Trial Outcomes & Findings for Treatment of Resistant Metastatic Melanoma Using Decitabine, Temozolomide and Panobinostat (NCT NCT00925132)
NCT ID: NCT00925132
Last Updated: 2017-07-02
Results Overview
A DLT was any Grade 4 toxicity for neutrophils or platelets for ≥ 7 days, Grade 3 toxicity for neutrophils for ≥ 21 days, any Grade 3 solid organ toxicity not explainable by another cause (e.g. neurotoxicity, GI toxicity), metabolic/laboratory toxicity (≥10 x ULN AST) for ≥ 14 days, any Grade 4 infection or QTcF\> 500msec EKG. DLTs were assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. All adverse events were collected and graded to determine DLTs as assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. DLTs were assessed to determine the recommended Decitabine and Panobinostat dose for the Phase II portion of the trial.
TERMINATED
PHASE1/PHASE2
39 participants
6 weeks (one full cycle)
2017-07-02
Participant Flow
Subjects were recruited between December 2009 through June 2015. The study population was accessed via the Principal Investigator's medical clinic at Holden Comprehensive Cancer Center.
Following consent, all subjects undergo screening procedures to verify eligibility for participation in the study. Screening included physical exam, blood and urine tests to check general health, blood test for fetal hemoglobin, blood test for pregnancy (only for women of childbearing age), ECG and Echo, CT and FDG-PET, and tumor measurements
Participant milestones
| Measure |
Phase I:Decitabine 0.1mg/kg + Panobinostat 10mg + Temozolomide
Cohort 1: Participants were administered Decitabine 0.1 mg/kg via subcutaneous injection (SQ) 3x weekly, Panobinostat 10mg orally (PO) once every 96 hours for 2 weeks and Temozolomide at a dose of 150 mg/m2 orally Day 9 through 13 for 5 doses. Dose for Temozolomide was escalated to 200 mg/m2 for 5 days after Cycle 1.
|
Phase I:Decitabine 0.1 mg/kg + Panobinostat 20mg +Temozolomide
Cohort 2: Participants were administered Decitabine 0.1 mg/kg via subcutaneous injection (SQ) 3x weekly, Panobinostat 20mg orally (PO) once every 96 hours for 2 weeks and Temozolomide at a dose of 150 mg/m2 orally Day 9 through 13 for 5 doses. Dose for Temozolomide was escalated to 200 mg/m2 for 5 days after Cycle 1.
|
Phase I:Decitabine 0.2 mg/kg + Panobinostat 20mg+Temozolomide
Cohort 3: Participants were administered Decitabine 0.2 mg/kg via subcutaneous injection (SQ) 3x weekly, Panobinostat 20mg orally (PO) once every 96 hours for 2 weeks and Temozolomide at a dose of 150 mg/m2 orally Day 9 through 13 for 5 doses. Dose for Temozolomide was escalated to 200 mg/m2 for 5 days after Cycle 1.
|
Phase I:Decitabine 0.2 mg/kg + Panobinostat 30mg +Temozolomide
Cohort 4: Participants were administered Decitabine 0.2 mg/kg via subcutaneous injection (SQ) 3x weekly and Panobinostat 30mg orally (PO) once every 96 hours for 2 weeks and Temozolomide at a dose of 150 mg/m2 orally Day 9 through 13 for 5 doses. Dose for Temozolomide was escalated to 200 mg/m2 for 5 days after Cycle 1.
|
Phase II:Decitabine 0.2 mg/kg+Panobinostat 30mg+Temozolomide
Participants were administered Decitabine 0.2 mg/kg via subcutaneous injection (SQ) 3x weekly and Panobinostat 30mg orally (PO) once every 96 hours for 2 weeks and Temozolomide at a dose of 150 mg/m2 orally Day 9 through 13 for 5 doses. Dose for Temozolomide was escalated to 200 mg/m2 for 5 days after Cycle 1.
