Metastatic Melanoma
Conditions
Keywords
Metastatic, Melanoma, Epigenetic, Temozolomide, Decitabine, Panobinostat, LBH589
Brief summary
The purpose of this study is to treat metastatic melanoma with a combination of standard chemotherapy (decitabine and Temozolomide in a dose escalation scheme) with an study drug called panobinostat. This combination is proposed to unlock genes that may contribute to mechanisms that cause tumor growth. The primary objectives of this study are: * To evaluate the safety and tolerability of the proposed schedule of decitabine, temozolomide and panobinostat in the treatment of metastatic melanoma. * To define any Dose Limiting Toxicity (DLT) and maximum tolerated dose (MTD) of the combination of decitabine, temozolomide and panobinostat.
Detailed description
Most chemotherapeutics target rapidly proliferating cells, leaving quiescent cells and those with extended cell cycles unaffected. The investigators propose that this combination of decitabine, temozolomide, and panobinostat will target both melanoma stem cells and rapidly proliferating melanoma cells. The use of two drugs that regulate gene expression epigenetically (panobinostat and decitabine) in combination with a chemotherapeutic agent (temozolomide) is hypothesized to: * induce expression genes (e.g., Apaf-1) that increase chemosensitivity of tumor cells and enhance apoptosis * potentiate the cytotoxic effect of temozolomide by epigenetic modulation, and * induce proliferation and differentiation of tumor stem cells, thus enabling senescence and apoptosis. Secondary objectives: * To measure overall survival * To measure the time to progression of patients treated with this combination in comparison to patients treated historically with DTIC (the current standard of care). * To evaluate treatment response with FDG PET and compare FDG PET with conventional imaging for treatment response assessment.
Interventions
DRUGTemozolomide, Decitabine, Panobinostat
Temozolomide - given each cycle. Decitabine - 6 cohorts with dose escalation. Panobinostat - 6 cohorts with dose escalation.
Sponsors
Holden Comprehensive Cancer Center
Novartis Pharmaceuticals
University of Iowa
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patients aged ≥ 18 years old 2. ECOG Performance Status of ≤ 2 3. Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed 4. Patients must have measurable disease according to RECIST and CHOI criteria. The minimum target-lesion diameter should have double the CT slice thickness, i.e., 10 mm 5. Patients must meet the following laboratory criteria: Hematology: Neutrophil count of \>1500/mm3;Platelet count of \> 100,000/mm3L; Hemoglobin ≥ 9 g/dL Biochemistry:AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x upper limit of normal if the transaminase elevation is due to disease involvement;Serum bilirubin ≤ 1.5 x upper limit of normal;Serum creatinine ≤ 1.5 x upper limit of normal or 24-hour creatinine clearance ≥ 50 ml/min; Total serum calcium (corrected for serum albumin) or ionized calcium ≥ lower limit of normal; Serum potassium ≥ lower limit of normal; Serum sodium ≥ lower limit of normal;Serum albumin ≥ lower limit of normal or 3g/dl;Patients with any elevated alkaline phosphatase due to bone metastasis can be enrolled 6. Baseline ECHO must demonstrate LVEF ≥ the lower limit of the institutional normal. 7. TSH and free T4 within normal limits (patients may be on thyroid hormone replacement) 8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 8 days of the first administration of study treatment and must be willing to use two methods of contraception one of them being a barrier method during the study and for 3 months after last study drug administration 9. Any patient with the diagnosis of metastatic melanoma from any site. These include untreated patients or those treated with chemotherapy or biochemotherapy. 10. Must not have taken a hypomethylating agent or a histone deacetylase agent in the treatment of their disease. Patients who receive targeted agents would only need a 2-week washout period. 11. Any patient with metastatic melanoma regardless of prior treatment will be eligible. 12. Patients must have had disease progression on or following their most recent treatment regimen or on presentation for the first time with metastatic disease, surgical option can be entertained if this is a localized relapse. 13. Patients with CNS disease are eligible for treatment only after their CNS disease has been directly addressed with radiation therapy.
Exclusion criteria
1. Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer 2. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment 3. Impaired cardiac function including any one of the following: Screening ECG with a QTc \> 450 msec confirmed by central laboratory prior to enrollment to the study; Patients with congenital long QT syndrome; History of sustained ventricular tachycardia; Any history of ventricular fibrillation or torsades de pointes; Bradycardia defined as heart rate \< 50 beats per minute. Patients with a pacemaker and heart rate ≥ 50 beats per minute are eligible; Patients with a myocardial infarction or unstable angina within 6 months of study entry; Congestive heart failure (NY Heart Association class III or IV);Right bundle branch block and left anterior hemiblock (bifascicular block) 4. Uncontrolled hypertension 5. Concomitant use of drugs with a risk of causing torsades de pointes 6. Concomitant use of CYP3A4 inhibitors 7. Patients with unresolved diarrhea \> CTCAE grade 1 8. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat 9. Other concurrent severe and/or uncontrolled medical conditions 10. Patients who have received chemotherapy, any investigational drug or undergone major surgery \< 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy. 11. Concomitant use of any anti-cancer therapy or radiation therapy. 12. Patients who have no measurable disease. 13. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)not willing to use a double barrier method of contraception during the study and 3 months after the end of treatment. One of these methods of contraception must be a barrier method. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months(i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 8 days of the first administration of oral panobinostat. 14. Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom 15. Patients with a history of another primary malignancy within 5 years other than curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin 16. Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required 17. Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level | 6 weeks (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. |
| Phase 2 -Number of Patients With a Decrease in Tumor Size Using RECIST and CHOI's Criteria | 12 weeks (2 cycles) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2 - Number of Participants With Disease Progression | 5 years | Number of participants who died or had disease progression |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
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
Participants by arm
| Arm | Count |
|---|---|
| Temozolomide, Decitabine, Panobinostat 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. | 39 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Removed due to disease progression | 0 | 0 | 0 | 0 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Temozolomide, Decitabine, Panobinostat |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 14 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 37 Participants |
| Region of Enrollment United States | 39 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 39 / 39 |
| serious Total, serious adverse events | 5 / 39 |
Outcome results
Primary
Phase 2 -Number of Patients With a Decrease in Tumor Size Using RECIST and CHOI's Criteria
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.
Time frame: 12 weeks (2 cycles)
Population: Number of patients evaluable for tumor response assessment following 2 cycles of treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I 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 I Dose Escalation | Phase 2 -Number of Patients With a Decrease in Tumor Size Using RECIST and CHOI's Criteria | Stable Disease (SD) | 5 Participants |
Primary
Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level
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.
Time frame: 6 weeks (one full cycle)
Population: Number of patients within the 4 dosing cohorts evaluable for DLTs following administration of one full cycle
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I 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 Dose Escalation | Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level | Cohort 2: Experienced DLT | 0 Participants |
| Phase I Dose Escalation | Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level | Cohort 3: Experienced DLT | 0 Participants |
| Phase I Dose Escalation | Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level | Cohort 4: Experienced DLT | 0 Participants |
Secondary
Phase 2 - Number of Participants With Disease Progression
Number of participants who died or had disease progression
Time frame: 5 years
Population: Number patients who received study drug in Phase II portion of trial
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Dose Escalation | Phase 2 - Number of Participants With Disease Progression | Died within 5 year time frame | 17 Participants |
| Phase I Dose Escalation | Phase 2 - Number of Participants With Disease Progression | Removed due to disease progression | 5 Participants |