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

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00729807
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 6
• Location: 1
• Arm: 1
• Actual Duration (Months): 52
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Melanoma (Skin)	Drug: pentamidine	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention 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.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)
• Primary Purpose: Treatment
• Official Title: Treatment of Melanoma With Wild-type p53 and Detectable S100B Using Pentamidine: a Phase II Trial With Correlative Biomarker Endpoints
• Actual Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pentamidine	Drug: pentamidine

Outcome Measures

Primary Outcome Measures

1. Response Rate in Patients Treated With Pentamidine [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]

   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)

Secondary Outcome Measures

1. Number of Participants With Both p21 and S100B Expression in Accessible Tumor Biopsies Pre Pentamidine Exposure in Cycle 1 [Pre-Study, an average of 12 days]

   Core Needle Tumor Biopsy

2. Number of Participants With p21 and S100B Expression in Accessible Tumor Biopsies Post Pentamidine Exposure [Day 12 Cycle 1]

   Core needle tumor biopsy - at Day 12 at first cycle of treatment

3. Expression of S100B Pre Pentamidine Exposure [Pre-Study]

   Serum for S100B

4. Expression of S100B [Cycle 1 Day 8, Cycle 1 Day 12, Cycle 2 Day 8, Cycle 2 Day 12]

   Serum for S100B level

5. Number of Participants With Serious and Non Serious Adverse Events [Up to 6 months]

   Metabolic Panel, Physical Exam, Vitals

6. Time to Progression [Every 8 weeks, assesed up to 6 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• University of Maryland, Baltimore
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Edward A. Sausville, MD, PhD, University of Maryland Greenebaum Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT00729807
• Other Study ID Numbers: H-29873;HP-00040559; CDR0000602047; HP-00047658; CINJ-090803; 0220090161; R21CA135624
• First Posted: Aug 8, 2008
• Last Update Posted: Aug 16, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by University of Maryland, Baltimore: recurrent melanoma
• Additional relevant MeSH terms: Melanoma; Pentamidine

Study Results

Participant Flow

Pre-assignment Detail	Pre-treatment Evaluation: Following informed consent, patients will be scheduled for a biopsy of accessible tumor. The specimen will be assessed for p53 status by sequencing and S100B, p53, and p21 expression

Arm/Group Title	Treatment Arm
Arm/Group Description	Pentamidine isethionate will be administered at a dose of 4 mg/kg/day over 120 minutes each day, Monday - Friday for two weeks followed by a drug free period of 2 weeks.
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment Arm
Arm/Group Description	Patients will receive 4 mg/kg/day IV pentamidine isethionate infused slowly over 2 hours on each treatment day. Each treatment cycle will consist of 2 weeks of therapy, five days per week, followed by 2 weeks of observation.
Overall Participants	6
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	63
Sex: Female, Male (Count of Participants)
Female	3 50%
Male	3 50%

Outcome Measures

1. Primary Outcome

Title	Response Rate in Patients Treated With Pentamidine
Description	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)
Time Frame	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

Outcome Measure Data

Analysis Population Description

Six participants analyzed.

Arm/Group Title	Pentamidine
Arm/Group Description	Pentamidine isethionate will be administered at a dose of 4 mg/kg/day over 120 minutes each day, Monday - Friday for two weeks followed by a drug free period of 2 weeks.
Measure Participants	6
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Number of Participants With Both p21 and S100B Expression in Accessible Tumor Biopsies Pre Pentamidine Exposure in Cycle 1
Description	Core Needle Tumor Biopsy
Time Frame	Pre-Study, an average of 12 days

Outcome Measure Data

Analysis Population Description

Only data for 1 site was analyzed for this outcome measure

Arm/Group Title	Pentamidine
Arm/Group Description	Pentamidine isethionate will be administered at a dose of 4 mg/kg/day over 120 minutes each day, Monday - Friday for two weeks followed by a drug free period of 2 weeks.
Measure Participants	4
Count of Participants [Participants]	3 50%

3. Secondary Outcome

Title	Number of Participants With p21 and S100B Expression in Accessible Tumor Biopsies Post Pentamidine Exposure
Description	Core needle tumor biopsy - at Day 12 at first cycle of treatment
Time Frame	Day 12 Cycle 1

Outcome Measure Data

Analysis Population Description

Only 1 participant from 1 site had a biopsy collected and analyzed

Arm/Group Title	Pentamidine
Arm/Group Description	Pentamidine isethionate will be administered at a dose of 4 mg/kg/day over 120 minutes each day, Monday - Friday for two weeks followed by a drug free period of 2 weeks.
Measure Participants	1
Count of Participants [Participants]	1 16.7%

4. Secondary Outcome

Title	Expression of S100B Pre Pentamidine Exposure
Description	Serum for S100B
Time Frame	Pre-Study

Outcome Measure Data

Analysis Population Description

Only data for 1 site was analyzed for this outcome measure.

