R-(-)-Gossypol Acetic Acid in Treating Patients With Recurrent Extensive-Stage Small Cell Lung Cancer

National Cancer Institute (NCI)

Status and phase: Completed; Phase 2

Conditions: Recurrent Small Cell Lung Cancer; Extensive Stage Small Cell Lung Cancer

Treatments: Drug: R-(-)-gossypol acetic acid; Other: laboratory biomarker analysis; Other: pharmacological study

Study type: Interventional

Funder types: NIH

Identifiers

NCT00773955

MC0721 (Other Identifier)

P30CA015083 (U.S. NIH Grant/Contract)

NCI-2009-01058 (Registry Identifier)

N01CM62209 (U.S. NIH Grant/Contract)

8027 (Other Identifier)

MAYO-MC0721

N01CM62205 (U.S. NIH Grant/Contract)

CDR0000616965

Details and patient eligibility

About

This phase II trial is studying how well R-(-)-gossypol acetic acid works in treating patients with recurrent extensive-stage small cell lung cancer. Drugs used in chemotherapy, such as R-(-)-gossypol acetic acid, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Full description

PRIMARY OBJECTIVES:

I. To determine the objective response rate of R-(-)-gossypol in patients with recurrent chemotherapy-sensitive extensive stage small cell lung cancer.

II. To determine the time to disease progression. III. To determine the overall survival. IV. To assess the toxicities associated with this drug. V. To explore whether intratumoral Bcl-2 family member expression correlates with sensitivity to targeting by R-(-)-gossypol.

VI. To explore whether the administration of R-(-)-gossypol causes specific induction of the intrinsic apoptotic pathway.

OUTLINE: This is a multicenter study.

Patients receive oral R-(-)-gossypol once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood is collected periodically during treatment for pharmacodynamic analysis. Peripheral blood mononuclear cells are analyzed via protein isolation and western blotting for Bcl-2, cytoplasmic release of cytochrome c, and caspase activation. Available tumor tissue blocks are assessed by immunohistochemistry.

After completion of study therapy, patients are followed periodically for up to 5 years.

Enrollment: 15 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Histologically or cytologically confirmed small cell lung cancer

  • Extensive stage disease
  • Recurrent disease

• Measurable disease

• Chemotherapy-sensitive disease, defined as:

  • No progression during first-line chemotherapy
  • No disease recurrence < 2 months after completion of first-line chemotherapy

• Must have received prior platinum-based chemotherapy

• No symptomatic or progressive brain metastases

  • Patients with previously treated brain metastases who are clinically and radiographically stable or improved and have been off steroids ≥ 14 days are eligible

• ECOG performance status 0-2

• Life expectancy > 12 weeks

• Leukocytes ≥ 3,000/μL

• ANC ≥ 1,500/μL

• Platelet count ≥ 100,000/μL

• Total bilirubin < 1.5 mg/dL

• AST and ALT ≤ 2.5 times upper limit of normal

• Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min

• Hemoglobin > 8 g/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception before, during, and for 30 days after completion of study therapy

• Able to take oral medications on a regular basis

• Willing to provide blood samples for mandatory correlative studies

• No condition that impairs the ability to swallow and retain R-(-)-gossypol tablets, including the following:

  • Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation
  • Active peptic ulcer disease

• No malabsorption syndrome or disease significantly affecting gastrointestinal function

• No ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction

• No uncontrolled concurrent 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

• No symptomatic hypercalcemia > grade 2

• No requirement for routine use of hematopoietic growth factors (including G-CSF, GM-CSF, or IL-11) or platelet transfusions to maintain ANC or platelet counts

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to R-(-)-gossypol

• No HIV positivity

• Recovered from all prior therapy, including prior surgical procedures

• No prior surgical procedures affecting absorption

• No prior resection of the stomach or small bowel

• No more than one prior chemotherapy regimen

• No prior racemic gossypol or R-(-)-gossypol

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)

• At least 4 weeks since prior radiotherapy, hormonal agents, or biologic response modifiers

• At least 4 weeks since prior and no concurrent investigational agents or devices

• No concurrent prophylactic hematopoietic growth factors (including filgrastim [G-CSF], sargramostim [GM-CSF], or interleukin-11 [IL-11]) during course one

• No concurrent combination antiretroviral therapy for HIV-positive patients

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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15 participants in 1 patient group

Treatment (R-(-)-gossypol)

Experimental group

Description:

Patients receive oral R-(-)-gossypol once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Treatment:

Other: laboratory biomarker analysis

Other: pharmacological study

Drug: R-(-)-gossypol acetic acid