Trial Outcomes & Findings for Combination of Decitabine and Temozolomide in the Treatment of Patients With Metastatic Melanoma (NCT NCT00715793)

NCT ID: NCT00715793

Last Updated: 2017-10-03

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 39 participants
• Primary outcome timeframe: Up to 26 months
• Results posted on: 2017-10-03

Participant Flow

Participant milestones

Measure	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 0.075 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.	DAC (Decitabine) 0.15 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.
Phase 1 RP2D DAC + TMZ STARTED	4	6
Phase 1 RP2D DAC + TMZ COMPLETED	3	6
Phase 1 RP2D DAC + TMZ NOT COMPLETED	1	0
Phase 2 DAC (0.15 mg/kg) + TMZ STARTED	0	29
Phase 2 DAC (0.15 mg/kg) + TMZ COMPLETED	0	27
Phase 2 DAC (0.15 mg/kg) + TMZ NOT COMPLETED	0	2

Reasons for withdrawal

Measure	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 0.075 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.	DAC (Decitabine) 0.15 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.
Phase 1 RP2D DAC + TMZ secondary disease in Cycle 1	1	0
Phase 2 DAC (0.15 mg/kg) + TMZ not assessable for tumor response	0	2

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	All Study Participants DAC (Decitabine) + TMZ (Temozolomide) n=39 Participants 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).
Age, Continuous	63.3 years n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants
Sex: Female, Male Male	27 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 26 months

Population: 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.

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.

Outcome measures

Measure	Dose Level 1:DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide) n=2 Participants 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 2:DAC (Decitabine) 0.15 mg/kg + TMZ (Temozolomide) n=6 Participants 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.
Percentage of Participants That Experienced a Dose Limiting Toxicity (DLT)	0 percentage of participants	17 percentage of participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Dose Level 1:DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide) n=33 Participants 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 2:DAC (Decitabine) 0.15 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.
Overall Response Rate (ORR)	18 percentage of participants	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Dose Level 1:DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide) n=8 Participants 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 2:DAC (Decitabine) 0.15 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.
Recommended Phase 2 Dose (RP2D) of DAC + TMZ	0.15 mg/kg DAC	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Dose Level 1:DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide) n=33 Participants 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 2:DAC (Decitabine) 0.15 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.
Disease Control Rate (DCR)	61 percentage of participants	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Dose Level 1:DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide) n=33 Participants 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 2:DAC (Decitabine) 0.15 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.
Progression-free Survival (PFS)	3.4 months Interval 1.0 to 20.4	—

SECONDARY outcome

Timeframe: 6 months

Population: Patients that either progressed or died by 6 months.

Outcome measures

Measure	Dose Level 1:DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide) n=33 Participants 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 2:DAC (Decitabine) 0.15 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.
6-month Progression-free Survival (PFS) Rate	32.4 percentage of participants	—

SECONDARY outcome

Timeframe: Up to 42 months

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

Outcome measures

Measure	Dose Level 1:DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide) n=33 Participants 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 2:DAC (Decitabine) 0.15 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.
Overall Survival (OS)	12.4 months Interval 10.4 to 20.4	—

SECONDARY outcome

Timeframe: 12 months

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

Outcome measures

Measure	Dose Level 1:DAC (Decitabine) 0.075 mg/kg + TMZ (Temozolomide) n=33 Participants 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 2:DAC (Decitabine) 0.15 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.
1-year Overall Survival (OS) Rate	56 percentage of participants	—

Adverse Events

DAC (Decitabine) + TMZ (Temozolomide)