Arm/Group Title	Pentamidine
Arm/Group Description	Pentamidine isethionate will be administered at a dose of 4 mg/kg/day over 120 minutes each day, Monday - Friday for two weeks followed by a drug free period of 2 weeks.
Measure Participants	4
Median (Full Range) [pg/ml]	332.5

5. Secondary Outcome

Title	Expression of S100B
Description	Serum for S100B level
Time Frame	Cycle 1 Day 8, Cycle 1 Day 12, Cycle 2 Day 8, Cycle 2 Day 12

Outcome Measure Data

Analysis Population Description

Only data from 1 site was analyzed for this outcome measure

Arm/Group Title	Pentamidine
Arm/Group Description	Pentamidine isethionate will be administered at a dose of 4 mg/kg/day over 120 minutes each day, Monday - Friday for two weeks followed by a drug free period of 2 weeks.
Measure Participants	4
C1D8	450
C1D12	137
C2D8	142.1
C2D12	150

6. Secondary Outcome

Title	Number of Participants With Serious and Non Serious Adverse Events
Description	Metabolic Panel, Physical Exam, Vitals
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentamidine
Arm/Group Description	Pentamidine isethionate will be administered at a dose of 4 mg/kg/day over 120 minutes each day, Monday - Friday for two weeks followed by a drug free period of 2 weeks.
Measure Participants	6
Count of Participants [Participants]	6 100%

7. Secondary Outcome

Title	Time to Progression
Description	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.
Time Frame	Every 8 weeks, assesed up to 6 months

Outcome Measure Data

Analysis Population Description

Only data for 1 site was analyzed for this outcome measure.

Arm/Group Title	Pentamidine
Arm/Group Description	Pentamidine isethionate will be administered at a dose of 4 mg/kg/day over 120 minutes each day, Monday - Friday for two weeks followed by a drug free period of 2 weeks.
Measure Participants	3
Median (Full Range) [days]	36

Adverse Events

Arm/Group Title	Treatment Arm
Arm/Group Description	Pentamidine isethionate will be administered at a dose of 4 mg/kg/day over 120 minutes each day, Monday - Friday for two weeks followed by a drug free period of 2 weeks.
All Cause Mortality
	Treatment Arm
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment Arm
	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)
Infections and infestations
Infection	1/6 (16.7%)	1
Metabolism and nutrition disorders
Hypoglycemia	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	Treatment Arm
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
Deep vein thrombosis	1/6 (16.7%)	1
Edema	1/6 (16.7%)	2
Neutropenia	1/6 (16.7%)	1
Reduced hemoglobin	1/6 (16.7%)	1
Cardiac disorders
Heart palpitation	1/6 (16.7%)	1
Sinus tachycardia	2/6 (33.3%)	2
Gastrointestinal disorders
Anorexia	2/6 (33.3%)	2
Dry heaves	1/6 (16.7%)	2
Increase in GERD symptoms	1/6 (16.7%)	1
Metallic taste in mouth	1/6 (16.7%)	1
Vomiting	2/6 (33.3%)	2
General disorders
Fatigue	3/6 (50%)	3
Headache	1/6 (16.7%)	1
Hypoalbuminemia	1/6 (16.7%)	1
Hypokalemia	1/6 (16.7%)	1
Hypotension	2/6 (33.3%)	3
Infiltration	1/6 (16.7%)	2
Insomnia	1/6 (16.7%)	1
Malaise	1/6 (16.7%)	1
Nausea	3/6 (50%)	5
Proteinuria	2/6 (33.3%)	3
Upper back pain	1/6 (16.7%)	1
Weakness	2/6 (33.3%)	2
Metabolism and nutrition disorders
Dehydration	1/6 (16.7%)	1
Hyperglycemia	2/6 (33.3%)	8
Hypoglycemia	3/6 (50%)	6
Nervous system disorders
Numbness of the face	1/6 (16.7%)	2
Psychiatric disorders
Anxiety	2/6 (33.3%)	2
Renal and urinary disorders
Blood in urine	2/6 (33.3%)	2
Creatinine	2/6 (33.3%)	4
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/6 (16.7%)	2
Sinus congestion	1/6 (16.7%)	1
Skin and subcutaneous tissue disorders
Erythema	1/6 (16.7%)	2
Rash	1/6 (16.7%)	1
Wound re-open	1/6 (16.7%)	1
Vascular disorders
Intermittent hypotension	1/6 (16.7%)	2

Limitations/Caveats

Unable to reach the target number of participants needed before study was closed at the suggestion of DSMB

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.