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

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 may be 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: *For patients in the dose escalation portion of the study, cisplatin and etoposide
will be started on day 2 during course 1; they will be given on day 1 during all subsequent
courses.

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

- Measurable or evaluable disease

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