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

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Bristol-Myers Squibb

ClinicalTrials.gov Identifier:

NCT00527735

First received: September 7, 2007

Last updated: June 11, 2012

Last verified: June 2012

History of Changes

Results First Received: February 23, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Conditions:	Lung Cancer Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung
Interventions:	Drug: Ipilimumab Drug: Placebo Drug: Paclitaxel Drug: Carboplatin

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of 334 participants enrolled in this study, 331 received treatment. One patient with nonsmall-cell lung cancer, randomized to the sequential arm but mistakenly treated with concurrent therapy, is included in the sequential arm for efficacy results and in the concurrent arm for safety results.

Reporting Groups

	Description
Ipilimumab/Placebo + Paclitaxil/Carboplatin (Concurrent)	During induction, participants received up to 6 doses of blinded ipilimumab with paclitaxel/carboplatin on a 3-week schedule. The initial 4 doses consisted of active ipilimumab with paclitaxel/carboplatin, and the last 2 doses consisted of placebo ipilimumab with paclitaxel/carboplatin. Ipilimumab, 10 mg/kg, was administered intravenously (IV) as a single dose over 90 minutes. Participants who did not progress and did not experience intolerable toxicity during the treatment phase were allowed to continue in the maintenance phase, receiving additional (blinded) ipilimumab at a dose of 10 mg/kg administered IV over 90 minutes every 12 weeks starting 24 weeks after the first dose until progressive disease (PD), drug intolerance, withdrawal of consent, pregnancy, death, loss to follow up, or study closure.
Ipilimumab + Paclitaxel/Carboplatin (Sequential)	During induction, participants received up to 6 doses of blinded ipilimumab with paclitaxel/carboplatin on a 3-week schedule. The initial 2 doses consisted placebo ipilimumab with paclitaxel/carboplatin followed by 4 doses of active ipilimumab with paclitaxel/carboplatin. Ipilimumab, 10 mg/kg, was administered IV as a single dose over 90 minutes. Participants who did not progress and did not experience intolerable toxicity during the treatment phase were allowed to continue in the maintenance phase, receiving additional (blinded) ipilimumab at a dose of 10 mg/kg administered IV over 90 minutes every 12 weeks starting 24 weeks after the first dose until PD, drug intolerance, withdrawal of consent, pregnancy, death, loss to follow up, or study closure.
Placebo + Paclitaxel/Carboplatin	During induction, participants received up to 6 doses of placebo ipilimumab with paclitaxel/carboplatin every 3 weeks. Matched placebo for ipilimumab was administered as a single dose IV over 90 minutes every 3 weeks (up to 6 doses) as part of induction. Participants who did not progress or experience intolerable toxicity during the treatment phase could continue in the maintenance phase, receiving maintenance placebo administered IV over 90 minutes every 12 weeks starting 24 weeks after the first dose.

Participant Flow: Overall Study

	Ipilimumab/Placebo + Paclitaxil/Carboplatin (Concurrent)	Ipilimumab + Paclitaxel/Carboplatin (Sequential)	Placebo + Paclitaxel/Carboplatin
STARTED	113 ^[1]	109 ^[1]	109 ^[1]
COMPLETED	5 ^[2]	2 ^[2]	2 ^[2]
NOT COMPLETED	108	107	107
Disease progression	47	61	53
Death	23	13	15
Completed treatment in treatment phase	14	13	18
Adverse Event	10	6	7
Not identified	5	5	5
Withdrawal by Subject	5	4	3
No longer met study criteria	2	2	1
Lost to Follow-up	0	0	3
Poor compliance or noncompliance	0	1	1
Completed treatment during maintenance	2	2	1

[1]	Treated
[2]	Still on treatment

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Ipilimumab/Placebo + Paclitaxil/Carboplatin (Concurrent)	During induction, participants received up to 6 doses of blinded ipilimumab with paclitaxel/carboplatin (concurrent). The initial 4 doses consisted of active ipilimumab with paclitaxel/carboplatin, and the last 2 doses consisted of placebo ipilimumab with paclitaxel/carboplatin. Ipilimumab, 10 mg/kg, was administered intravenously (IV) as a single dose over 90 minutes every 3 weeks. Participants who experienced clinical benefit on treatment phase without intolerable toxicity were allowed to continue in the maintenance phase, receiving additional ipilimumab at a dose of 10 mg/kg administered IV over 90 minutes every 12 weeks starting 24 weeks after the first dose until immune-related progressive disease (irPD), drug intolerance, withdrawal of consent, pregnancy, death, loss to follow up, or study closure.
Placebo/Ipilimumab + Paclitaxel/Carboplatin (Sequential)	During induction, participants received up to 6 doses of blinded ipilimumab with paclitaxel/carboplatin (sequential). The initial 2 doses consisted placebo ipilimumab with paclitaxel/carboplatin followed by 4 doses of active ipilimumab with paclitaxel/carboplatin. Ipilimumab, 10 mg/kg, was administered IV as a single dose over 90 minutes every 3 weeks. Participants who experienced clinical benefit on treatment phase without intolerable toxicity were allowed to continue in the maintenance phase, receiving additional ipilimumab at a dose of 10 mg/kg administered IV over 90 minutes every 12 weeks starting 24 weeks after the first dose until irPD, drug intolerance, withdrawal of consent, pregnancy, death, loss to follow up, or study closure.
Placebo + Paclitaxel/Carboplatin	During induction, participants received up to 6 doses of placebo ipilimumab with paclitaxel/carboplatin. Matched placebo for ipilimumab was administered as a single dose IV over 90 minutes every 3 weeks (up to 6 doses) as part of induction. Participants who experienced clinical benefit on treatment phase without intolerable toxicity could continue in the maintenance phase, receiving maintenance placebo administered IV over 90 minutes every 12 weeks starting 24 weeks after the first dose.
Total	Total of all reporting groups

