Tipifarnib in Treating Patients With Metastatic Malignant Melanoma

Study Overview
=================
Brief Summary
-----------------
This phase II trial is studying how well tipifarnib works in treating patients with metastatic malignant melanoma. Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To estimate the clinical response rate in patients with metastatic malignant melanoma treated with R115777 (tipifarnib). II. To evaluate the safety of R115777 in patients with metastatic melanoma. SECONDARY OBJECTIVES: I. To assess RhoC expression in tumor samples pre- and post- therapy with R115777. II. To evaluate Ftase levels in peripheral blood and tumor samples pre- and post-therapy with R115777. III. To assess the effect of R115777 treatment on T lymphocyte cytokine production, pre- and post- therapy with R115777. IV. Estimate time to treatment failure (TTF). Time to treatment failure is defined as time to withdrawal for unacceptable toxicity or progressive disease. OUTLINE Patients receive oral tipifarnib twice daily on days 1-21. Treatment repeats every 28 days for at least 2 courses and for a maximum of 2 years in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response (CR) receive 2 additional courses beyond CR. Patients who discontinue therapy due to toxicity or complete response are followed every 3 months for 2 years after study entry. Patients who discontinue therapy due to disease progression are followed every 6 months for 2 years after study entry. Patients with stable or partially responding disease who complete treatment are followed at 2 years after study entry.

Official Title
-----------------
PHASE II TRIAL OF R115777 IN PATIENTS WITH METASTATIC MALIGNANT MELANOMA

Conditions
-----------------
Recurrent Melanoma, Stage IV Melanoma

Intervention / Treatment
-----------------
* Drug: tipifarnib
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological or cytological diagnosis of cutaneous melanoma and clinical evidence of distant metastatic, non-resectable regional lymphatic, or extensive in transit recurrent disease Patients must have at least 2 cutaneous lesions amenable to excisional biopsy for correlative studies; in addition, patients must have measurable disease; the disease remaining after the first excisional biopsy must be measurable; lesions that are considered intrinsically non-measurable include the following: Bone lesions Leptomeningeal disease Ascites Pleural/pericardial effusion Lymphangitis cutis/pulmonis Abdominal masses that are not confirmed and followed by imaging techniques Cystic lesions Lesions that are situated in a previously irradiated area No history of brain metastases No allergies to azoles (e.g. ketoconazole) or allergies to compounds structurally similar to R115777 No more than 1 prior immunotherapy regimen for treatment of advanced melanoma; an additional immunologic therapy in the adjuvant setting (e.g. IFN-a) is acceptable; prior chemotherapy for any stage of melanoma is not allowed No radiotherapy or immunotherapy within four weeks prior to the initiation of therapy on this study CTC (ECOG) performance status 0-1 Non-pregnant, non-nursing; treatment under this protocol would expose an unborn child to significant risks; women and men of reproductive potential should agree to use an effective means of birth control; women of child-bearing age will undergo pregnancy testing ANC >= 1500/uL Platelets >= 100,000/uL Bilirubin =< 1.5 mg/dL Creatinine =< 2.0 mg/dL

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (tipifarnib)<br>Patients receive oral tipifarnib twice daily on days 1-21. Treatment repeats every 28 days for at least 2 courses and for a maximum of 2 years in the absence of disease progression or unacceptable toxicity. Patients who achieve CR receive 2 additional courses beyond CR. | Drug: tipifarnib<br>* Given orally<br>* Other names: Zarnestra;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (complete response [CR] and partial response [PR]} | Estimated confidence intervals will be adjusted for the number of stages. | Up to 2 years | 
| Progression-free survival (PFS) | Estimated using the method of Kaplan and Meier. | From date of entry onto the trial until documented progression or death from any cause, assessed up to 2 years | 
| Time to treatment failure (TTF) | Estimated using the method of Kaplan and Meier. | From trial entry until a patient ends protocol therapy due to unacceptable toxicity, progression or death from any cause, assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between RhoC expression levels and response |  | From baseline to up to 2 years | 
| Change in FTAse levels |  | From baseline to up to 2 years | 
| Change in the production of IL-2 and IFN-g by T cells | Descriptive statistics will be used to describe the mean and spread of production of IL-2 and IFN-g. | From baseline to up to 2 years | 
| Adverse events as assessed by Common Toxicity Criteria (CTC) version 2.0 |  | Up to 2 years |