Serious events: 7 serious events

Other events: 39 other events

Deaths: 0 deaths

Serious adverse events

Measure	DAC (Decitabine) + TMZ (Temozolomide) n=39 participants at risk Comprehensive listing of adverse events are presented in total (includes events from both Phase 1 and and Phase 2 of study).
Respiratory, thoracic and mediastinal disorders Dyspnea (shortness of breath)	5.1% 2/39
Infections and infestations Febrile neutropenia	7.7% 3/39
Respiratory, thoracic and mediastinal disorders Hypoxia	2.6% 1/39
Nervous system disorders Neuropathy: motor	2.6% 1/39
General disorders Pain, Abdomen NOS	5.1% 2/39
General disorders Pain, Back	2.6% 1/39
Vascular disorders Peripheral arterial ischemia	2.6% 1/39

Other adverse events

Measure	DAC (Decitabine) + TMZ (Temozolomide) n=39 participants at risk Comprehensive listing of adverse events are presented in total (includes events from both Phase 1 and and Phase 2 of study).
Metabolism and nutrition disorders Albumin, serum-low (hypoalbuminemia)	15.4% 6/39
Immune system disorders Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	12.8% 5/39
General disorders Anorexia	38.5% 15/39
Nervous system disorders Confusion	7.7% 3/39
Gastrointestinal disorders Constipation	64.1% 25/39
Respiratory, thoracic and mediastinal disorders Cough	30.8% 12/39
Gastrointestinal disorders Diarrhea	25.6% 10/39
Nervous system disorders Dizziness	15.4% 6/39
Respiratory, thoracic and mediastinal disorders Dyspnea (shortness of breath)	23.1% 9/39
Blood and lymphatic system disorders Edema: limb	25.6% 10/39
General disorders Fatigue (asthenia, lethargy, malaise)	89.7% 35/39
General disorders Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	12.8% 5/39
Gastrointestinal disorders Heartburn/dyspepsia	12.8% 5/39
Blood and lymphatic system disorders Hemoglobin	20.5% 8/39
Blood and lymphatic system disorders Hemorrhage/Bleeding - Other (Specify, __)	7.7% 3/39
Cardiac disorders Hypertension	15.4% 6/39
Infections and infestations Infection with normal ANC or Grade 1 or 2 neutrophils, Skin (cellulitis)	10.3% 4/39
Infections and infestations Infection with normal ANC or Grade 1 or 2 neutrophils, Upper airway NOS	7.7% 3/39
General disorders Insomnia	20.5% 8/39
Blood and lymphatic system disorders Leukocytes (total WBC)	79.5% 31/39
Metabolism and nutrition disorders Metabolic/Laboratory - Other (Specify, __)	17.9% 7/39
Nervous system disorders Mood alteration, Anxiety	28.2% 11/39
Nervous system disorders Mood alteration, Depression	20.5% 8/39
Gastrointestinal disorders Mucositis/stomatitis (clinical exam), Oral cavity	17.9% 7/39
Gastrointestinal disorders Nausea	79.5% 31/39
Nervous system disorders Neuropathy: sensory	23.1% 9/39
Blood and lymphatic system disorders Neutrophils/granulocytes (ANC/AGC)	82.1% 32/39
General disorders Pain, Abdomen NOS	35.9% 14/39
General disorders Pain, Back	28.2% 11/39
General disorders Pain, Chest wall	7.7% 3/39
General disorders Pain, Extremity-limb	28.2% 11/39
General disorders Pain, Head/headache	43.6% 17/39
General disorders Pain, Joint	15.4% 6/39
Metabolism and nutrition disorders Phosphate, serum-low (hypophosphatemia)	10.3% 4/39
Blood and lymphatic system disorders Platelets	15.4% 6/39
Skin and subcutaneous tissue disorders Pruritus/itching	20.5% 8/39
Skin and subcutaneous tissue disorders Rash/desquamation	12.8% 5/39
Gastrointestinal disorders Taste alteration (dysgeusia)	12.8% 5/39
Gastrointestinal disorders Vomiting	20.5% 8/39
General disorders Weight loss	7.7% 3/39

Additional Information

Hussein Tawbi, MD, PhD

University of Pittsburgh

Phone: 713-792-6111

Email: HTawbi@mdanderson.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place