Acral/Lentiginous Melanoma, Chronically Sun Damaged Melanomas, Mucosal Melanoma
Conditions
Keywords
Imatinib, Gleevec
Brief summary
The purpose of this study is to evaluate how effective imatinib (Gleevec) is in treating acral/lentiginous and mucosal melanoma which has spread to other parts of the body in patients who's disease carries a c-kit mutation. Imatinib is a protein-kinase inhibitor. It is believed that imatinib may be effective in blocking signals on certain cancer cells which allow the malignant cells to multiply and spread.
Detailed description
OBJECTIVES: Primary * To determine the response rate of patients with metastatic mucosal, acral/lentiginous, or chronically sun damaged melanomas to treatment with of imatinib. * To determine the time to progression. Secondary * To correlate c-kit mutational status with response to therapy. * To evaluate the use of FDG-PET scanning in determining early biologic response to therapy. * Tolerability of imatinib. * To assess amplification of c-kit status through quantitative PCR and/or FISH and other related molecular pathway targets. * To correlate c-kit amplification status with response to therapy.
Interventions
DRUGImatinib
Imatinib was given at a dose of 400 mg orally daily (4 100mg pills). Patients received treatment up to 12 months as long as they were receiving clinical benefit. Dosage may have been increased to twice daily if disease worsened and patient was in otherwise good clinical condition.
Sponsors
Novartis
Dana-Farber Cancer Institute
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
* Melanomas that arise on chronically sun damaged skin and have pathologic evidence of solar elastosis * History of primary mucosal or acral/lentiginous melanoma * Histologically documented stage IV metastatic melanoma * ECOG performance status 0,1, or 2 * Estimated life expectancy of 6 months or greater * Age 18 years or older * Creatinine \< 1.5 x ULN * ANC \> 1500 ul * Platelets \> 100,000 ul * Total bilirubin, AST, and ALT \< 2 x ULN * Amylase and lipase \< 1.5 x ULN * C-kit mutation documented from either primary or metastatic tumor site * \> 4 weeks from prior chemotherapy or investigational drug * At least one measurable site of disease as defined by at least 1 cm in greatest dimension
Exclusion criteria
* Severe and/or uncontrolled medical disease * Pregnant or nursing mothers * Any other significant medical, surgical, or psychiatric condition that my interfere with compliance * Patient is \< 5 years free of another primary malignancy except: basal cell skin cancer or a cervical carcinoma in situ * Concurrent treatment with Warfarin * Prior treatment with c-kit inhibitor * Patient with Grade III/IV cardiac problems as defined by NYHA criteria * No H2 blockers or proton pump inhibitors * Known brain metastasis * Known chronic liver disease * Known diagnosis of HIV infection * Previous radiotherapy to \> 25% of the bone marrow * Major surgery within 2 weeks prior to study entry * Patient has received any other investigational agent within 28 days of first study drug dosing * Chemotherapy within 4 weeks prior to study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response | Disease was evaluated radiologically at baseline, after 6-weeks, and at 2-month intervals on treatment. Mean treatment duration was 4 months (range 1-11; amplified/mutated 3m/ 6m). | Best overall response (BOR) on treatment was based on RECIST 1.0 criteria. For target lesions, complete response (CR) is complete disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR or PR confirmation required within 4 weeks. Progressive disease (PD) is at least a 20% increase in the sum LD of target lesions from smallest sum LD as reference or the appearance of one or more new lesions. Stable disease (SD) is neither meeting PR or PD. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. CR is disappearance of all non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | Disease was evaluated radiologically at baseline, after 6-weeks, and at 2-month intervals on treatment and every 3 months long-term. Mean treatment duration was 4 months (range 1-11; amplified/mutated 3m/ 6m). | Time to progression (TTP) based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. |
| Overall Survival | Patients were followed long-term every 3 months until first progression, death or lost to follow-up. Median survival follow-up was 10.6 months (range 3.7-27.1). | Overall survival (OS) is defined as the time from study entry to death or date last known alive. |
Countries
United States
Participant flow
Recruitment details
The study was activated on July 6, 2006 and closed March 1, 2011. Patients enrolled from 9 medical centers beginning April 2007 through December 2010.
