Nilotinib in TKI Resistant or Intolerant Patients With Metastatic Mucosal, Acral, or Chronically Sun Damaged Melanoma

Phase 2

Completed

Conditions: Mucosal Lentiginous Melanoma
Acral Melanoma
Melanoma

Interventions: Drug: Nilotinib

Registration Number: NCT00788775

Lead Sponsor: Dana-Farber Cancer Institute

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Nilotinib	Nilotinib	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (8): Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States
The Angeles Clinic and Research Institute
🇺🇸
Santa Monica, California, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
University of Chicago
🇺🇸
Chicago, Illinois, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
University of Colorado
🇺🇸
Aurora, Colorado, United States