Melanoma (Skin)
Conditions
Keywords
recurrent melanoma
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.
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.
Interventions
DRUGpentamidine
Sponsors
National Cancer Institute (NCI)
University of Maryland, Baltimore
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Expression of S100B Pre Pentamidine Exposure | Pre-Study | Serum for S100B |
| 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 |
| Number of Participants With Serious and Non Serious Adverse Events | Up to 6 months | Metabolic Panel, Physical Exam, Vitals |
| 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. |
| Expression of S100B | Cycle 1 Day 8, Cycle 1 Day 12, Cycle 2 Day 8, Cycle 2 Day 12 | Serum for S100B level |
Countries
United States
Participant flow
Pre-assignment details
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
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm 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. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Treatment Arm |
|---|---|
| Age, Continuous | 63 years |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 2 / 6 |
Outcome results
Primary
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)
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
Population: Six participants analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pentamidine | Response Rate in Patients Treated With Pentamidine | 0 Participants |
Secondary
Expression of S100B
Serum for S100B level
Time frame: Cycle 1 Day 8, Cycle 1 Day 12, Cycle 2 Day 8, Cycle 2 Day 12
Population: Only data from 1 site was analyzed for this outcome measure
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pentamidine | Expression of S100B | C1D8 | 450 pg/ml |
| Pentamidine | Expression of S100B | C1D12 | 137 pg/ml |
| Pentamidine | Expression of S100B | C2D8 | 142.1 pg/ml |
| Pentamidine | Expression of S100B | C2D12 | 150 pg/ml |
Secondary
Expression of S100B Pre Pentamidine Exposure
Serum for S100B
Time frame: Pre-Study
Population: Only data for 1 site was analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pentamidine | Expression of S100B Pre Pentamidine Exposure | 332.5 pg/ml |
Secondary
Number of Participants With Both p21 and S100B Expression in Accessible Tumor Biopsies Pre Pentamidine Exposure in Cycle 1
Core Needle Tumor Biopsy
Time frame: Pre-Study, an average of 12 days
Population: Only data for 1 site was analyzed for this outcome measure
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pentamidine | Number of Participants With Both p21 and S100B Expression in Accessible Tumor Biopsies Pre Pentamidine Exposure in Cycle 1 | 3 Participants |
Secondary
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
Time frame: Day 12 Cycle 1
Population: Only 1 participant from 1 site had a biopsy collected and analyzed
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pentamidine | Number of Participants With p21 and S100B Expression in Accessible Tumor Biopsies Post Pentamidine Exposure | 1 Participants |
Secondary
Number of Participants With Serious and Non Serious Adverse Events
Metabolic Panel, Physical Exam, Vitals
Time frame: Up to 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pentamidine | Number of Participants With Serious and Non Serious Adverse Events | 6 Participants |
Secondary
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.
Time frame: Every 8 weeks, assesed up to 6 months
Population: Only data for 1 site was analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pentamidine | Time to Progression | 36 days |