Phase II Study for Previously Untreated Subjects With Non Small Cell Lung Cancer (NSCLC) or Small Cell Lung Cancer (SCLC)

Study Overview
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Brief Summary
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The purpose of the study is to determine whether ipilimumab given with paclitaxel/carboplatin has clinical benefit when compared with paclitaxel/carboplatin alone in patients with previously untreated lung cancer.

Official Title
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A Randomized, Double Blind, Parallel, Three Arm Trial Evaluating the Efficacy and Safety of Ipilimumab (BMS-734016) in Combination With Paclitaxel/Carboplatin Compared to Paclitaxel/Carboplatin Alone in Previously Untreated Subjects With Lung Cancer

Conditions
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Lung Cancer, Small Cell Lung Cancer, Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Ipilimumab
* Drug: Placebo
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed lung cancer (Stage IIIb/IV nonsmall-cell lung cancer or extensive stage small-cell lung cancer [SCLC]) Measurable tumor lesion (as long as it is not located in a previously irradiated area) as defined by modified World Health Organization criteria Eastern Cooperative Oncology Group performance status of ≤1 at study entry Accessible for treatment and follow-up Exclusion Criteria: Brain metastases Malignant pleural effusion Autoimmune disease Motor neuropathy of autoimmune origin SCLC-related paraneoplastic syndromes Any concurrent malignancy other than nonmelanoma skin cancer; carcinoma in situ of the cervix or breast; or prostate cancer treated with systemic therapy (participants with a previous malignancy but without evidence of disease for 5 years were allowed to enter the study) Prior systemic therapy for lung cancer. Prior radiation therapy or locoregional surgeries performed later than at least 3 weeks prior to randomization date were allowed. Grade 2 peripheral neuropathy (motor or sensory) Known HIV or hepatitis B or C infection Chronic use of immunosuppressants and/or systemic corticosteroids (used in the management of cancer or noncancer-related illnesses). However, use of corticosteroids was allowed if used as premedication for paclitaxel infusion or for treating immune-related adverse events or adrenal insufficiencies. Inadequate hematologic function defined by an absolute neutrophil count <1,500/mm^3, a platelet count <100,000/mm^3, or hemoglobin level <9 g/dL. Inadequate hepatic function defined by a total bilirubin level >2.0 times the upper limit of normal (ULN), or ≥2.5 times the ULN if liver metastases are present, aspartate aminotransferase and alanine aminotransferase levels ≥2.5 times the ULN or ≥5 times the ULN if liver metastases are present. Inadequate renal function defined by a serum creatinine level ≥2.5 times the ULN Inadequate creatinine clearance defined as less than 50 mL/min.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ipilimumab/ placebo + paclitaxel + carboplatin (concurrent)<br> | Drug: Ipilimumab<br>* Ipilimumab, 10 mg/kg, administered as a single-dose, intravenously (IV), over 90 minutes depending on randomization every 3 weeks (up to 6 doses). Participants could receive additional maintenance ipilimumab at a dose of 10 mg/kg every 12 weeks starting 24 weeks after the first ipilimumab dose.<br>Drug: Placebo<br>* Matched placebo for ipilimumab administered as a single dose IV over 90 minutes every 3 weeks (up to 6 doses) as part of induction. Participants could also receive additional maintenance placebo administered IV over 90 minutes every 12 weeks starting 24 weeks after the first placebo dose.<br>Drug: Paclitaxel<br>* 175 mg/m^2, administered as a single IV dose over 3 hours every 3 weeks (up to 6 doses). Dose modifications (reductions as well as delays) done as per product label.<br>Drug: Carboplatin<br>* Area under the concentration curve (AUC)=6, administered as a single IV dose over 30 minutes every 3 weeks (up to 6 doses) as per randomization. Dose modifications (reductions as well as delays) done as per product label.<br>|
