 daily for 4 weeks starting on week 2 of a 6-week cycle.

biopsy: Fine needle aspirates (FNA) and/or core biopsies of tumor samples will be obtained from consenting patients with accessible, evaluable disease, on days 1, 8, 15, and 29 of the first cycle and when patients go off study. Biopsies are optional in Phase I and required for all consenting subjects in Phase II.

Spots Global Cancer Trial Database for Combination of Decitabine and Temozolomide in the Treatment of Patients With Metastatic Melanoma

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Study Description

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