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

• Sponsor: Hussein Tawbi (Other)
• Overall Status: Completed
• CT.gov ID: NCT00715793
• Collaborator: Eisai Inc. (Industry), Schering-Plough (Industry)
• Enrollment: 39
• Location: 1
• Arm: 1
• Duration (Months): 86
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: Decitabine; Drug: Temozolomide; Procedure: biopsy	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of the Combination of Decitabine and Temozolomide in the Treatment of Patients With Metastatic Melanoma
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Single Arm

Drug: 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.; Other Names: DTIC ; Drug: 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.; Other Names: TMZ ; Procedure: 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.; Other Names: fine needle aspirate FNA core biopsy

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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

1. 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.

2. 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.

3. 6-month Progression-free Survival (PFS) Rate [6 months]

4. Overall Survival (OS) [Up to 42 months]

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

5. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UPMC Cancer Centers	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• Hussein Tawbi
• Eisai Inc.
• Schering-Plough

Investigators

• Principal Investigator: Hussein Tawbi, MD, University of Pittsburgh

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hussein Tawbi, Principal Investigator, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT00715793
• Other Study ID Numbers: UPCI 07-008
• First Posted: Jul 15, 2008
• Last Update Posted: Oct 3, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by Hussein Tawbi, Principal Investigator, University of Pittsburgh: Decitabine; Temozolomide; Metastatic; Melanoma; Non-resectable; Stage IIIB melanoma; stage IV melanoma; TMZ; DTIC; promoter methylation; skin cancer; chemotherapy
• Additional relevant MeSH terms: Melanoma; Temozolomide; Decitabine

Study Results

Participant Flow

Arm/Group Title	DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide)	DAC (Decitabine) 0.15 mg/kg + TMZ (Temozolomide)
Arm/Group Description	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.	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.
Period Title: Phase 1 RP2D DAC + TMZ
STARTED	4	6
COMPLETED	3	6
NOT COMPLETED	1	0
Period Title: Phase 1 RP2D DAC + TMZ
STARTED	0	29
COMPLETED	0	27
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	All Study Participants DAC (Decitabine) + TMZ (Temozolomide)
Arm/Group Description	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).
Overall Participants	39
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63.3
Sex: Female, Male (Count of Participants)
Female	12 30.8%
Male	27 69.2%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Dose Level 1:DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide)	Dose Level 2:DAC (Decitabine) 0.15 mg/kg + TMZ (Temozolomide)
Arm/Group Description	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.	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.
Measure Participants	2	6
Number [percentage of participants]	0 0%	17 NaN

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAC (Decitabine) + TMZ (Temozolomide)
Arm/Group Description	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.
Measure Participants	33
Number [percentage of participants]	18 46.2%

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	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.
Measure Participants	8
Number [mg/kg DAC]	0.15

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAC (Decitabine) + TMZ (Temozolomide)
Arm/Group Description	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.
Measure Participants	33
Number [percentage of participants]	61 156.4%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAC (Decitabine) + TMZ (Temozolomide)
Arm/Group Description	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.
Measure Participants	33
Median (Full Range) [months]	3.4

6. Secondary Outcome

Title	6-month Progression-free Survival (PFS) Rate
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Patients that either progressed or died by 6 months.

Arm/Group Title	DAC (Decitabine) + TMZ (Temozolomide)
Arm/Group Description	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.
Measure Participants	33
Number [percentage of participants]	32.4 83.1%

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAC (Decitabine) + TMZ (Temozolomide)
Arm/Group Description	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.
Measure Participants	33
Median (95% Confidence Interval) [months]	12.4

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAC (Decitabine) + TMZ (Temozolomide)
Arm/Group Description	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.
Measure Participants	33
Number [percentage of participants]	56 143.6%

Adverse Events

Arm/Group Title	DAC (Decitabine) + TMZ (Temozolomide)
Arm/Group Description	Comprehensive listing of adverse events are presented in total (includes events from both Phase 1 and and Phase 2 of study).
All Cause Mortality
	DAC (Decitabine) + TMZ (Temozolomide)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	DAC (Decitabine) + TMZ (Temozolomide)
	Affected / at Risk (%)	# Events
Total	7/39 (17.9%)
General disorders
Pain, Abdomen NOS	2/39 (5.1%)
Pain, Back	1/39 (2.6%)
Infections and infestations
Febrile neutropenia	3/39 (7.7%)
Nervous system disorders
Neuropathy: motor	1/39 (2.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	2/39 (5.1%)
Hypoxia	1/39 (2.6%)
Vascular disorders
Peripheral arterial ischemia	1/39 (2.6%)
Other (Not Including Serious) Adverse Events
	DAC (Decitabine) + TMZ (Temozolomide)
	Affected / at Risk (%)	# Events
Total	39/39 (100%)
Blood and lymphatic system disorders
Edema: limb	10/39 (25.6%)
Hemoglobin	8/39 (20.5%)
Hemorrhage/Bleeding - Other (Specify, __)	3/39 (7.7%)
Leukocytes (total WBC)	31/39 (79.5%)
Neutrophils/granulocytes (ANC/AGC)	32/39 (82.1%)
Platelets	6/39 (15.4%)
Cardiac disorders
Hypertension	6/39 (15.4%)
Gastrointestinal disorders
Constipation	25/39 (64.1%)
Diarrhea	10/39 (25.6%)
Heartburn/dyspepsia	5/39 (12.8%)
Mucositis/stomatitis (clinical exam), Oral cavity	7/39 (17.9%)
Nausea	31/39 (79.5%)
Taste alteration (dysgeusia)	5/39 (12.8%)
Vomiting	8/39 (20.5%)
General disorders
Anorexia	15/39 (38.5%)
Fatigue (asthenia, lethargy, malaise)	35/39 (89.7%)
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	5/39 (12.8%)
Insomnia	8/39 (20.5%)
Pain, Abdomen NOS	14/39 (35.9%)
Pain, Back	11/39 (28.2%)
Pain, Chest wall	3/39 (7.7%)
Pain, Extremity-limb	11/39 (28.2%)
Pain, Head/headache	17/39 (43.6%)
Pain, Joint	6/39 (15.4%)
Weight loss	3/39 (7.7%)
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	5/39 (12.8%)
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils, Skin (cellulitis)	4/39 (10.3%)
Infection with normal ANC or Grade 1 or 2 neutrophils, Upper airway NOS	3/39 (7.7%)
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	6/39 (15.4%)
Metabolic/Laboratory - Other (Specify, __)	7/39 (17.9%)
Phosphate, serum-low (hypophosphatemia)	4/39 (10.3%)
Nervous system disorders
Confusion	3/39 (7.7%)
Dizziness	6/39 (15.4%)
Mood alteration, Anxiety	11/39 (28.2%)
Mood alteration, Depression	8/39 (20.5%)
Neuropathy: sensory	9/39 (23.1%)
Respiratory, thoracic and mediastinal disorders
Cough	12/39 (30.8%)
Dyspnea (shortness of breath)	9/39 (23.1%)
Skin and subcutaneous tissue disorders
Pruritus/itching	8/39 (20.5%)
Rash/desquamation	5/39 (12.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.