| Experimental: Ipilimumab/ placebo + paclitaxel + carboplatin (sequential)<br> | Drug: Ipilimumab<br>* Ipilimumab, 10 mg/kg, administered as a single-dose, intravenously (IV), over 90 minutes depending on randomization every 3 weeks (up to 6 doses). Participants could receive additional maintenance ipilimumab at a dose of 10 mg/kg every 12 weeks starting 24 weeks after the first ipilimumab dose.<br>Drug: Placebo<br>* Matched placebo for ipilimumab administered as a single dose IV over 90 minutes every 3 weeks (up to 6 doses) as part of induction. Participants could also receive additional maintenance placebo administered IV over 90 minutes every 12 weeks starting 24 weeks after the first placebo dose.<br>Drug: Paclitaxel<br>* 175 mg/m^2, administered as a single IV dose over 3 hours every 3 weeks (up to 6 doses). Dose modifications (reductions as well as delays) done as per product label.<br>Drug: Carboplatin<br>* Area under the concentration curve (AUC)=6, administered as a single IV dose over 30 minutes every 3 weeks (up to 6 doses) as per randomization. Dose modifications (reductions as well as delays) done as per product label.<br>|
| Active Comparator: Ipilimumab placebo + paclitaxel + carboplatin<br> | Drug: Placebo<br>* Matched placebo for ipilimumab administered as a single dose IV over 90 minutes every 3 weeks (up to 6 doses) as part of induction. Participants could also receive additional maintenance placebo administered IV over 90 minutes every 12 weeks starting 24 weeks after the first placebo dose.<br>Drug: Paclitaxel<br>* 175 mg/m^2, administered as a single IV dose over 3 hours every 3 weeks (up to 6 doses). Dose modifications (reductions as well as delays) done as per product label.<br>Drug: Carboplatin<br>* Area under the concentration curve (AUC)=6, administered as a single IV dose over 30 minutes every 3 weeks (up to 6 doses) as per randomization. Dose modifications (reductions as well as delays) done as per product label.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune-related Progression-free Survival (irPFS) in Participants With Nonsmall-cell Lung Cancer (NSCLC) Per Immune-related Response Criteria (irRC) | irPFS is defined as the time between the randomization date and date of immune-related Progressive Disease (irPD) (at least 25% increase percentage change in total tumor burden, including new lesions) or death, whichever occurs first. For patients with no recorded postbaseline tumor assessments, irPFS is censored at randomization. Participant who die without reported irPD are considered to have progressed on the date of death. For those who remain alive and have no irPD, irPFS is censored on the date of last evaluable tumor assessment. Independent review committee performed tumor assessment. | Tumor assessed at screening, every 6 weeks on treatment to Week 24, and every 12 weeks on maintenance until immune-related Progressive Disease (irPD) or death (of censored, maximum reached: 16.5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) in Participants With NSCLC Per Modified World Health Organization (mWHO) Criteria | By mWHO criteria, PFS is defined as the time between the randomization date and the date of progression or death, whichever occurs first. For participants with no recorded postbaseline tumor assessment, PFS was censored at the day of randomization. A participant who died without reported prior progression was considered to have progressed on the date of death. For those who remain alive and have not progressed, PFS was censored on the date of last evaluable tumor assessment. Independent review committee performed tumor assessment. | Randomization date to date of progression or death (of censored, maximum reached: 13.6 months) | 