Participants by arm
| Arm | Count |
|---|---|
| Amplified KIT Imatinib was given at a dose of 400 mg orally daily (4 100 mg pills). Patients received treatment up to 12 months as long as they were receiving clinical benefit. Dosage may have been increased to twice daily if disease worsened and patient was in otherwise good clinical condition. Patients were classified into two cohorts based upon KIT molecular status. | 11 |
| Mutated KIT Imatinib was given at a dose of 400 mg orally daily (4 100 mg pills). Patients received treatment up to 12 months as long as they were receiving clinical benefit. Dosage may have been increased to twice daily if disease worsened and patient was in otherwise good clinical condition. Patients were classified into two cohorts based upon KIT molecular status. | 13 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Intercurrent Illness | 0 | 1 |
| Overall Study | Progressive Disease | 10 | 11 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Mutated KIT | Total | Amplified KIT |
|---|---|---|---|
| Age, Continuous | 64 years | 65 years | 69 years |
| Melanoma Type Acral | 2 participants | 6 participants | 4 participants |
| Melanoma Type Chronically Sun-Damaged | 0 participants | 1 participants | 1 participants |
| Melanoma Type Mucosal | 11 participants | 17 participants | 6 participants |
| Region of Enrollment United States | 13 participants | 24 participants | 11 participants |
| Sex: Female, Male Female | 11 Participants | 18 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 11 | 13 / 13 |
| serious Total, serious adverse events | 1 / 11 | 3 / 13 |
Outcome results
Primary
Best Overall Response
Best overall response (BOR) on treatment was based on RECIST 1.0 criteria. For target lesions, complete response (CR) is complete disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR or PR confirmation required within 4 weeks. Progressive disease (PD) is at least a 20% increase in the sum LD of target lesions from smallest sum LD as reference or the appearance of one or more new lesions. Stable disease (SD) is neither meeting PR or PD. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. CR is disappearance of all non-target lesions.
Time frame: Disease was evaluated radiologically at baseline, after 6-weeks, and at 2-month intervals on treatment. Mean treatment duration was 4 months (range 1-11; amplified/mutated 3m/ 6m).
Population: The analysis dataset is comprised of treated patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amplified KIT | Best Overall Response | Complete Response | 0 participants |
| Amplified KIT | Best Overall Response | Partial Response | 0 participants |
| Amplified KIT | Best Overall Response | Stable Disease | 2 participants |
| Amplified KIT | Best Overall Response | Progressive Disease | 9 participants |
| Mutated KIT | Best Overall Response | Progressive Disease | 3 participants |
| Mutated KIT | Best Overall Response | Complete Response | 0 participants |
| Mutated KIT | Best Overall Response | Stable Disease | 3 participants |
| Mutated KIT | Best Overall Response | Partial Response | 7 participants |
Secondary
Overall Survival
Overall survival (OS) is defined as the time from study entry to death or date last known alive.
Time frame: Patients were followed long-term every 3 months until first progression, death or lost to follow-up. Median survival follow-up was 10.6 months (range 3.7-27.1).
Population: The analysis dataset is comprised of treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amplified KIT | Overall Survival | 11.9 months |
| Mutated KIT | Overall Survival | 12.9 months |
Secondary
Time to Progression
Time to progression (TTP) based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Time frame: Disease was evaluated radiologically at baseline, after 6-weeks, and at 2-month intervals on treatment and every 3 months long-term. Mean treatment duration was 4 months (range 1-11; amplified/mutated 3m/ 6m).
Population: The analysis dataset is comprised of treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amplified KIT | Time to Progression | 3.4 months |
| Mutated KIT | Time to Progression | 3.9 months |