0794GCC: Pentamidine in Treating Patients With Relapsed or Refractory Melanoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as pentamidine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This phase II trial is studying how well pentamidine works in treating patients with relapsed or refractory melanoma.

Detailed Description
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OBJECTIVES: Primary To determine the response rate in patients with relapsed or refractory melanoma that expresses wild-type p53 and S100 calcium binding protein B (S100B) treated with pentamidine. Secondary To observe the effect of this drug on the expression of S100B and p21 in tumor biopsy samples. To observe the effect of this drug on S100B detectable in serum. To observe the time to progression in these patients. To assess the toxicities associated with the administration of this drug in these patients. OUTLINE: Patients receive pentamidine IV over 2 hours 5 days a week for 2 weeks. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo tumor tissue and blood sample collection periodically for correlative laboratory studies. Samples are assessed for p53 status and S100B, p53, and p21 expression by immunohistochemistry, polymerase chain reaction, western blotting, luminescence assay, and ELISA. After completion of study treatment, patients are followed for 30 days.

Official Title
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Treatment of Melanoma With Wild-type p53 and Detectable S100B Using Pentamidine: a Phase II Trial With Correlative Biomarker Endpoints

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Drug: pentamidine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed melanoma Relapsed or refractory disease Tumor expresses wild-type p53 Measurable S100B by immunohistochemistry Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques or as ≥ 10 mm by spiral CT scan Tumor amenable to biopsy Must have been evaluated for potentially curative resection No unstable or symptomatic brain metastases (e.g., seizures, headache related to tumor, or presence of neurologic deficits attributable to tumor) Patients with stable brain metastases (by CT scan or MRI) are eligible provided they were treated with local therapy > 4 weeks ago AND do not require maintenance steroid treatment PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy > 12 weeks White Blood Cell count (WBC) ≥ 3,000/mcL Absolute Neutrophil Count (ANC) ≥ 1,500/mcL Platelet count ≥ 80,000/mcL Hemoglobin ≥ 8 g/dL Total bilirubin ≤ 1.5 times normal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times upper limit of normal Creatinine ≤ 1.5 times normal or creatinine clearance ≥ 60 mL/min Not pregnant or nursing Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment Able to take oral medications on a regular basis No history of allergic reactions attributed to pentamidine Mean Corrected QT Interval (QTc) ≤ 470 msec (with Bazett's correction) on screening ECG No history of familial long QT syndrome Proteinuria ≤ 1 on two consecutive dipsticks taken ≥ 1 week apart No concurrent uncontrolled illness including, but not limited to, any of the following: Hypertension Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Renal failure Cardiac arrhythmia Psychiatric illness/social situations that would limit compliance with study requirements PRIOR CONCURRENT THERAPY: Recovered from all prior therapy Any number of prior chemotherapy regimens allowed More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) More than 4 weeks since prior radiotherapy or major surgery More than 30 days since prior participation in an investigational trial No concurrent medication that may markedly affect renal function (e.g., vancomycin, amphotericin, zoledronic acid) No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent investigational agents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is an open label Phase II trial that will utilize a Simon two stage acquisition of patients with evaluable relapsed and/or refractory melanoma.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pentamidine<br> | Drug: pentamidine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate in Patients Treated With Pentamidine | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease, taking as reference the smallest sum of the longest diameter since the treatment started. (Therasse, P., Arbuck, S.G., Eisenhauer, E.A., Wanders, J., Kaplan, R.S., Rubinstein, J., Van Glabbeke, M., van Oosterom, A.T., Christian, M.C., Gwyther, S.G. (2000) J Natl Cancer Inst 92, 205-16) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Both p21 and S100B Expression in Accessible Tumor Biopsies Pre Pentamidine Exposure in Cycle 1 | Core Needle Tumor Biopsy | Pre-Study, an average of 12 days | 
| Number of Participants With p21 and S100B Expression in Accessible Tumor Biopsies Post Pentamidine Exposure | Core needle tumor biopsy - at Day 12 at first cycle of treatment | Day 12 Cycle 1 | 
| Expression of S100B Pre Pentamidine Exposure | Serum for S100B | Pre-Study | 
| Expression of S100B | Serum for S100B level | Cycle 1 Day 8, Cycle 1 Day 12, Cycle 2 Day 8, Cycle 2 Day 12 | 
| Number of Participants With Serious and Non Serious Adverse Events | Metabolic Panel, Physical Exam, Vitals | Up to 6 months | 
| Time to Progression | Radiologic intervention using RECIST (x-ray, CT, MRI) Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR., or similar definition that is accurate and appropriate. | Every 8 weeks, assesed up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent melanoma