| Overall Survival in Participants With NSCLC | Overall Survival is defined as the time from the date of randomization until the date of death. For participants who have not died, Overall Survival was censored at the recorded last date of contact; participants with a missing recorded last date of contact were censored at the last date the participant was known to be alive. | Randomization date to date of death (of censored, maximum reached: 26.5 months) | 
| Best Overall Response Rate (BORR) Per mWHO Criteria in Participants With NSCLC and SCLC | mWHO criteria define BORR as the number of patients with best overall response of Complete Response (CR) or Partial Response (PR), divided by the total number of participants in the data set (multiplied by 100 for percentage). CR=Complete disappearance of all index lesions; PR=decrease from baseline of >=50% in the sum of products of the 2 largest perpendicular diameters of all index lesions. Independent review committee performed tumor assessment. | Tumor assessment at screening, every 6 weeks on treatment to Week 24, and every 12 weeks on maintenance | 
| Immune-related Best Overall Response Rate (irBORR) Per irRC in Participants With NSCLC and Small-cell Lung Cancer (SCLC) | irBORR=number of participants with irBORR of immune-related Complete Response (irCR) or immune-related Partial Response (irPR), divided by total participants in the data set. irCR=Complete disappearance of all index lesions. irPR=Decrease, relative to baseline, of 50% or greater in the sum of the products of the 2 largest perpendicular diameters of all index and of all new measurable lesions. Independent review committee performed the tumor assessments. | Tumor assessment at screening, every 6 weeks on treatment to Week 24, and every 12 weeks on maintenance | 
| Immune-related Disease Control Rate (irDCR) Per irRC and Disease Control Rate (DCR) Per mWHO Criteria in Participants With NSCLC and SCLC | irDCR is defined as the proportion of participants whose immune-related best overall response is irPR, irCR, or immune-related Stable Disease (irSD) in the analysis data set. irSD=Does not meet criteria for irCR or irPR, in the absence of progressive disease. By mWHO criteria, DCR is defined as the proportion of participants whose best overall response is PR, CR, or SD in the analysis data set. SD=A decrease or tumor stabilization of 1 or more nonindex lesions. Independent review committee assessed response. | Tumor assessment at screening, every 6 weeks on treatment to Week 24, and every 12 weeks on maintenance until irPD, progressive disease, or death (maximum reached: 22 months) | 
| Immune-related Duration of Response (irDoR) Per irRC and DoR Per mWHO Criteria in Participants With NSCLC and SCLC | irDoR is defined as the time between the date of response of confirmed irCR or irPR and the date of irPD or death, whichever occurs first. For those participants who remain alive and did progress following response, irDoR was censored on the date of last evaluable tumor assessment. By mWHO criteria, DoR is defined as the time between the date of response of confirmed CR or PR and the date of PD or death, whichever occurs first. For those who remain alive and did not progress following response, DoR was censored on the date of last evaluable tumor assessment. | Date of irCR or irPR to date of irPD or death (maximum reached: 14.2 months) | 
| Number of Participants With NSCLC Who Have Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs), AEs Leading to Discontinuation, and Drug-related AEs by Worst Common Terminology Criteria (CTC) Grade | 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. Drug-related=possibly, probably, or certainly related to and of unknown relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. | Weeks 4, 7, 10, 16, 19, and 24; at end of treatment; and at follow-up (70 days from last dose) | 
