Acral Melanoma, Melanoma, Mucosal Lentiginous Melanoma
Conditions
Keywords
nilotinib
Brief summary
Given the poor prognosis and limited treatment options available for patients with mucosal or acral/lentiginous melanomas who develop metastatic disease, genetic discoveries of KIT mutations in these cancers present the need to test multi-targeted kinase inhibitors with potent KIT inhibitory activity in this patient population. Imatinib and other tyrosine kinase inhibitors (TKIs) have the potential to be effective in this patient population, but patients may develop resistance to treatment. Therefore, in this study, we propose to test nilotinib in patients with metastatic mucosal, acral, or chronically sun-damaged melanoma following treatment with another TKI.
Detailed description
OBJECTIVES: Primary \* To estimate the proportion of patients, with metastatic mucosal, acral, or chronically sun damaged melanomas, whose tumors have KIT aberrations, and who progressed or could not tolerate a KIT targeting tyrosine kinase inhibitor (TKI) (e.g. including but not limited to imatinib mesylate, sunitinib, or dasatanib), who are alive and without progression of disease four months after beginning treatment with nilotinib. Secondary * To determine early evidence of biologic and clinical activity by best overall response rate. * To estimate time to progression of disease and overall survival. * To determine the tolerability of nilotinib. * To evaluate the use of FDG-PET scanning in determining early biologic response to therapy. * To correlate c-kit mutational status and amplification status with response to therapy. * To evaluate the feasibility of nilotinib. * To evaluate the tolerability of nilotinib in patients with brain metastases.
Interventions
DRUGNilotinib
Sponsors
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Beth Israel Deaconess Medical Center
Massachusetts General Hospital
Novartis
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
* 18 years of age or older * Histologically documented diagnosis of mucosal melanoma or acral melanoma or chronically sun damaged melanoma as evidenced by solar elastosis on pathology * Patient's tumor with evidence for KIT mutation or amplification. Patient tumors that already have documented mutations or amplification do not have to have tissue submitted again for analysis to confirm eligibility * Have failed, progressed, or not been able to tolerate other tyrosine kinase inhibitors including but not limited to imatinib mesylate, sunitinib or dasatinib treatment. * At least one measurable site of disease * ECOG Performance Status 0, 1 or 2 * Adequate organ function as outlined in the protocol * Negative pregnancy test for female patients of childbearing potential
Exclusion criteria
* Patient has received any other investigational agents within 28 days of first day of study drug dosing unless the disease is rapidly progressing * Patient is \< 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 a cervical carcinoma in situ * Female patients who are pregnant or breast-feeding * Patient has a severe and/or uncontrolled medical disease * Patient has a rare hereditary problem of galactose intolerance, severe lactase deficiency or of glucose-galactose malabsorption * Patient with electrolyte abnormality unless the level can be corrected to normal levels prior to initiating study drug * Known brain metastasis * Known chronic liver disease * Patient has received chemotherapy within 4 weeks prior to study entry, unless the disease is rapidly progressing (6 weeks for nitrosourea or mitomycin-C) * Patient previously received radiotherapy to 25% or greater of the bone marrow * Patient had a major surgery within 2 weeks prior to study entry * Impaired cardiac function * QTc \> 450msec on screening ECG * Myocardial infarction within one year prior to starting nilotinib * Other clinically significant heart disease * Patients who are currently receiving treatment with any of the medications that have the potential to prolong QT interval * Patients who are currently receiving Warfarin \> 1mg/day * Patient with any significant history of non-compliance to medical regimens or with the inability to grant reliable informed consent * Prior therapy with nilotinib
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 4-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 4 months. | 4-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 4 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 |
|---|---|---|
| Progression-Free Survival | 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 5.5 months (range 0-45; no/with CNS mets 7.4m/ 3m). | Progression-free survival (PFS) 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 or death. 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 16.2 months (90%CI 11.7-17.7 months; no/with CNS mets 16.2m/ 11.7m). | Overall survival (OS) is defined as the time from study entry to death or date last known alive. |
| Best Overall Response | 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 5.5 months (range 0-45; no/with CNS mets 7.4m/ 3m). | 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. |
Countries
United States
Participant flow
Recruitment details
The study was activated on January 23, 2009 and closed early in December 2011 due to slow accrual. Patients enrolled from 8 medical centers beginning March 2009 through June 2011.
