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Combination of Decitabine and Temozolomide in the Treatment of Patients With Metastatic Melanoma (UPCI-07-008)

Primary Purpose

Malignant Melanoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Decitabine
Temozolomide
biopsy
Sponsored by
Hussein Tawbi
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Melanoma focused on measuring Decitabine, Temozolomide, Metastatic, Melanoma, Non-resectable, Stage IIIB melanoma, stage IV melanoma, TMZ, DTIC, promoter methylation, skin cancer, chemotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • UPMC Cancer Centers

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single Arm

Arm Description

Outcomes

Primary Outcome Measures

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

Disease Control Rate (DCR)
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)
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
Overall Survival (OS)
OS was defined as the time from study entry until the death or date of last contract.
1-year Overall Survival (OS) Rate
Percentage of patients alive at one year (number of patients alive / total number of evaluable (analyzed) patients).

Full Information

First Posted
June 27, 2008
Last Updated
September 5, 2017
Sponsor
Hussein Tawbi
Collaborators
Eisai Inc., Schering-Plough
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1. Study Identification

Unique Protocol Identification Number
NCT00715793
Brief Title
Combination of Decitabine and Temozolomide in the Treatment of Patients With Metastatic Melanoma
Acronym
UPCI-07-008
Official Title
Phase I/II Trial of the Combination of Decitabine and Temozolomide in the Treatment of Patients With Metastatic Melanoma
Study Type
Interventional

2. Study Status

Record Verification Date
September 2017
Overall Recruitment Status
Completed
Study Start Date
June 2008 (undefined)
Primary Completion Date
May 2015 (Actual)
Study Completion Date
August 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Hussein Tawbi
Collaborators
Eisai Inc., Schering-Plough

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Melanoma
Keywords
Decitabine, Temozolomide, Metastatic, Melanoma, Non-resectable, Stage IIIB melanoma, stage IV melanoma, TMZ, DTIC, promoter methylation, skin cancer, chemotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
39 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Single Arm
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Decitabine
Other Intervention Name(s)
DTIC
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
TMZ
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
biopsy
Other Intervention Name(s)
fine needle aspirate, FNA, core biopsy
Intervention Description
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.
Primary Outcome Measure Information:
Title
Percentage of Participants That Experienced a Dose Limiting Toxicity (DLT)
Description
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.
Time Frame
Up to 26 months
Title
Overall Response Rate (ORR)
Description
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.
Time Frame
Up to 30 months
Title
Recommended Phase 2 Dose (RP2D) of DAC + TMZ
Description
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.
Time Frame
Up to 26 months
Secondary Outcome Measure Information:
Title
Disease Control Rate (DCR)
Description
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.
Time Frame
Up to 30 months
Title
Progression-free Survival (PFS)
Description
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.
Time Frame
Up to 42 months
Title
6-month Progression-free Survival (PFS) Rate
Time Frame
6 months
Title
Overall Survival (OS)
Description
OS was defined as the time from study entry until the death or date of last contract.
Time Frame
Up to 42 months
Title
1-year Overall Survival (OS) Rate
Description
Percentage of patients alive at one year (number of patients alive / total number of evaluable (analyzed) patients).
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hussein Tawbi, MD
Organizational Affiliation
University of Pittsburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
UPMC Cancer Centers
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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