|
|---|---|---|---|---|---|
|
Overall Study
STARTED
|
5
|
4
|
4
|
4
|
22
|
|
Overall Study
COMPLETED
|
3
|
4
|
4
|
4
|
17
|
|
Overall Study
NOT COMPLETED
|
2
|
0
|
0
|
0
|
5
|
Reasons for withdrawal
| Measure |
Phase I:Decitabine 0.1mg/kg + Panobinostat 10mg + Temozolomide
Cohort 1: Participants were administered Decitabine 0.1 mg/kg via subcutaneous injection (SQ) 3x weekly, Panobinostat 10mg orally (PO) once every 96 hours for 2 weeks and Temozolomide at a dose of 150 mg/m2 orally Day 9 through 13 for 5 doses. Dose for Temozolomide was escalated to 200 mg/m2 for 5 days after Cycle 1.
|
Phase I:Decitabine 0.1 mg/kg + Panobinostat 20mg +Temozolomide
Cohort 2: Participants were administered Decitabine 0.1 mg/kg via subcutaneous injection (SQ) 3x weekly, Panobinostat 20mg orally (PO) once every 96 hours for 2 weeks and Temozolomide at a dose of 150 mg/m2 orally Day 9 through 13 for 5 doses. Dose for Temozolomide was escalated to 200 mg/m2 for 5 days after Cycle 1.
|
Phase I:Decitabine 0.2 mg/kg + Panobinostat 20mg+Temozolomide
Cohort 3: Participants were administered Decitabine 0.2 mg/kg via subcutaneous injection (SQ) 3x weekly, Panobinostat 20mg orally (PO) once every 96 hours for 2 weeks and Temozolomide at a dose of 150 mg/m2 orally Day 9 through 13 for 5 doses. Dose for Temozolomide was escalated to 200 mg/m2 for 5 days after Cycle 1.
|
Phase I:Decitabine 0.2 mg/kg + Panobinostat 30mg +Temozolomide
Cohort 4: Participants were administered Decitabine 0.2 mg/kg via subcutaneous injection (SQ) 3x weekly and Panobinostat 30mg orally (PO) once every 96 hours for 2 weeks and Temozolomide at a dose of 150 mg/m2 orally Day 9 through 13 for 5 doses. Dose for Temozolomide was escalated to 200 mg/m2 for 5 days after Cycle 1.
|
Phase II:Decitabine 0.2 mg/kg+Panobinostat 30mg+Temozolomide
Participants were administered Decitabine 0.2 mg/kg via subcutaneous injection (SQ) 3x weekly and Panobinostat 30mg orally (PO) once every 96 hours for 2 weeks and Temozolomide at a dose of 150 mg/m2 orally Day 9 through 13 for 5 doses. Dose for Temozolomide was escalated to 200 mg/m2 for 5 days after Cycle 1.
|
|---|---|---|---|---|---|
|
Overall Study
Withdrawal by Subject
|
2
|
0
|
0
|
0
|
1
|
|
Overall Study
Removed due to disease progression
|
0
|
0
|
0
|
0
|
4
|
Baseline Characteristics
Treatment of Resistant Metastatic Melanoma Using Decitabine, Temozolomide and Panobinostat
Baseline characteristics by cohort
| Measure |
Temozolomide, Decitabine, Panobinostat
n=39 Participants
Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation.
Temozolomide, Decitabine, Panobinostat: Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation.
|
|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
25 Participants
n=5 Participants
|
|
Age, Categorical
>=65 years
|
14 Participants
n=5 Participants
|
|
Sex: Female, Male
Female
|
16 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
23 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
37 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
2 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
39 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 6 weeks (one full cycle)Population: Number of patients within the 4 dosing cohorts evaluable for DLTs following administration of one full cycle
A DLT was any Grade 4 toxicity for neutrophils or platelets for ≥ 7 days, Grade 3 toxicity for neutrophils for ≥ 21 days, any Grade 3 solid organ toxicity not explainable by another cause (e.g. neurotoxicity, GI toxicity), metabolic/laboratory toxicity (≥10 x ULN AST) for ≥ 14 days, any Grade 4 infection or QTcF\> 500msec EKG. DLTs were assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. All adverse events were collected and graded to determine DLTs as assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. DLTs were assessed to determine the recommended Decitabine and Panobinostat dose for the Phase II portion of the trial.
