Gossypol, Cisplatin, and Etoposide in Treating Patients With Advanced Solid Tumors or Extensive Stage Small Cell Lung Cancer

Condition(s) targeted: Lung Cancer; Unspecified Adult Solid Tumor, Protocol Specific

Intervention: L-gossypol (Drug); cisplatin (Drug); etoposide (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: University of Wisconsin, Madison

Official(s) and/or principal investigator(s):
George Wilding, MD, Principal Investigator, Affiliation: University of Wisconsin, Madison

RATIONALE: Gossypol may stop the growth of cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as cisplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving gossypol together with combination chemotherapy may help kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of gossypol when given together with cisplatin and etoposide in treating patients with advanced solid tumors or extensive stage small cell lung cancer.

Official title: A Phase 1 Study of R-(-)-Gossypol (AT-101) in Combination With Cisplatin and Etoposide in Patients With Advanced Solid Tumors and Extensive-Stage Small Cell Lung Cancer

Study design: Treatment

Primary outcome:

Toxicity and tolerability

Response (complete and partial response, stable disease, or progressive disease; early death from systemic progression, CNS progression, or both; early death from toxicity, early death because of other cause, or unknown) as assessed by RECIST criteria

Secondary outcome: Pharmacokinetics

Detailed description: OBJECTIVES:

Primary

- To determine the maximum tolerated dose or recommended phase II dose of R-(-)-gossypol

when combined with cisplatin and etoposide in patients with advanced, refractory solid tumors and/or extensive stage small cell lung cancer (ES-SCLC).

- To evaluate the toxicity and tolerability of R-(-)-gossypol in combination with

cisplatin and etoposide in patients with advanced, refractory solid tumors and/or ES-SCLC.

- To evaluate the antitumor activity of this combination per tumor measurements using the

RECIST criteria.

Secondary

- To evaluate the pharmacokinetics of R-(-)-gossypol as a single agent and in combination

with cisplatin and etoposide in plasma.

- To perform pharmacodynamic studies (i. e., genotyping of drug metabolizing enzymes, gene

expression, and proteomics of drug-related pathways) on archived blood samples from patients treated with R-gossypol in combination with cisplatin and etoposide.

OUTLINE: This is a dose-escalation study of R-(-)-gossypol.

Patients receive oral R-(-)-gossypol twice daily on days 1-3, cisplatin IV over 60 minutes on day 1*, and etoposide IV over 30 minutes on days 1*-3. Treatment repeats every 21 days for up to 6 courses during the dose escalation and 4 courses in the expanded extensive stage small cell lung cancer cohort, in the absence of disease progression or unacceptable toxicity.

Blood samples are collected on day 1 of courses 1 and 2 for pharmacokinetic analysis, biomarker assays, and correlative studies.

After completion of study treatment, patients are followed for 30 days.

NOTE: *Cisplatin and etoposide will be started on day 2 during course 1; they will be given on day 1 during all subsequent courses.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Diagnosis of 1 of the following:

- Histologically confirmed malignancy that is metastatic or unresectable and for

which standard curative or palliative measures do not exist or are no longer effective (dose-escalation cohorts)

- Histologically or cytologically confirmed extensive stage small cell lung cancer

(ES-SCLC) (maximum tolerated dose expansion cohort)

- Patients with small cell lung carcinoma and brain metastases should have

stable/improved lesions for at least 1 month following treatment, no neurological symptoms, and no requirement for corticosteroids

- Prior whole-brain radiotherapy for brain metastases allowed for patients with

small cell lung carcinoma

PATIENT CHARACTERISTICS:

Inclusion criteria

- ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)

- Life expectancy > 12 weeks

- Leukocytes ≥ 3,000/mcL

- Absolute neutrophil count ≥ 1,500/mcL (no transfusions allowed)

- Platelets ≥ 100,000/mcL (no transfusions allowed)

- Total bilirubin < 1. 5 mg/dL

- AST(SGOT)/ALT(SGPT) ≤ 2. 5 X institutional upper limit of normal

- Serum creatinine < 1. 5 X institutional upper limit of normal OR creatinine clearance ≥

45 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for at least 1 month

after completion of study treatment

Exclusion criteria

- History of allergic reactions attributed to compounds of similar chemical or biologic

composition to L-gossypol or other agents used in study

- Any condition (e. g., gastrointestinal tract disease resulting in an inability to take

oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs ability to swallow and retain R-(-)-gossypol tablets

- Patients with malabsorption syndrome, disease significantly affecting gastrointestinal

function, or resection of the stomach or small bowel

- Patients with ulcerative colitis, inflammatory bowel disease, or a partial or complete

small bowel obstruction

- Uncontrolled intercurrent illness including, but not limited to, any of the

following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situations that would limit compliance with study

requirements

- Patients with > grade 2 symptomatic hypercalcemia (based on investigator discretion)

PRIOR CONCURRENT THERAPY:

Inclusion criteria

- See Disease Characteristics

- Recovered from prior therapy

- At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin C)

- At least 4 weeks since prior radiotherapy

- More than 4 weeks since prior and no other concurrent investigational agents

- Concurrent routine use of erythropoietin allowed at investigator's discretion

Exclusion criteria

- Prior therapy that inhibits the Bcl-2 family

- Prior chemotherapy or radiotherapy in patients with ES-SCLC

- Prior use of R-(-)-gossypol

- Requirement for routine or prophylactic use of hematopoietic growth factors (including

granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, or interleukin-11)

- Concurrent combination antiretroviral therapy for HIV-positive patients

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin 53792-6164, United States; Recruiting
Clinical Trials Office - University of Wisconsin Paul P. Carbo, Phone: 608-262-5223

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: September 2007
Last updated: October 8, 2008