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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study of AT-101 in Recurrent Extensive Stage Small Cell Lung Cancer

Conditions
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Extensive Stage Small Cell Lung Cancer, Recurrent Small Cell Lung Cancer

Intervention / Treatment
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* Drug: R-(-)-gossypol acetic acid
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (R-(-)-gossypol)<br>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. | Drug: R-(-)-gossypol acetic acid<br>* Given orally<br>* Other names: AT-101;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Confirmed Tumor Response Defined to be Either a Complete Response (CR) or Partial Response (PR) | The number of successes will be estimated by counting the number of participants with confirmed responses. A confirmed tumor response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: A Complete Response (CR) requires the disappearance of all target lesions A Partial Response (PR) requires a >=30% decrease in the sum of the longest diameter of target lesions from baseline measurements. | During the first 6 courses of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Time | Estimated using the method of Kaplan-Meier. | From registration to death due to any cause, assessed up to 5 years | 
| Time to Disease Progression | Time to disease progression is defined as the time from registration to the earliest date documentation of disease progression. Estimated using the method of Kaplan-Meier. Per the RECIST criteria, progression is defined as at least a 20% increase in the sum of Longest Dimension (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | From registration to the earliest date documentation of disease progression, assessed up to 5 years | 
| Duration of Response |  | From the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented, assessed up to 5 years |