Japanese Study of Ipilimumab Administered in Combination With Paclitaxel/Carboplatin in Patients With Nonsmall-cell Lung Cancer

Study Overview
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Brief Summary
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The primary purpose of this study was to establish the recommended dose of ipilimumab administered in combination with paclitaxel and carboplatin in Japanese patients with nonsmall-cell lung cancer.

Official Title
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Phase 1 Study of Ipilimumab (BMS-734016) in Combination With Paclitaxel and Carboplatin in Japanese Patients With Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Ipilimumab, 3 mg
* Drug: Ipilimumab, 10 mg
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically or cytologically documented nonsmall-cell lung cancer (NSCLC) presenting as stage IIIB disease without indications for definitive radiotherapy, stage IV disease, or recurrent disease following radiation therapy or surgical resection No prior chemotherapy, hormonal therapy, immunotherapy, or targeted-therapy-containing regimens for the treatment of NSCLC Life expectancy of at least 3 months Eastern Cooperative Oncology Group performance score of 0-1 Adequate bone marrow function Hemoglobin ≥9.0 g/dL Absolute neutrophil count ≥1,500/mm^3 Platelet count ≥100,000/mm^3 Adequate liver function Total bilirubin level ≤2.0*the upper limit of normal (ULN) Asparate aminotransferase level ≤2.5*ULN Alanine aminotransferase level ≤2.5*ULN Adequate renal function Calculated creatinine clearance based on Cockcroft and Gault formula ≥50 mL/min. Key Exclusion Criteria: Symptomatic central nervous system (CNS) metastasis or active CNS metastasis requiring medication Malignant body cavity fluid (eg, pleural effusion, cardiac effusion, ascites) that recurred despite appropriate supportive care Prior radiation of ≥30% of major bone-marrow containing areas (pelvis, lumbar spine) Documented history of severe autoimmune or immune-mediated symptomatic disease that required prolonged (longer than 2 months) systemic immunosuppressant treatment Documented history of motor neuropathy considered of autoimmune origin (eg, Guillain Barré syndrome) Any concurrent malignancy other than nonmelanoma skin cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast, carcinoma of the mucous membrane of the gastrointestinal tract, or superficial bladder cancer treated with systemic therapy ≥Grade 2 diarrhea History of or concurrent disease of gastrointestinal tract perforations ≥Grade 2 peripheral neuropathy (motor or sensory) Uncontrolled intercurrent illness including infection requiring systemic therapy, symptomatic congestive heart failure, uncontrolled hypertension, uncontrolled angina pectoris, uncontrolled peptic ulcer, and cardiac arrhythmia requiring medication Positive finding for human immunodeficiency virus antibody, hepatitis B surface antigen, or hepatitis C virus antibody.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1: Ipilimumab, 3 mg/kg + Paclitaxel + Carboplatin<br>Participants received ipilimumab, 3 mg/kg, administered as a single dose intravenously (IV) over 90 minutes every 3 weeks, plus paclitaxel, 175 mg/m^2 , administered as a single dose IV over 3 hours every 3 weeks (up to 6 doses), and carboplatin, area under the curve (AUC)=6, administered as a single dose IV over 30-60 minutes every 3 weeks (up to 6 doses). | Drug: Ipilimumab, 3 mg<br>* Intervenous (IV) injection, administered every 3 weeks for up to 6 cycles<br>Drug: Paclitaxel<br>* IV injection, 175 mg/m^2, administered every 3 weeks for up to 6 cycles<br>Drug: Carboplatin<br>* IV injection, AUC=6, administered every 3 weeks for up to 6 cycles. (AUC=area under the concentration curve)<br>|
| Experimental: Dose Level 2: Ipilimumab, 10 mg/kg + Paclitaxel + Carboplatin<br>Participants received ipilimumab, 10 mg/kg, administered as a single dose IV over 90 minutes every 3 weeks, plus paclitaxel, 175 mg/m^2 , administered as a single dose IV over 3 hours every 3 weeks (up to 6 doses), and carboplatin, AUC=6, administered as a single dose IV over 30-60 minutes every 3 weeks (up to 6 doses). | Drug: Ipilimumab, 10 mg<br>* IV injection, administered every 3 weeks for up to 6 cycles<br>* Other names: BMS-734016;Drug: Paclitaxel<br>* IV injection, 175 mg/m^2, administered every 3 weeks for up to 6 cycles<br>Drug: Carboplatin<br>* IV injection, AUC=6, administered every 3 weeks for up to 6 cycles. (AUC=area under the concentration curve)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | A DLT was defined as study drug-related adverse event occurring during the first 2 cycles after ipilimumab administration in the induction phase and was any of the following: Grade 4 absolute neutrophil count (ANC) decreased (<500 cells/ mm^3) for 7 or more consecutive days; febrile Neutropenia (body temperature ≥38.5° C with ANC <1000 /mm^3) lasting >3 days; Grade 4 platelet count decreased (<25,000 cells/mm^3) or Grade 3 platelet count decreased requiring a platelet transfusion; Grade 3 or greater nausea, vomiting, diarrhea, despite the use of adequate/maximal medical intervention; Grade 3 or greater aspartate transaminase/alanine transaminase level and rash that has not resolved to Grade 2 or lower within 2 weeks after onset; or any Grade 3 or greater nonhematologic toxicity (except Grade 3 fatigue, Grade 3 asthenia, Grade 3 transient arthralgia/myalgia, or Grade 3 