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

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

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.

Study Overview

• Status: Terminated
• Conditions: Melanoma (Skin)
• Intervention / Treatment: Drug: pentamidine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Pentamidine	Drug: pentamidine

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Edward A. Sausville, MD, PhD, University of Maryland Greenebaum Cancer Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2008
• Primary Completion (ACTUAL): August 1, 2012
• Study Completion (ACTUAL): November 1, 2012

Study Registration Dates

• First Submitted: August 7, 2008
• First Submitted That Met QC Criteria: August 7, 2008
• First Posted (ESTIMATE): August 8, 2008

Study Record Updates

• Last Update Posted (ACTUAL): August 16, 2019
• Last Update Submitted That Met QC Criteria: August 14, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: recurrent melanoma
• 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; Anti-Infective Agents; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Trypanocidal Agents; Pentamidine
• Other Study ID Numbers: H-29873;HP-00040559; HP-00047658 (OTHER: University of Maryland Human Research Protections Office); CDR0000602047 (REGISTRY: PDQ (Physician Data Query)); CINJ-090803 (OTHER: Cancer Institute of New Jersey); 0220090161 (OTHER: UMDNJ IRB Number); R21CA135624 (NIH)