Acral Lentiginous Malignant Melanoma, Mucosal Lentiginous Melanoma
Conditions
Keywords
Sutent, malignant melanoma
Brief summary
The purpose of this study is to evaluate how effective Sunitinib works in treating acral lentiginous and mucosal melanoma which has spread beyond the local region. Suninitib is a protein-tyrosine kinase inhibitor and acts as a c-kit inhibitor drug. It is believed to work by blocking signals on certain cancer cells which allow the malignant cells to multiply and spread due to a change in the genetic make up of the cancer cell.
Detailed description
OBJECTIVES: Primary * To determine the proportion of participants with metastatic mucosal or acral/lentiginous melanoma who are alive and without disease progression at two months after beginning treatment with sunitinib. * To determine the best overall response rate. Secondary * To determine the time to progression and overall survival. * 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. * To assess amplification of c-kit status through quantitative PCR and/or FISH and other related molecular pathway targets.
Interventions
DRUGSunitinib
Sponsors
Beth Israel Deaconess Medical Center
Massachusetts General Hospital
Pfizer
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
* History of primary mucosal or acral/lentiginous melanoma * Histologically documented stage III unresectable or IV metastatic melanoma * ECOG Performance Status 0,1 or 2 * Estimated life expectancy of 6 months or greater * 18 years of age or older * Lab values as outlined in protocol * Tumor blocks or slides must be available of either primary or metastatic tumor site for c-kit mutation testing * Negative pregnancy test within 48 hours of starting treatment * At least one measurable site of disease as defined by at least 1cm in greatest dimension
Exclusion criteria
* Severe and/or uncontrolled medical disease * Pregnant or nursing mothers * Known brain metastasis. History of or known spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease on screening CT or MRI scan * Less than 5 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or cervical carcinoma in situ * Grade III/IV cardiac problems as defined by the New York Heart Association Criteria * Ongoing cardiac dysrhythmias of grade 2 or greater, atrial fibrillation, QTc interval \>450msec for males of \>470 msec for females * Hypertension that cannot be controlled by medication * Any of the following within 12 months prior to starting treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism * NCI CTCAE version 3.0 grade 3 hemorrhage within 4 weeks of starting the study treatment * Concurrent treatment with warfarin * Prior treatment with SU011248 or any other antiangiogenic agent * No H2 blockers or proton pump inhibitors * Known chronic liver disease * Known HIV infection * Previous radiotherapy to 25% or more of the bone marrow and/or radiation therapy within 4 weeks prior to study entry * Major surgery within 4 weeks prior to study entry * Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2-month Progression-free Survival Rate | Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Treatment continued for 12 months unless disease progression or unacceptable toxicity. Relevant for this endpoint was disease status at 2 months. | 2-month progression-free survival rate was defined as the proportion of patients absent death or progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST) before 2 months. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate | Disease was evaluated radiologically at baseline and every 8 weeks on treatment. Mean treatment duration was 3 cycles (Cohort A/B mean 2/3 cycles). The range of treatment duration overall was 1-11 cycles. | The best overall response rate was defined as achieving partial response (PR) or complete response (CR) on treatment based on RECIST 1.0 criteria. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response criteria are first met. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new 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 6.7 months (range 0.8-47.3 months; Cohort A/B median 7.7 m/ 6.2 m). | Overall survival (OS) is defined as the time from study entry to death or date last known alive. |
| Time to Progression | Disease was evaluated radiologically at baseline and every 8 weeks on treatment and long-term every 3 months until first progression, death or lost to follow-up. Mean treatment duration was 3 cycles (range 1-11; Cohort A/B mean 2/3 cycles). | Time to progression 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. |
Countries
United States
Participant flow
Recruitment details
The study, conducted at 7 medical centers, was activated on August 8, 2007 and closed on August 1, 2014. Patient enrollment to Cohort A occurred from September 2007 to January 2009 and Cohort B from March 2009 to June 2013.
Pre-assignment details
The trial was amended in 2009 to revise sunitinib dosing due to difficulty with tolerability and evidence of progressive disease following treatment breaks. As such, there are two study cohorts: the first employing intermittent dosing of Sunitinib (Cohort A) and the second with continuous dosing (Cohort B).
Participants by arm
| Arm | Count |
|---|---|
| Cohort A-Sunitinib Intermittent Dosing Cohort A participants received 50 mg sunitinib orally daily for 4 weeks followed by a two-week break from treatment. These 6-week cycles would be repeated until progression or unacceptable toxicity up to 1 year. | 21 |
| Cohort B-Sunitinib Continuous Dosing Cohort B participants received 37.5 mg sunitinib daily on a continuous basis until progression or unacceptable toxicity up to 1 year. | 31 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 6 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Intercurrent Illness | 1 | 2 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Progressive Disease | 17 | 19 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort A-Sunitinib Intermittent Dosing | Total | Cohort B-Sunitinib Continuous Dosing |
|---|---|---|---|
| Age, Continuous | 63 years | 63 years | 63 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 49 Participants | 28 Participants |
| Region of Enrollment United States | 21 participants | 52 participants | 31 participants |
| Sex: Female, Male Female | 10 Participants | 30 Participants | 20 Participants |
| Sex: Female, Male Male | 11 Participants | 22 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 21 | 24 / 31 |
| serious Total, serious adverse events | 10 / 21 | 13 / 31 |
Outcome results
Primary
2-month Progression-free Survival Rate
2-month progression-free survival rate was defined as the proportion of patients absent death or progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST) before 2 months. 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 and every 8 weeks on treatment; Treatment continued for 12 months unless disease progression or unacceptable toxicity. Relevant for this endpoint was disease status at 2 months.
Population: The analysis dataset is comprised of treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A-Sunitinib Intermittent Dosing | 2-month Progression-free Survival Rate | .52 proportion of patients |
| Cohort B-Sunitinib Continuous Dosing | 2-month Progression-free Survival Rate | .52 proportion of patients |
Secondary
Best Overall Response Rate
The best overall response rate was defined as achieving partial response (PR) or complete response (CR) on treatment based on RECIST 1.0 criteria. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response criteria are first met. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Disease was evaluated radiologically at baseline and every 8 weeks on treatment. Mean treatment duration was 3 cycles (Cohort A/B mean 2/3 cycles). The range of treatment duration overall was 1-11 cycles.
Population: The analysis dataset is comprised of treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A-Sunitinib Intermittent Dosing | Best Overall Response Rate | 0.095 proportion of participants |
| Cohort B-Sunitinib Continuous Dosing | Best Overall Response Rate | 0.065 proportion of 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 6.7 months (range 0.8-47.3 months; Cohort A/B median 7.7 m/ 6.2 m).
Population: The analysis dataset is comprised of treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A-Sunitinib Intermittent Dosing | Overall Survival | 7.7 months |
| Cohort B-Sunitinib Continuous Dosing | Overall Survival | 6.8 months |
Secondary
Time to Progression
Time to progression 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 and every 8 weeks on treatment and long-term every 3 months until first progression, death or lost to follow-up. Mean treatment duration was 3 cycles (range 1-11; Cohort A/B mean 2/3 cycles).
Population: The analysis dataset is comprised of treated patients. The majority of patients were off-treatment due to disease progression and thus the relevant observation time frame for this outcome is time on treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A-Sunitinib Intermittent Dosing | Time to Progression | 2.7 months |
| Cohort B-Sunitinib Continuous Dosing | Time to Progression | 3.6 months |