Baseline Measures

	Ipilimumab/Placebo + Paclitaxil/Carboplatin (Concurrent)	Placebo/Ipilimumab + Paclitaxel/Carboplatin (Sequential)	Placebo + Paclitaxel/Carboplatin	Total
Number of Participants [units: participants]	113	110	111	334
Age, Customized ^[1] [units: Participants]
Younger than 65 years	79	73	76	228
65 years and older	34	37	35	106
Gender [units: Participants]
Female	27	29	29	85
Male	86	81	82	249
Age Customized, by Disease Type ^[2] [units: Participants]
Younger than 65 years (NSCLC patients)	44	44	40	128
65 years and older (NSCLC patients)	26	24	26	76
Younger than 65 years (SCLC patients)	35	29	36	100
65 years and older (SCLC patients)	8	13	9	30
Gender, by Disease Type ^[2] [units: Participants]
Female (NSCLC patients)	17	19	17	53
Male (NSCLC patients)	53	49	49	151
Female (SCLC patients)	10	10	12	32
Male (SCLC patients)	33	32	33	98
Disease Stage at Study Entry ^[3] [units: Participants]
Stage IIIB (NSCLC patients)	11	7	17	35
Stage IV (NSCLC patients)	59	61	49	169
Extensive (SCLC patients)	43	42	44	129
Recurrent disease (SCLC patients)	0	0	1	1
Cell Type ^[2] [units: Participants]
Adenocarcinoma (NSCLC patients)	35	30	38	103
Bronchoalveolar carcinoma (NSCLC patients)	1	1	0	2
Large-cell carcinoma (NSCLC patients)	6	11	7	24
Other (NSCLC patients)	6	4	3	13
Squamous-cell carcinoma (NSCLC patients)	21	21	15	57
Unknown (NSCLC patients)	1	1	3	5
Other (SCLC patients)	2	2	0	4
Small-cell carcinoma (SCLC patients)	41	38	45	124
Unknown (SCLC patients)	0	1	0	1
Not reported (SCLC patients)	0	1	0	1

[1]	Age of participants who received treatment.
[2]	NSCLC=nonsmall-cell lung cancer; SCLC=small-cell lung cancer
[3]	NSCLC=nonsmall-cell lung cancer; SCLC=small-cell lung cancer. Staging of NSCLC is based on the findings of several clinical tests, including magnetic resonance imaging scans and fine needle biopsy. Stages range from 1 (best prognosis) to IV (worst prognosis). Stage I cancer is confined to the lung. Stages II and III cancers are locally advanced. Stage IV cancer has spread outside the lung to other organs. SCLC is staged using a 2-tiered system: Limited stage SCLC is confined to its area of origin in the lung and lumph nodes. Extensive-stage SCLC has spread beyond the lung to other organs.

Outcome Measures

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1. Primary:

Immune-related Progression-free Survival (irPFS) in Participants With Nonsmall-cell Lung Cancer (NSCLC) Per Immune-related Response Criteria (irRC) [ Time Frame: 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) ]

Show Outcome Measure 1

2. Secondary:

Progression-free Survival (PFS) in Participants With NSCLC Per Modified World Health Organization (mWHO) Criteria [ Time Frame: Randomization date to date of progression or death (of censored, maximum reached: 13.6 months) ]

Show Outcome Measure 2

3. Secondary:

Overall Survival in Participants With NSCLC [ Time Frame: Randomization date to date of death (of censored, maximum reached: 26.5 months) ]

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4. Secondary:

Best Overall Response Rate (BORR) Per mWHO Criteria in Participants With NSCLC and SCLC [ Time Frame: Tumor assessment at screening, every 6 weeks on treatment to Week 24, and every 12 weeks on maintenance ]