Outcome measures
| Measure |
Phase I Dose Escalation
n=15 Participants
Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation.
|
|---|---|
|
Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level
Cohort 1: Experienced DLT
|
0 Participants
|
|
Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level
Cohort 2: Experienced DLT
|
0 Participants
|
|
Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level
Cohort 3: Experienced DLT
|
0 Participants
|
|
Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level
Cohort 4: Experienced DLT
|
0 Participants
|
PRIMARY outcome
Timeframe: 12 weeks (2 cycles)Population: Number of patients evaluable for tumor response assessment following 2 cycles of treatment
Tumor response rate was assessed using RECIST criteria in which a complete response was the disappearance of all target lesions; Partial response was a 30% decrease in the sum of the longest dimension (LD) of target lesions, relative to baseline measurement; Progressive disease was an increase of 20% or more in the sum of the LD of target lesions; and Stable disease was a decrease in tumor size of less than 30% or increase of less than 20%. Tumor response rate was also assessed using CHOI's criteria in which a response was a 10% decrease in tumor size or a 15% decrease in tumor density on contrast-enhanced computed tomography scan. Tumor response rates were assessed in order to determine effectiveness of the treatment regimen which was defined by the response rate of at least 30% as measured by either the RECIST or Choi's criteria, and ineffective if the rate is less than 15% on both.
Outcome measures
| Measure |
Phase I Dose Escalation
n=17 Participants
Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation.
|
|---|---|
|
Phase 2 -Number of Patients With a Decrease in Tumor Size Using RECIST and CHOI's Criteria
Progressive Disease (PD)
|
12 Participants
|
|
Phase 2 -Number of Patients With a Decrease in Tumor Size Using RECIST and CHOI's Criteria
Stable Disease (SD)
|
5 Participants
|
SECONDARY outcome
Timeframe: 5 yearsPopulation: Number patients who received study drug in Phase II portion of trial
Number of participants who died or had disease progression
Outcome measures
| Measure |
Phase I Dose Escalation
n=22 Participants
Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation.
|
|---|---|
|
Phase 2 - Number of Participants With Disease Progression
Died within 5 year time frame
|
17 Participants
|
|
Phase 2 - Number of Participants With Disease Progression
Removed due to disease progression
|
5 Participants
|
Adverse Events
Temozolomide, Decitabine, Panobinostat
Serious adverse events
| Measure |
Temozolomide, Decitabine, Panobinostat
n=39 participants at risk
Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation.
Temozolomide, Decitabine, Panobinostat: Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation.
|
|---|---|
|
Gastrointestinal disorders
Obstruction, GI (small bowel)
|
2.6%
1/39 • Number of events 1
|
|
Nervous system disorders
Syncope
|
2.6%
1/39 • Number of events 1
|
|
Renal and urinary disorders
Obstruction, GU (ureter)
|
2.6%
1/39 • Number of events 1
|
|
Respiratory, thoracic and mediastinal disorders
Pleural Effusion
|
2.6%
1/39 • Number of events 1
|
|
Vascular disorders
Edema-lower extremity
|
2.6%
1/39 • Number of events 1
|
Other adverse events
| Measure |
Temozolomide, Decitabine, Panobinostat
n=39 participants at risk
Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation.
Temozolomide, Decitabine, Panobinostat: Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation.