transient abnormal electrolyte levels). | Day 1 of Cycles 1 and 2 From Day 1 of Cycle 3 to Day 21 of Cycle 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Death As Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Drug-related Adverse Events (AEs), AEs Leading to Discontinuation, Drug-related AEs Leading to Discontinuation | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or unknown relationship to study drug. AE incidence was assessed from Day 1 until Week 24 and every 12 weeks thereafter during the maintenance period, until discontinuation of study drug, due to progression of disease, toxicities requiring discontinuation, withdrawal of consent, or study closure, and at least every 4 weeks(±1 week) until all study drug-related toxicities had recovered to resolved, stabilized or returned to baseline or were deemed irreversible during the follow-up period). | Continuously from Day 1 to Week 24 and every12 weeks thereafter during maintenance until discontinuation of drug | 
| Number of Participants With Best Overall Response (BOR) of Partial Response (PR) or Stable Disease | Tumor response was determined for all participants with measurable lesions by radiologic responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The BOR was the best response recorded from start of treatment until disease progression/recurrence. RECIST for target lesions: PR=at least a 30% decrease in the sum of the longest dimension (LD) of target lesions, taking as reference the baseline sum LD; stable disease=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD since the treatment started. At minimum, tumor measurements were to be obtained at screening, every 6 weeks (±1 week) during the induction phase and every 12 weeks (±1 week) during the maintenance phase. | Day 1 of Cycle 3, Day 1 of Cycle 5, and Day 22 of Cycle 6 | 
| Maximum Serum Concentration (Cmax) of Ipilimumab | Cmax was recorded directly from experimental observations. Actual times were used for the analyses. Cmax measurements were performed during the 3rd cycle; at predose and at 1.5, 4 , 24 (Day 2), 48 (Day 3), 168 hrs (Day 8),and 336 (Day 15) hours postdose; during the 4th and subsequent cycle, predose ipilimumab; and off-treatment until progression of disease, toxicities requiring discontinuation, withdrawal of consent, or study closure. | During Cycle 3: predose and 1.5, 4, 24, 48, 168, and 336 hours postdose ipilimumab | 
| Trough Observed Serum Concentration (Cmin) of Ipilimumab | Cmin was recorded directly from experimental observations. Actual times were used for the analyses. Cmin measurements were performed during the 3rd cycle, at predose and at 1.5, 4 , 24 (Day 2), 48 (Day 3), 168 (Day 8), and 336 (Day 15) hours postdose; during the 4th and subsequent cycle, predose ipilimumab; and off-treatment until progression of disease, toxicities requiring discontinuation, withdrawal of consent; or study closure. | During Cycle 3: predose and 1.5, 4, 24, 48, 168, and 336 hours postdose ipilimumab | 
| Area Under the Concentration Curve From Time 0 to Day 21 (in 1 Interval Dosing) (AUC[0-21d]) for Ipilimumab | The AUC(0-21d) was calculated using a mixture of log- and linear-trapezoidal summations. Using no weighting factor, the terminal log-liner phase of the concentration-time curve was determined by least-square linear regression of at least 3 data points. Individual patient pharmacokinetic (PK) parameter values were derived by noncompartmental methods using a validated PK analysis program. Actual times were used for the analyses. AUC(0-21d) measurements were performed during the 3rd cycle, at predose and at 1.5, 4 , 24 (Day 2), 48 (Day 3), 168 hrs (Day 8),and 336 (Day 15) hours postdose; during the 4th and subsequent cycle, predose ipilimumab; and off-treatment until progression of disease, toxicities requiring discontinuation, withdrawal of consent; or study closure. | During Cycle 3: predose and 1.5, 4, 24, 48, 168, and 336 hours postdose ipilimumab | 
| Time of Maximum Observed Serum Concentration (Tmax) | Tmax was recorded directly from experimental observations. Actual times were used for the analyses. Tmax measurements were performed during the 3rd cycle; at predose and at 1.5, 4 , 24 (Day 2), 48 (Day 3), 168 hrs (Day 8),and 336 (Day 15) hours postdose; during the 4th and subsequent cycle, predose ipilimumab; and off-treatment until progression of disease, toxicities requiring discontinuation, withdrawal of consent, or study closure. | During Cycle 3: predose and 1.5, 4, 24, 48, 168, and 336 hours postdose ipilimumab | 
| Serum Half-life (T-HALF) of Ipilimumab | T-HALF was calculated as the ratio of ln(2) to elimination rate constant (K), where K was estimated as negative slope obtained by regression of the terminal log-linear portion of the serum concentration vs time profile following the ipilimumab dose on Day 1 of Cycle 3. Individual patient pharmacokinetic (PK) parameter values were derived by noncompartmental methods, using a validated PK analysis program. Actual times were used for the analyses. T-HALF measurements were performed during the 3rd cycle; at predose and at 1.5, 4 , 24 (Day 2), 48 (Day 3), 168 hrs (Day 8),and 336 (Day 15) hours postdose; during the 4th and subsequent cycle, predose ipilimumab; and off-treatment until progression of disease, toxicities requiring discontinuation, withdrawal of consent, or study closure. | During Cycle 3: predose and 1.5, 4, 24, 48, 168, and 336 hours postdose ipilimumab |