Ixabepilone in Combination With Carboplatin in Patients With Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the maximum tolerated dose, dose-limiting toxicity, and recommended Phase II dose of ixabepilone in combination with carboplatin in patients with non-small cell lung cancer.

Official Title
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A Phase I Study of Ixabepilone in Combination With Carboplatin in Patients With Non-small Cell Lung Cancer as First-line Treatment

Conditions
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Non-small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: Ixabepilone, 32 mg/m^2 + Carboplatin, 5 mg/min/mL
* Drug: Ixabepilone, 32 mg/m^2 + Carboplatin, 6 mg/min/mL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥20 years Histologic or cytologic diagnosis of advanced non-small cell lung cancer (NSCLC) Advanced NSCLC, defined as stage IIIB (without indications for radiotherapy), stage IV, or recurrent No prior chemotherapy-containing regimens for the treatment of NSCLC Eastern Cooperative Oncology Group performance status of 0-1 Life expectancy of at least 12 weeks Accessible for treatment and follow up; patients who could be hospitalized for first 15 days of Cycle 1 Adequate recovery from previous systemic therapy (at least 3 weeks for surgery or radiation therapy) Exclusion Criteria: Women of childbearing potential (WOCBP) unwilling or unable to use an acceptable method to avoid pregnancy for study period and for up to 4 weeks after last dose of study drug Women pregnant or breast feeding Women with a positive pregnancy test result on enrollment or prior to study drug administration Sexually active fertile men not using effective birth control for the entire study period and for up to 3 months after the last dose of study drug if their partners are WOCBP Patients with symptomatic or requiring treatment for brain metastases and/or leptomeningeal metastases Prior radiation must not have included ≥30% of major bone-marrow-containing areas (pelvis, lumbar spine) Common Terminology Criteria (CTC) Grade 2 or greater neuropathy Psychiatric or other disorders rendering the patient incapable of complying with protocol requirements Any concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ of the cervix (Patients with a history of malignancy but without evidence of disease for 5 years are eligible) Serious uncontrolled medical disorder or active systemic infection that would impair the ability of the subject to receive protocol therapy. Myocardial infarction, unstable angina, or unstable congestive heart failure within 6 months Known history of infection with human immunodeficiency virus Inadequate bone marrow function Inadequate hepatic function Inadequate renal function Known prior severe hypersensitivity reaction (CTC Grade 2 or greater) to agents containing Cremophor®EL Known severe hypersensitivity reaction to agents containing carboplatin and other platinum Prior treatment with an epothilone and/or with platinum History of high-dose chemotherapy with bone marrow transplant or peripheral blood stem cell support within 2 years On treatment with strong Cytochrome P450 3A4 inhibitor Current imprisonment Compulsorily detention for treatment of psychiatric or physical illness