| Percentage of Participants With NSCLC Who Have Abnormalities in On-study Hematology Laboratory Test Results by Worst CTC Grade | CTC, Version 3 used to assess parameters. LLN=lower limit of normal. CTC criteria: ANC=absolute neutrophil count. White blood cells Grade (Gr) 1:<LLN to 3.0*10^9/L, Gr 2:<3.0 to 2.0*10^9/L, Gr 3:<2.0 to 1.0*10^9/L, Gr 4:<1.0*10^9/L. ANC Gr 1:<LLN to 1.5*10^9/L, Gr 2:<1.5 to 1.0*10^9/L, Gr 3:<1.0 to 0.5*10^9/L, Gr 4:<0.5*10^9/L. Platelet count Gr 1:LLN to 75.0*10^9/L, Gr 2:<75.0 to 50.0*10^9/L, Gr 3:<50.0 to 25.0*10^9/L, Gr 4:<25.0 to 10^9/L. Hemoglobin Gr 1:<LLN to 10.0 g/dL, Gr 2:<10.0 to 8.0 g/dL, Gr 3:<8.0 to 6.5 g/dL, Gr 4:<6.5 g/dL. | At screening; predose Day 1; and Weeks 4, 7, 10, 13, 16, 19, and 24; and every 12 weeks on maintenance until disease progression, study closure, or withdrawal of consent | 
| irPFS in Participants With SCLC Per irRC | IRC performed TA. | Randomization date to date of irPD or death (maximum reached: 22 months) | 
| Number of Participants With NSCLC Who Have Abnormalities in On-Study Liver Function Test Results By Worst CTC Grade | ULN=Upper limit of normal among all laboratory ranges. ALT=alanine transaminase; AST=aspartate aminotransferase; ALK=alkaline phosphatase. CTC grade criteria: ALT Grade 1:>ULN to 2.5*ULN; Grade 2: >2.5 to 5.0*ULN; Grade 3: >5.0 to 20.0*ULN; Grade 4: >20.0*ULN. AST Grade 1: >ULN to 2.5*ULN; Grade 2: >2.5 to 5.0*ULN; Grade 3: >5.0 to 20.0*ULN; Grade 4: >20.0*ULN. Total bilirubin Grade 1: >ULN to 1.5*ULN; Grade 2: >1.5 to 3.0*ULN; Grade 3: >3.0 to 10.0*ULN; Grade 4: >10.0*ULN. ALK (U/L) G1:>ULN to 2.5*ULN, G2:>2.5 to 5.0*ULN, G3:>5.0 to 20.0*ULN, G4:>20.0*ULN. | At screening; predose Day 1; Weeks 4, 7, 10, 13, 16, 19, and 24; and every 12 weeks on maintenance until disease progression, study closure, or withdrawal of consent | 
| Number of Participants With NSCLC Who Had Abnormalities in Vital Sign Measurements and Physical Examination Findings | Vital signs measurements consisted of systolic and diastolic blood pressure, heart rate, temperature, and respiratory rate. Physical examinations assessed weight, height, performance status, and body surface area. | At screening; Day 1; Weeks 4, 7, 10, 13, 16, and 24; and every 12 weeks on maintenance until disease progression, study closure, or withdrawal of consent | 
| Percentage of Participants With NSCLC Who Have Abnormalities in Pancreatic Enzyme Clinical Laboratory Test Results by Worst CTC Grade | ULN=upper limit of normal. Lipase (U/L) Gr 1: 1.1 to 1.39*ULN; Gr 2: >1.5 to 2.0*ULN; Gr 3: 2.5 to 5; Gr 4: 5*ULN. Amylase (U/L) Gr 1: >ULN to 1.5*ULN; Grade 2 >1.5 to 2.0*ULN, Grade 3 >2.0 to 5.0*ULN, Grade 4 >5.0*ULN. Creatine (mg/dL) Grade 1: >ULN to 1.5*ULN, Gr 2: 1.5 to 3.0*ULN, Gr 3: >3.0 to 6.0*ULN, Gr 4: >6.0*ULN. | At screening; predose Day 1; Weeks 4, 7, 10, 13, 16, 19, and 24; and at end of treatment | 
| Number of Participants With NSCLC Who Have Positive Human Antihuman Antibody (HAHA) Status Postbaseline | An electrochemilumiluminescent immunoassay was used to detect HAHA antibodies to ipilimumab in human serum. Baseline, either negative or positive, is the maximum of all measurements closest and prior to the first ipilimumab dose. Positive status postbaseline=participants with an increase in HAHA measurement from baseline. | Day 1; Weeks 4, 7, 10, 13, 16, 19, and 24; and at end of treatment | 
| Number of Participants With SCLC With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs), AEs Leading to Discontinuation, Drug-related AEs by Worst CTC Grade | 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. Drug-related=possibly, probably, or certainly related to and of unknown relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. | Weeks 4, 7, 10, 16, 19, and 24; at end of treatment; and at follow-up (70 days from last dose) | 