|
|---|---|
|
Blood and lymphatic system disorders
Leukocytes
|
61.5%
24/39 • Number of events 24
|
|
Blood and lymphatic system disorders
Lymphopenia
|
74.4%
29/39 • Number of events 29
|
|
Blood and lymphatic system disorders
RBC Decreased
|
5.1%
2/39 • Number of events 2
|
|
Blood and lymphatic system disorders
Hemoglobin
|
35.9%
14/39 • Number of events 14
|
|
Blood and lymphatic system disorders
Neutrophils
|
69.2%
27/39 • Number of events 27
|
|
Blood and lymphatic system disorders
Platelets
|
61.5%
24/39 • Number of events 24
|
|
General disorders
Fatigue
|
61.5%
24/39 • Number of events 24
|
|
General disorders
Fever
|
7.7%
3/39 • Number of events 3
|
|
Gastrointestinal disorders
Anorexia
|
33.3%
13/39 • Number of events 13
|
|
Gastrointestinal disorders
Constipation
|
23.1%
9/39 • Number of events 9
|
|
Gastrointestinal disorders
Nausea
|
56.4%
22/39 • Number of events 22
|
|
Gastrointestinal disorders
Vomiting
|
28.2%
11/39 • Number of events 11
|
|
Cardiac disorders
Tachycardia
|
7.7%
3/39 • Number of events 3
|
|
Metabolism and nutrition disorders
ALT
|
28.2%
11/39 • Number of events 11
|
|
Metabolism and nutrition disorders
Albumin
|
2.6%
1/39 • Number of events 1
|
|
Metabolism and nutrition disorders
Bicarbonate-Serum low
|
10.3%
4/39 • Number of events 4
|
|
Metabolism and nutrition disorders
Bilirubin
|
5.1%
2/39 • Number of events 2
|
|
Metabolism and nutrition disorders
Creatinine
|
7.7%
3/39 • Number of events 3
|
|
Metabolism and nutrition disorders
GGT
|
5.1%
2/39 • Number of events 2
|
|
Metabolism and nutrition disorders
Hyperglycemia
|
35.9%
14/39 • Number of events 14
|
|
Metabolism and nutrition disorders
Chloride decreased
|
2.6%
1/39 • Number of events 1
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal joint pain
|
2.6%
1/39 • Number of events 1
|
|
Gastrointestinal disorders
Gastrointestinal pain
|
15.4%
6/39 • Number of events 6
|
|
Nervous system disorders
Left Sided Weakness
|
2.6%
1/39 • Number of events 1
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
5.1%
2/39 • Number of events 2
|
|
Metabolism and nutrition disorders
Alkaline Phosphatase
|
20.5%
8/39 • Number of events 8
|
|
Metabolism and nutrition disorders
Hyponatremia
|
25.6%
10/39 • Number of events 10
|
|
General disorders
Headache
|
7.7%
3/39 • Number of events 3
|
|
Nervous system disorders
Anxiety
|
5.1%
2/39 • Number of events 2
|
|
Blood and lymphatic system disorders
Coagulation PTT
|
2.6%
1/39 • Number of events 1
|
|
General disorders
Failure to thrive
|
2.6%
1/39 • Number of events 1
|
|
Metabolism and nutrition disorders
Albumin-Serum low (hypoalbuminemia)
|
17.9%
7/39 • Number of events 7
|
|
Metabolism and nutrition disorders
Potassium-Serum low (hypokalemia)
|
15.4%
6/39 • Number of events 6
|
|
Metabolism and nutrition disorders
Phosphorous
|
28.2%
11/39 • Number of events 11
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
2.6%
1/39 • Number of events 1
|
|
General disorders
Confusion
|
5.1%
2/39 • Number of events 2
|
|
General disorders
Neuropathy
|
5.1%
2/39 • Number of events 2
|
|
Metabolism and nutrition disorders
Weight Loss
|
7.7%
3/39 • Number of events 3
|
|
General disorders
Insomnia
|
2.6%
1/39 • Number of events 1
|
|
Gastrointestinal disorders
Taste alteration (dysgeusia)
|
2.6%
1/39 • Number of events 1
|
|
General disorders
Speech impairment
|
2.6%
1/39 • Number of events 1
|
|
General disorders
Dizziness
|
2.6%
1/39 • Number of events 1
|
|
Musculoskeletal and connective tissue disorders
General pain: chest and body
|
5.1%
2/39 • Number of events 2
|
|
Gastrointestinal disorders
Diarrhea
|
15.4%
6/39 • Number of events 6
|
|
Gastrointestinal disorders
Gastritis
|
2.6%
1/39 • Number of events 1
|
|
Metabolism and nutrition disorders
Calcium, serum-low (hypocalcemia)
|
15.4%
6/39 • Number of events 6
|
|
General disorders
Somnolence
|
5.1%
2/39 • Number of events 2
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnea
|
2.6%
1/39 • Number of events 1
|
|
General disorders
Flu-like symptoms
|
2.6%
1/39 • Number of events 1
|
Additional Information
Mohammed Milhem
University of Iowa
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place