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

A Phase II Study of Nilotinib (AMN107) In TKI Resistant or Intolerant Patients With Metastatic Mucosal, Acral or Chronically Sun Damaged Melanoma

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.

Study Overview

• Status: Completed
• Conditions: Melanoma; Acral Melanoma; Mucosal Lentiginous Melanoma
• Intervention / Treatment: Drug: Nilotinib

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Santa Monica, California, United States, 90404
      • The Angeles Clinic and Research Institute
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Nilotinib; Other Names: Tasigna; AMN107

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).
Overall Survival	Overall survival (OS) is defined as the time from study entry to death or date last known alive.	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).
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.	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).

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Massachusetts General Hospital; Novartis; Beth Israel Deaconess Medical Center; Brigham and Women's Hospital
• Investigators: Principal Investigator: F. Stephen Hodi, MD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• Carvajal RD, Lawrence DP, Weber JS, Gajewski TF, Gonzalez R, Lutzky J, O'Day SJ, Hamid O, Wolchok JD, Chapman PB, Sullivan RJ, Teitcher JB, Ramaiya N, Giobbie-Hurder A, Antonescu CR, Heinrich MC, Bastian BC, Corless CL, Fletcher JA, Hodi FS. Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition. Clin Cancer Res. 2015 May 15;21(10):2289-96. doi: 10.1158/1078-0432.CCR-14-1630. Epub 2015 Feb 18.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2009
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: November 10, 2008
• First Submitted That Met QC Criteria: November 10, 2008
• First Posted (Estimate): November 11, 2008

Study Record Updates

• Last Update Posted (Actual): November 15, 2018
• Last Update Submitted That Met QC Criteria: October 16, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: nilotinib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma
• Other Study ID Numbers: 08-244

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO