Recurrent Small Cell Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific
Conditions
Brief summary
This phase I/II trial is studying the side effects and best dose of obatoclax mesylate when given together with topotecan hydrochloride and to see how well they work in treating patients with relapsed or refractory small cell lung cancer or advanced solid tumors. Obatoclax mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving obatoclax mesylate together with topotecan hydrochloride may help kill more tumor cells
Detailed description
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose, recommended phase II dose, and toxicity profile of obatoclax mesylate when administered with topotecan hydrochloride in patients with advanced solid tumors. (Phase I) II. Determine the response rate in patients with relapsed or refractory small cell lung cancer treated with obatoclax mesylate and topotecan hydrochloride. (Phase II) SECONDARY OBJECTIVES: I. Evaluate the expression of pro- and anti-apoptotic proteins which may correlate with obatoclax mesylate sensitivity or resistance. OUTLINE: This is a phase I dose-escalation study of obatoclax mesylate followed by a phase II study. PHASE I (solid tumor): Patients receive obatoclax mesylate IV over 3 hours on day 1 OR days 1 and 3 and topotecan hydrochloride IV over 30 minutes on days 1-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. PHASE II (small cell lung cancer): Patients receive obatoclax mesylate and topotecan hydrochloride at the recommended phase II dose (RPTD) determined in phase I. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Tumor tissue samples from patients with small cell lung cancer may be collected at baseline for correlative studies. Tissue samples are analyzed for biomarkers and protein expression of Bcl-2, Bcl-Xl, MCL-1, Bax, Bad, c-Myc, L-Myc, and N-Myc by immunohistochemistry. After completion of study treatment, patients are followed for 30 days.
Interventions
Given IV
DRUGtopotecan hydrochloride
Given IV
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 diagnosis of 1 of the following: * Advanced solid tumor (phase I) * Topotecan hydrochloride must be an appropriate treatment for this cancer * Small cell lung cancer (SCLC) (phase II) * Progressed after one prior platinum-based chemotherapy regimen * Pathology materials (tumor tissue) will be used for correlative studies, if available * No progressive brain metastases * Treated brain metastases allowed provided patient is neurologically stable and does not require steroids * No leptomeningeal involvement * ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100% * Leukocytes ≥ 3,000/mcL * Absolute neutrophil count ≥ 1,500/mcL * Platelet count ≥ 100,000/mcL * Total bilirubin normal * AST and ALT ≤ 2.5 times upper limit of normal * Creatinine normal OR creatinine clearance ≥ 60 mL/min * Not pregnant or nursing * Fertile patients must use effective double barrier method of contraception during and for 3 months after completion of study therapy * At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered * At least 4 weeks since prior radiotherapy and recovered * No concurrent combination antiretroviral therapy for HIV-positive patients * No other concurrent investigational agents or anticancer therapy
Exclusion criteria
* History of allergic reactions attributed to compounds of similar chemical or biological composition to obatoclax mesylate or topotecan hydrochloride (e.g., irinotecan) * Concurrent uncontrolled 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 * History of seizure disorder or other neurological dysfunction (except peripheral neuropathy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (Phase II) | Every 6 weeks, assessed up to 30 days | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR)=CR +PR |
Countries
United States
Participant flow
Recruitment details
Protocol Open to Accrual 8/7/2007 Primary Completion Date 8/10/2010 Recruitment Location at medical clinic
Participants by arm
| Arm | Count |
|---|---|
| Phase I Obatoclax Mesylate + Topotecan in Solid Tumors Level 1 Level 1: Obatoclax Mesylate (GX15-070MS) 3 hour infusion, days 1 (and 3), q21 days, 14 mg/m2: Topotecan days 1-5, q21 days, 1.25 mg/m2 | 6 |
| Phase I Obatoclax Mesylate + Topotecan in Solid Tumors Level 2 Level 2: Obatoclax Mesylate (GX15-070MS) 3 hour infusion, days 1 (and 3), q21 days, 20 mg/m2: Topotecan days 1-5, q21 days, 1.25 mg/m2 | 5 |
| Phase I Obatoclax Mesylate + Topotecan in Solid Tumors Level 3 Level 3: Obatoclax Mesylate (GX15-070MS) 3 hour infusion, days 1 (and 3), q21 days, 14 + 14 mg/m2: Topotecan days 1-5, q21 days, 1.25 mg/m2 | 3 |
| Phase I Obatoclax Mesylate + Topotecan in Solid Tumors Level 4 Level 4: Obatoclax Mesylate (GX15-070MS) 3 hour infusion, days 1 (and 3), q21 days, 20 + 20 mg/m2: Topotecan days 1-5, q21 days, 1.25 mg/m2 | 1 |
| Phase II Obatoclax Mesylate + Topotecan in SCLC Obatoclax Mesylate 14 + 14 mg/m2 and Topotecan 1.25 mg/m2 | 7 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Not Treated | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Progressive Disease | 4 | 2 | 2 | 0 | 6 |
Baseline characteristics
| Characteristic | Phase I Obatoclax Mesylate + Topotecan in Solid Tumors Level 1 | Phase I Obatoclax Mesylate + Topotecan in Solid Tumors Level 2 | Phase I Obatoclax Mesylate + Topotecan in Solid Tumors Level 3 | Phase I Obatoclax Mesylate + Topotecan in Solid Tumors Level 4 | Phase II Obatoclax Mesylate + Topotecan in SCLC | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 3 Participants | 2 Participants | 0 Participants | 4 Participants | 14 Participants |
| Region of Enrollment United States | 6 participants | 5 participants | 3 participants | 1 participants | 7 participants | 22 participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 1 Participants | 1 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 2 Participants | 0 Participants | 1 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 3 / 5 | 2 / 3 | 0 / 1 | 7 / 7 |
| serious Total, serious adverse events | 4 / 6 | 4 / 5 | 2 / 3 | 0 / 1 | 4 / 7 |
Outcome results
Primary
Overall Response Rate (Phase II)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR)=CR +PR
Time frame: Every 6 weeks, assessed up to 30 days
Population: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I; Level 1: Obatoclax Mesylate + Topetecan | Overall Response Rate (Phase II) | 0 participants |
| Phase I; Level 2: Obatoclax Mesylate + Topetecan | Overall Response Rate (Phase II) | 0 participants |
| Phase I; Level 3: Obatoclax Mesylate + Topetecan | Overall Response Rate (Phase II) | 0 participants |
| Phase II Obatoclax Mesylate + Topotecan in SCLC | Overall Response Rate (Phase II) | 0 participants |