| Number of Participants With SCLC Who Have Abnormalities in On-study Hematology Laboratory Test Results by Worst CTC Grade | CTC, Version 3 used to assess parameters. LLN=lower limit of normal. CTC criteria: ANC=absolute neutrophil count. White blood cells Gr 1:<LLN to 3.0*10^9/L, Gr 2:<3.0 to 2.0*10^9/L, Gr 3:<2.0 to 1.0*10^9/L, Gr 4:<1.0*10^9/L. ANC Gr 1:<LLN to 1.5*10^9/L, Gr 2:<1.5 to 1.0*10^9/L, Gr 3:<1.0 to 0.5*10^9/L, Gr 4:<0.5*10^9/L. Platelet count Gr 1:LLN to 75.0*10^9/L, Gr 2:<75.0 to 50.0*10^9/L, Gr 3:<50.0 to 25.0*10^9/L, Gr 4:<25.0 to 10^9/L. Hemoglobin Gr 1:<LLN to 10.0 g/dL, Gr 2:<10.0 to 8.0 g/dL, Gr 3:<8.0 to 6.5 g/dL, Gr 4:<6.5 g/dL. | At screening, predose Day 1, and Weeks 4, 7, 10, 13, 16, 19, 24, and at end of treatment | 
| Number of Participants With SCLC Who Have Abnormalities in Liver Function Test Results by Worst CTC Grade | ALT=alanine aminotransferase; AST=aspartate aminotransferase; ALK=alkaline phosphatase. ULN=Upper limit of normal among all laboratory ranges. CTC grade criteria: ALT Grade 1:>ULN to 2.5*ULN; Grade 2: >2.5 to 5.0*ULN; Grade 3: >5.0 to 20.0*ULN; Grade 4: >20.0*ULN. AST Grade 1: >ULN to 2.5*ULN; Grade 2: >2.5 to 5.0*ULN; Grade 3: >5.0 to 20.0*ULN; Grade 4: >20.0*ULN. Total bilirubin Grade 1: >ULN to 1.5*ULN; Grade 2: >1.5 to 3.0*ULN; Grade 3: >3.0 to 10.0*ULN; Grade 4: >10.0*ULN. ALK (U/L) G1:>ULN to 2.5*ULN, G2:>2.5 to 5.0*ULN, G3:>5.0 to 20.0*ULN, G4:>20.0*ULN. | At screening; predose Day 1; Weeks 4, 7, 10, 13, 16, 19, and 24; and at end of treatment | 
| Percentage of Participants With SCLC Who Have Abnormalities in Pancreatic Enzyme and Other Clinical Laboratory Test Results by Worst CTC Grade | ULN=upper limit of normal. Lipase (U/L) Grade (Gr) 1: 1.1 to 1.39*ULN; Gr 2: >1.5 to 2.0*ULN; Gr 3: 2.5 to 5; Gr 4: 5*ULN. Amylase (U/L) Gr 1: >ULN to 1.5*ULN; Gr 2 >1.5 to 2.0*ULN, Gr 3 >2.0 to 5.0*ULN, Gr 4 >5.0*ULN. Creatine (mg/dL) Gr 1: >ULN to 1.5*ULN, Gr 2: 1.5 to 3.0*ULN, Gr 3: >3.0 to 6.0*ULN, Gr 4: >6.0*ULN. | At screening, predose Day 1, and Weeks 4, 7, 10, 13, 16, 19, 24, and at end of treatment | 
| Progression-free Survival (PFS) in Participants With SCLC Per mWHO Criteria | By mWHO criteria, PFS is defined as the time between the randomization date and the date of progression or death, whichever occurs first. For participants with no recorded postbaseline tumor assessment, PFS was censored at the day of randomization. A participant who died without reported prior progression was considered to have progressed on the date of death. For those who remain alive and have not progressed, PFS was censored on the date of last evaluable tumor assessment. | Randomization date to date of progression or death (of censored, maximum reached: 22 months) | 
| Number of Participants With SCLC Who Had Abnormalities in Vital Sign Measurements and Physical Examination Findings | Vital signs measurements consisted of systolic and diastolic blood pressure, heart rate, temperature, and respiratory rate. Physical examinations assessed weight, height, performance status, and body surface area. | Predose Day 1; Weeks 4, 7, 10, 13, 16, and 24; and every 12 weeks on maintenance until end of treatment | 
| Number of Participants With SCLC Who Have Positive HAHA Status Postbaseline | An electrochemilumiluminescent immunoassay was used to detect HAHA antibodies to ipilimumab in human serum. Baseline, either negative or positive, is the maximum of all measurements closest and prior to the first ipilimumab dose. Positive status postbaseline=participants with an increase in HAHA measurement from baseline. | Day 1; Weeks 4, 7, 10, 13, 16, 19, and 24; and at end of treatment | 
| Overall Survival in Participants With SCLC | Overall Survival is defined as the time from the date of randomization until the date of death. For participants who have not died, Overall Survival was censored at the recorded last date of contact; participants with a missing recorded last date of contact were censored at the last date the participant was known to be alive. | Randomization date to date of death (of censored, maximum reached: 22 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC)