Extensive Stage Small Cell Lung Cancer, Recurrent Small Cell Lung Cancer
Conditions
Brief summary
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
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.
Interventions
Given orally
OTHERpharmacological study
Correlative studies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Confirmed Tumor Response Defined to be Either a Complete Response (CR) or Partial Response (PR) | During the first 6 courses of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival Time | From registration to death due to any cause, assessed up to 5 years | Estimated using the method of Kaplan-Meier. |
| Time to Disease Progression | From registration to the earliest date documentation of disease progression, assessed up to 5 years | 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. |
| 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 | — |
Countries
United States
Participant flow
Recruitment details
From November 2008 to January 2010, 15 patients were accrued to the study from five sites within the Mayo Clinic Phase 2 Consortium and the California Consortium.
Pre-assignment details
One patient discontinued therapy after one cycle of treatment due to persistent grade 1 thrombocytopenia. Therefore, fourteen patients were evaluable for the primary end point at the interim analysis. All 15 patients were included in secondary endpoint analysis.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (R-(-)-Gossypol) 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. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Treatment (R-(-)-Gossypol) |
|---|---|
| Age, Continuous | 67.0 years |
| Region of Enrollment Australia | 1 participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 4 / 15 |
Outcome results
Primary
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.
Time frame: During the first 6 courses of treatment
Population: One patient discontinued therapy after one cycle of treatment due to persistent grade 1 thrombocytopenia. Therefore, fourteen patients were evaluable for the primary end point at the interim analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (R-(-)-Gossypol) | Number of Participants With Confirmed Tumor Response Defined to be Either a Complete Response (CR) or Partial Response (PR) | Confirmed Complete Response (CR) | 0 participants |
| Treatment (R-(-)-Gossypol) | Number of Participants With Confirmed Tumor Response Defined to be Either a Complete Response (CR) or Partial Response (PR) | Confirmed Partial Response (PR) | 0 participants |
Secondary
Duration of Response
Time frame: 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
Population: There were no confirmed responses qualifying for this endpoint.
Secondary
Survival Time
Estimated using the method of Kaplan-Meier.
Time frame: From registration to death due to any cause, assessed up to 5 years
Population: All 15 patients were analyzed for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (R-(-)-Gossypol) | Survival Time | 8.5 months |
Secondary
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.
Time frame: From registration to the earliest date documentation of disease progression, assessed up to 5 years
Population: All 15 patients were analyzed for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (R-(-)-Gossypol) | Time to Disease Progression | 1.7 months |