Ages Eligible for Study
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Minimum Age: 20 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ixabepilone, 32 mg/m^2 + Carboplatin, 5 mg/min/mL<br> | Drug: Ixabepilone, 32 mg/m^2 + Carboplatin, 5 mg/min/mL<br>* On Day 1 of each 21-day cycle, ixabepilone, 32 mg/m^2, intravenous (IV) solution administered as a 3-hour infusion; 30 minutes after the end of ixabepilone infusion, carboplatin, 5 mg/min/mL, intravenous IV solution infused over 30 minutes. Repeated once every 3 weeks, for a maximum of 6 cycles.<br>* Other names: BMS-247550;|
| Active Comparator: Ixabepilone, 32 mg/m^2 + Carboplatin, 6 mg/min/mL<br> | Drug: Ixabepilone, 32 mg/m^2 + Carboplatin, 6 mg/min/mL<br>* After all participants in Dose Level 1 (ixabepilone, 32 mg/m^2 + carboplatin, 5 mg/min/mL) have been observed for 1 full 21-day cycle, Dose Level 2(ixabepilone, 32 mg/m^2 + carboplatin, 6 mg/min/mL) opened. On Day 1 of each 21-day cycle, ixabepilone, 32 mg/m^2, IV solution administered as a 3-hour infusion; 30 minutes after the end of ixabepilone infusion, carboplatin, 6 mg/min/mL, IV solution infused over 30 minutes. Repeated once every 3 weeks, for a maximum of 6 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicity (DLT) | DLT is defined as any of the following: Common Terminology Criteria (CTC), Version 3, Grade(Gr) 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for at least 5 days or febrile neutropenia; Gr 4 thrombocytopenia (<25,000 cells/mm^3 or bleeding needing platelet transfusion); Gr 3 or 4 nausea, vomiting, or diarrhea, despite medical intervention; any other drug-related Gr 3 or 4 nonhematologic toxicity, except Gr 3 injection site reaction, fatigue/asthenia, transient arthralgia/myalgia, or transient electrolytes abnormal. Gr 1=Mild; Gr 2=Moderate; Gr 3=Severe; Gr 4=Life-threatening. | Days 1 through 21 (Cycle 1) | 
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose of Carboplatin in Combination With Ixabepilone, 32 mg/m^2 | The MTD was defined as the highest dose evaluated for which less than one sixth of patients experience a DLT in Cycle 1. The recommended phase 2 dose is the MTD defined in Cycle 1, with consideration given to chronic cumulative toxicity occurring at later cycles. | Days 1 through 21 (Cycle 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Death as Outcome, Treatment-related Serious Adverse Events (SAEs), SAEs, Adverse Events (AEs), and Treatment-related AEs Leading to Discontinuation | An SAE is any untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires inpatient hospitalization or prolongs existing hospitalization. An AE is any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. Treatment-related comprises certainly, probably, and possibly related and of unknown relationship to study drug. | Days 1 through 21 (Cycle 1) | 
| Number of Participants With Grade 3 or Greater Treatment-related AEs | An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with treatment. AEs graded according to CTC, Version 3.0. Gr 1=Mild; Gr 2=Moderate; Gr 3=Severe; Gr 4=Life-threatening. Treatment-related comprises certainly, probably, and possibly related and of unknown relationship to study drug. | Days 1 through 21 (Cycle 1) | 
| Number of Participants With Abnormalities in Hematology Laboratory Values by Worst CTC Grade | LLN=lower level of normal; ULN=upper level of normal. Hemoglobin (g/dL; LLN=11.3; ULN=14.9); leukocytes (*10^3 c/uL; LLN=4.1; ULN=6.1); lymphocytes (*10^3 c/uL); neutrophils (absolute), neutrophils + bands (*10^3 c/uL); platelet count (*10^9 c/L; LLN=131; ULN=365) Appendix 7.1.2 | At screening and Days 8 and 15 of Cycle 1 (21 days) | 
| Number of Participants With Abnormalities in Serum Chemistry Laboratory Values by Worst CTC Grade | ULN=upper limit of normal; LLN=lower limit of normal. Alkaline phosphatase=ALP(LLN=115; ULN=359) (U/L); alanine aminotransferase=ALT (LLN=8; ULN=42)(U/L); aspartate aminotransferase=AST (LLN=13; ULN=33) (U/L); albumin (LLN=3.7; ULN=5.2)(g/dL); bilirubin (LLN=0.3; ULN=1.2)(mg/dL); calcium (LLN=8.7; ULN=10.3)(mg/dL); creatinine (LLN=0.6; ULN=1.1)(mg/dL); potassium (LLN=3.6; ULN=4.9) (mEq/L); sodium (LLN=138; ULN=146) (mEq/L) | At screening and Days 8 and 15 of Cycle 1 (21 days) | 
| Number of Participants With Abnormalities in Urine Testing Results by Worst CTC Grade | Toxicities graded according to CTC, Version 3. Protein Gr 1: <1.0 g/24 hrs (1+); Gr 2: 1.0 to 3.4 g/24 hrs (2+ to 3+ ); Gr 3: >=3.5 g/24 hrs (4+); Gr 4: Nephrotic syndrome. Note: + = qualitative measure of urine chemistry. | At screening and Days 8 and 15 of Cycle 1 (21 days) | 
| Number of Participants With Abnormalities in Blood Pressure and Heart Rate | Blood pressure and heart rate obtained before ixabepilone infusion, every 1 hour during and at the end of ixabepilone infusion, and at the end of carboplatin infusion in Cycle 1. For subsequent cycles, vital signs obtained before ixabepilone infusion, at the end of ixabepilone infusion, and at the end of carboplatin infusion. Any new or worsening clinically significant changes since last entry were recorded as appropriate AE or SAE. | At screening and Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (Study day 22) | 
| Number of Participants With Abnormalities in Weight and Eastern Cooperative Oncology Group (ECOG) Performance Status | Participants weighed same day as serum chemistry tests. Body surface area recalculated only if body weight changes >10%. ECOG criteria used to assess disease progression and affects on daily living abilities and to determine appropriate treatment and prognosis. Grade 1=Restricted physical activity but ambulatory and capable of light work; Grade 2=Ambulatory, capable of self care, but unable to carry out any work activities; Grade 3=Capable of limited self care, confined to bed or chair 50% or more of waking hours; Grade 4=Completely disabled, totally confined to bed or chair. | At screening of Cycle 1 (21 days) and Day 1 of Cycle 2 (Study day 22) | 
| Number of Participants at Each Response Evaluation Criteria in Solid Tumors (RECIST) Assessment | Tumor response was assessed using the RECIST assessment: Complete response (CR)=Disappearance of all clinical and radiologic evidence of target lesions; Partial response (PR)=At least 30% reduction in the sum of the longest diameters of all target lesions; Progressive disease (PD)=At least 20% increase in the sum of the longest diameters of all target lesions; Stable disease (SD)=Neither PR nor PD criteria were met. | Days 1 through 21 (Cycle 1) | 
| Maximum Observed Plasma Concentration of Ixabepilone |  | Days 1 to 8 of Cycle 1 (21 days) | 
| Time of Maximum Observed Plasma Concentration of Ixabepilone |  | Days 1 to 8 of Cycle 1 (21 days) | 
| Area Under the Plasma Concentration-time Curve (AUC) From Time Zero Extrapolated to Infinite Time of Ixabepilone |  | Days 1 to 8 of Cycle 1 (21 days) | 
| Volume of Distribution at Steady State of Ixabepilone |  | Days 1 to 8 of Cycle 1 (21 days) | 
| Total Body Clearance of Ixabepilone |  | Days 1 to 8 of Cycle 1 (21 days) |