Participants by arm
| Arm | Count |
|---|---|
| No CNS Metastastic Cohort Nilotinib was given at a dose of 400 mg orally daily (200 mg pills twice per day). Patients received treatment up to 12 months as long as they were receiving clinical benefit. Patients were classified into two cohorts based upon presence or absence of measurable brain metastases. | 11 |
| CNS Metastatic Cohort Nilotinib was given at a dose of 400 mg orally daily (200 mg pills twice per day). Patients received treatment up to 12 months as long as they were receiving clinical benefit. Patients were classified into two cohorts based upon presence or absence of measurable brain metastases. | 8 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Patient Non-Compliance | 1 | 0 |
| Overall Study | Patient's measurable disease resected. | 1 | 0 |
| Overall Study | Progressive Disease | 8 | 6 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | CNS Metastatic Cohort | Total | No CNS Metastastic Cohort |
|---|---|---|---|
| Age, Continuous | 60 years | 67 years | 68 years |
| CNS Metastatic Status CNS Metastaic: No | 0 Participants | 11 Participants | 11 Participants |
| CNS Metastatic Status CNS Metastaic: Yes | 8 Participants | 8 Participants | 0 Participants |
| ECOG Performance Status ECOG PS0 | 4 Participants | 11 Participants | 7 Participants |
| ECOG Performance Status ECOG PS1 | 4 Participants | 8 Participants | 4 Participants |
| ECOG Performance Status ECOG PS2 | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 10 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 3 Participants |
| Melanoma Type Acral | 3 participants | 6 participants | 3 participants |
| Melanoma Type Chronically Sun-Damaged (CSD) | 1 participants | 3 participants | 2 participants |
| Melanoma Type Mucosal | 4 participants | 10 participants | 6 participants |
| 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 | 1 Participants | 1 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 | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 16 Participants | 10 Participants |
| Region of Enrollment United States | 8 Participants | 19 Participants | 11 Participants |
| Sex: Female, Male Female | 5 Participants | 14 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 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 | 6 / 8 |
| serious Total, serious adverse events | 3 / 11 | 1 / 8 |
Outcome results
Primary
4-month Progression-Free Survival Rate
4-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 4 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 4 months.
Population: The analysis dataset is comprised of treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No CNS Metastastic Cohort | 4-month Progression-Free Survival Rate | 0.27 proportion of patients |
| CNS Metastatic Cohort | 4-month Progression-Free Survival Rate | 0.125 proportion of patients |
Secondary
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 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 5.5 months (range 0-45; no/with CNS mets 7.4m/ 3m).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| No CNS Metastastic Cohort | Best Overall Response | Unevaluable | 1 participants |
| No CNS Metastastic Cohort | Best Overall Response | Complete Response | 0 participants |
| No CNS Metastastic Cohort | Best Overall Response | Partial Response | 2 participants |
| No CNS Metastastic Cohort | Best Overall Response | Stable Disease | 4 participants |
| No CNS Metastastic Cohort | Best Overall Response | Progressive Disease | 4 participants |
| CNS Metastatic Cohort | Best Overall Response | Progressive Disease | 1 participants |
| CNS Metastatic Cohort | Best Overall Response | Stable Disease | 6 participants |
| CNS Metastatic Cohort | Best Overall Response | Complete Response | 0 participants |
| CNS Metastatic Cohort | Best Overall Response | Unevaluable | 1 participants |
| CNS Metastatic Cohort | Best Overall Response | Partial Response | 0 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 16.2 months (90%CI 11.7-17.7 months; no/with CNS mets 16.2m/ 11.7m).
Population: The analysis dataset is comprised of treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| No CNS Metastastic Cohort | Overall Survival | 14.2 months |
| CNS Metastatic Cohort | Overall Survival | 4.3 months |
Secondary
Progression-Free Survival
Progression-free survival (PFS) 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 or death. 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 5.5 months (range 0-45; no/with CNS mets 7.4m/ 3m).
Population: The analysis dataset is comprised of treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| No CNS Metastastic Cohort | Progression-Free Survival | 3.4 months |
| CNS Metastatic Cohort | Progression-Free Survival | 2.4 months |