Show Outcome Measure 4

5. Secondary:

Immune-related Best Overall Response Rate (irBORR) Per irRC in Participants With NSCLC and Small-cell Lung Cancer (SCLC) [ Time Frame: Tumor assessment at screening, every 6 weeks on treatment to Week 24, and every 12 weeks on maintenance ]

Show Outcome Measure 5

6. Secondary:

Immune-related Disease Control Rate (irDCR) Per irRC and Disease Control Rate (DCR) Per mWHO Criteria in Participants With NSCLC and SCLC [ Time Frame: 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) ]

Show Outcome Measure 6

7. Secondary:

Immune-related Duration of Response (irDoR) Per irRC and DoR Per mWHO Criteria in Participants With NSCLC and SCLC [ Time Frame: Date of irCR or irPR to date of irPD or death (maximum reached: 14.2 months) ]

Show Outcome Measure 7

8. Secondary:

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 [ Time Frame: Weeks 4, 7, 10, 16, 19, and 24; at end of treatment; and at follow-up (70 days from last dose) ]

Show Outcome Measure 8

9. Secondary:

Percentage of Participants With NSCLC Who Have Abnormalities in On-study Hematology Laboratory Test Results by Worst CTC Grade [ Time Frame: 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 ]

Show Outcome Measure 9

10. Secondary:

irPFS in Participants With SCLC Per irRC [ Time Frame: Randomization date to date of irPD or death (maximum reached: 22 months) ]

Show Outcome Measure 10

11. Secondary:

Number of Participants With NSCLC Who Have Abnormalities in On-Study Liver Function Test Results By Worst CTC Grade [ Time Frame: 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 ]

Show Outcome Measure 11

12. Secondary:

Number of Participants With NSCLC Who Had Abnormalities in Vital Sign Measurements and Physical Examination Findings [ Time Frame: 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 ]

Show Outcome Measure 12

13. Secondary:

Percentage of Participants With NSCLC Who Have Abnormalities in Pancreatic Enzyme Clinical Laboratory Test Results by Worst CTC Grade [ Time Frame: At screening; predose Day 1; Weeks 4, 7, 10, 13, 16, 19, and 24; and at end of treatment ]

Show Outcome Measure 13

14. Secondary:

Number of Participants With NSCLC Who Have Positive Human Antihuman Antibody (HAHA) Status Postbaseline [ Time Frame: Day 1; Weeks 4, 7, 10, 13, 16, 19, and 24; and at end of treatment ]

Show Outcome Measure 14

15. Secondary:

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 [ Time Frame: Weeks 4, 7, 10, 16, 19, and 24; at end of treatment; and at follow-up (70 days from last dose) ]

Show Outcome Measure 15

16. Secondary:

Number of Participants With SCLC Who Have Abnormalities in On-study Hematology Laboratory Test Results by Worst CTC Grade [ Time Frame: At screening, predose Day 1, and Weeks 4, 7, 10, 13, 16, 19, 24, and at end of treatment ]

Hide Outcome Measure 16

Measure Type	Secondary
Measure Title	Number of Participants With SCLC Who Have Abnormalities in On-study Hematology Laboratory Test Results by Worst CTC Grade
Measure Description	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 3.010^9/L, Gr 2:<3.0 to 2.010^9/L, Gr 3:<2.0 to 1.010^9/L, Gr 4:<1.010^9/L. ANC Gr 1:<LLN to 1.510^9/L, Gr 2:<1.5 to 1.010^9/L, Gr 3:<1.0 to 0.510^9/L, Gr 4:<0.510^9/L. Platelet count Gr 1:LLN to 75.010^9/L, Gr 2:<75.0 to 50.010^9/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.
Time Frame	At screening, predose Day 1, and Weeks 4, 7, 10, 13, 16, 19, 24, and at end of treatment
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants with SCLC who received at least 1 dose of ipilimumab and/or chemotherapy and had at least 1 on-study hematology test result available.

Reporting Groups

	Description
Ipilimumab/Placebo + Paclitaxil/Carboplatin (Concurrent)	During induction, participants received up to 6 doses of blinded ipilimumab with paclitaxel/carboplatin on a 3-week schedule. The initial 4 doses consisted of active ipilimumab with paclitaxel/carboplatin, and the last 2 doses consisted of placebo ipilimumab with paclitaxel/carboplatin. Ipilimumab, 10 mg/kg, was administered IV as a single dose over 90 minutes. Participants who did not progress or experience intolerable toxicity during the treatment phase were allowed to continue in the maintenance phase, receiving additional (blinded) ipilimumab at a dose of 10 mg/kg administered IV over 90 minutes every 12 weeks starting 24 weeks after the first dose until irPD, drug intolerance, withdrawal of consent, pregnancy, death, loss to follow up, or study closure.
Placebo/Ipilimumab + Paclitaxel/Carboplatin (Sequential)	During induction, participants received up to 6 doses of blinded ipilimumab with paclitaxel/carboplatin on a 3-week schedule. The initial 2 doses consisted placebo ipilimumab with paclitaxel/carboplatin followed by 4 doses of active ipilimumab with paclitaxel/carboplatin. Ipilimumab, 10 mg/kg, was administered IV as a single dose over 90 minutes. Participants who did not progress or experience intolerable toxicity during the treatment phase were allowed to continue in the maintenance phase, receiving additional (blinded) ipilimumab at a dose of 10 mg/kg administered IV over 90 minutes every 12 weeks starting 24 weeks after the first dose until PD, drug intolerance, withdrawal of consent, pregnancy, death, loss to follow up, or study closure.
Placebo + Paclitaxel/Carboplatin	During induction, participants received up to 6 doses of placebo ipilimumab with paclitaxel/carboplatin every 3 weeks. Matched placebo for ipilimumab was administered as a single dose IV over 90 minutes every 3 weeks (up to 6 doses) as part of induction. Participants who did not progress or experience intolerable toxicity during the treatment phase could continue in the maintenance phase, receiving maintenance placebo administered IV over 90 minutes every 12 weeks starting 24 weeks after the first dose.

Measured Values

	Ipilimumab/Placebo + Paclitaxil/Carboplatin (Concurrent)	Placebo/Ipilimumab + Paclitaxel/Carboplatin (Sequential)	Placebo + Paclitaxel/Carboplatin
Number of Participants Analyzed [units: participants]	42	42	44
Number of Participants With SCLC Who Have Abnormalities in On-study Hematology Laboratory Test Results by Worst CTC Grade [units: Participants]
White blood cells, Grade 1 (n=39, 42, 43)	7	11	13
White blood cells, Grade 2 (n= 39, 42, 43)	10	9	7
White blood cells, Grades 3 (n= 39, 42, 43)	0	2	0
White blood cells, Grade 4 (n= 39, 42, 43)	0	0	0
Absolute neutrophil count, Grade 1 (n= 39, 42, 43)	8	8	8
Absolute neutrophil count, Grade 2 (n= 39, 42, 43)	8	9	91
Absolute neutrophil count, Grade 3 (n= 39, 42, 43)	2	2	1
Absolute neutrophil count, Grade 4 (n= 39, 42, 43)	1	2	0
Platelet count, Grade 1 (n= 39, 42, 43)	15	18	23
Platelet count, Grade 2 (n= 39, 42, 43)	2	3	3
Platelet count, Grade 3 (n= 39, 42, 43)	1	2	1
Platelet count, Grade 4 (n= 39, 42, 43)	0	1	0
Hemoglobin, Grade 1 (n= 39, 42, 43)	26	24	25
Hemoglobin, Grade 2 (n= 39, 42, 43)	8	10	11
Hemoglobin, Grade 3 (n= 39, 42, 43)	2	2	3
Hemoglobin, Grade 4 (n= 39, 42, 43)	0	2	0

No statistical analysis provided for Number of Participants With SCLC Who Have Abnormalities in On-study Hematology Laboratory Test Results by Worst CTC Grade

17. Secondary:

Number of Participants With SCLC Who Have Abnormalities in Liver Function Test Results by Worst CTC Grade [ Time Frame: At screening; predose Day 1; Weeks 4, 7, 10, 13, 16, 19, and 24; and at end of treatment ]

Show Outcome Measure 17

18. Secondary:

Percentage of Participants With SCLC Who Have Abnormalities in Pancreatic Enzyme and Other Clinical Laboratory Test Results by Worst CTC Grade [ Time Frame: At screening, predose Day 1, and Weeks 4, 7, 10, 13, 16, 19, 24, and at end of treatment ]

Show Outcome Measure 18

19. Secondary:

Progression-free Survival (PFS) in Participants With SCLC Per mWHO Criteria [ Time Frame: Randomization date to date of progression or death (of censored, maximum reached: 22 months) ]

Show Outcome Measure 19

20. Secondary:

Number of Participants With SCLC Who Had Abnormalities in Vital Sign Measurements and Physical Examination Findings [ Time Frame: Predose Day 1; Weeks 4, 7, 10, 13, 16, and 24; and every 12 weeks on maintenance until end of treatment ]

Show Outcome Measure 20

21. Secondary:

Number of Participants With SCLC Who Have Positive HAHA Status Postbaseline [ Time Frame: Day 1; Weeks 4, 7, 10, 13, 16, 19, and 24; and at end of treatment ]

Show Outcome Measure 21

22. Secondary:

Overall Survival in Participants With SCLC [ Time Frame: Randomization date to date of death (of censored, maximum reached: 22 months) ]

Show Outcome Measure 22

Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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