Small Cell Lung Cancer
Conditions
Keywords
Cancer, Extensive-Stage Small Cell Lung Cancer, Nivolumab, Ipilimumab, Rovalpituzumab tesirine
Brief summary
The purpose of this study is to assess the safety and efficacy of rovalpituzumab tesirine administered in combination with nivolumab or nivolumab and ipilimumab in participants with extensive-stage small cell lung cancer (SCLC).
Detailed description
The study planned to enroll three cohorts with approximately 30 participants in each, including a dose-limiting toxicity (DLT) evaluation phase (the first 12 weeks of any treatment) and an expansion phase. Initially, up to 12 participants were to be enrolled into Cohort 1 in order to obtain 6 evaluable participants through the DLT evaluation period of 12 weeks. Safety data were reviewed by a Safety Monitoring Committee (SMC) for each cohort during the DLT evaluation phase before the next cohort opened. Once a new cohort was opened, the previously opened cohort was permitted to continue enrolling participants for the expansion phase for a total of 30 participants per cohort. Only two of the planned three cohorts enrolled participants in the study based on the SMC recommendation after DLTs were identified in Cohort 2.
Interventions
DRUGIpilimumab
Administered by intravenous infusion
DRUGNivolumab
Administered by intravenous infusion
Administered by intravenous infusion
Sponsors
Bristol-Myers Squibb
AbbVie
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with histologically or cytologically confirmed extensive-stage small cell lung cancer (SCLC) with progressive disease after at least one platinum-based chemotherapeutic regimen and with evaluable or measurable disease * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate hematologic, hepatic, and renal function
Exclusion criteria
* Has active, known, or suspected autoimmune disease * Had prior exposure to an immuno-oncology or pyrrolobenzodiazepine (PBD)-based drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLT) | Up to 12 weeks | Dose-limiting toxicities were defined as any of the following in the 12-week DLT-evaluation period, graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03: * Grade 4 thrombocytopenia (or Grade 3 thrombocytopenia with bleeding) lasting more than 7 days and/or requiring platelet transfusion * Grade 4 neutropenia lasting more than 7 days, and/or requiring hematopoietic growth factor rescue, or any febrile neutropenia (Grade 3 or 4 neutropenia with concurrent fever ≥ 38.3°C) * Grade 4 anemia unrelated to underlying disease * Clinically significant Grade 3 or 4 non-hematologic laboratory abnormality that did not resolve to Grade 0/1 or baseline within 7 days * Grade 3 or 4 non-laboratory adverse event (AE), except fatigue, asthenia, nausea, or other manageable constitutional symptom |
| Number of Participants With Adverse Events (AEs) | From the first dose of study drug until 100 days after the last dose of study drug; median duration of treatment was 65 days and 53 days in each cohort respectively. | The investigator rated the severity of each AE according to the NCI CTCAE Version 4.03 and according to the following: Grade 1: The AE is transient and easily tolerated by the subject (mild). Grade 2: The AE causes the subject discomfort and interrupts the subject's usual activities (moderate). Grade 3/4: The AE causes considerable interference with the subject's usual activities and may be incapacitating or life-threatening (severe). Grade 5: The AE resulted in death of the subject (severe). The maximum severity AE for each participant is reported. A serious adverse event was defined as an AE meeting any of the following: * Death * Life-threatening * Resulted in hospitalization or prolongation of hospitalization * Resulted in congenital abnormality * Resulted in persistent or significant disability or incapacity * Was an important medical event requiring medical intervention to prevent a serious outcome. Relationship to study drug was assessed by the Investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Cohort 1: at Week 6, Week 13, and every 8 weeks thereafter; Cohort 2: at Week 6, Week 12, Week 18, and every 8 weeks thereafter, to the end of follow-up; median duration on follow-up was 31.7 and 48.0 weeks in each cohort respectively. | Treatment response was assessed by radiographic tumor evaluations conducted by a central radiology review. Objective response rate (ORR) is defined as the percentage of participants whose best overall response is either a confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria for Solid Tumors (RECIST) v1.1. Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. Partial response (PR): A ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR or PR must have been confirmed at least 4 weeks (28 days) from the initial determination per RECIST v 1.1. |
| Duration of Response (DOR) | Cohort 1: at Week 6, Week 13, and every 8 weeks thereafter; Cohort 2: at Week 6, Week 12, Week 18 and every 8 weeks thereafter, to the end of follow-up; median duration on follow-up was 31.7 and 48.0 weeks in each cohort respectively. | Duration of overall response is defined as the time from the date of first documented CR or PR, assessed by central radiology review and based on RECIST v. 1.1, to the documented date of progressive disease (PD) or death, whichever occurred first. Participants who neither progressed nor died were censored at the last evaluable disease assessment. Duration of response was evaluated using Kaplan-Meier methodology. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 0.5 cm, or the unequivocal progression of non-target lesions, or the appearance of one or more new lesions. |
| Progression-free Survival (PFS) | From first dose of study drug to the end of follow-up; median duration on follow-up was 31.7 and 48.0 weeks in each cohort respectively. | Progression-free survival is defined as the time from the first dose date to the documented date of PD or death, whichever occurred first, based on central radiology review according to RECIST v 1.1. Progression-free survival was evaluated using Kaplan-Meier methodology. Participants who neither progressed nor died were censored at the last evaluable disease assessment. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 0.5 cm, or the unequivocal progression of non-target lesions, or the appearance of one or more new lesions. |
| Overall Survival (OS) | From first dose of study drug to the end of follow-up; median duration on follow-up was 31.7 and 48.0 weeks in each cohort respectively. | Overall survival is defined as the time from the first dose date to death for any reason. Participants who were still alive were censored at the last known alive date. Overall survival was evaluated using Kaplan-Meier methodology. |
Countries
France, Germany, Italy, Spain, United States
Participant flow
Recruitment details
Participants were enrolled at 17 clinical study sites in 4 countries: United States, France, Italy, and Germany.
Pre-assignment details
Three study cohorts were planned to enroll approximately 30 participants in each, including a dose-limiting toxicity (DLT) evaluation phase (the first 12 weeks of any treatment for all participants) and an expansion phase. However, Cohort 2 was limited to 12 participants and Cohort 3 was not opened.
Participants by arm
| Arm | Count |
|---|---|
| Rovalpituzumab Tesirine and Nivolumab Participants received 2 doses of 0.3 mg/kg rovalpituzumab tesirine by intravenous (IV) infusion 6 weeks apart (Day 1 of Cycles 1 and 3), and 2 doses of 360 mg nivolumab IV 3 weeks apart beginning on Cycle 2 (Day 1 of Cycles 2 and 3).
Participants then received maintenance therapy with 480 mg nivolumab IV once every 4 weeks from Cycle 4 until disease progression. | 30 |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab Participants received 2 doses of 0.3 mg/kg rovalpituzumab tesirine IV 6 weeks apart (Day 1 of Cycles 1 and 3), nivolumab 1 mg/kg every 3 weeks for 4 cycles beginning on Cycle 2 (Day 1 of Cycles 2-5), and ipilimumab 1 mg/kg IV every 3 weeks for 4 cycles beginning on Cycle 2 (Day 1 of Cycles 2-5).
After a 6-week washout, participants then received maintenance therapy with 480 mg nivolumab IV once every 4 weeks from Cycle 6 until disease progression. | 12 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 22 | 7 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Study Terminated by Sponsor | 3 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Rovalpituzumab Tesirine and Nivolumab | Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Total |
|---|---|---|---|
| Age, Continuous | 61.87 years STANDARD_DEVIATION 8.195 | 57.25 years STANDARD_DEVIATION 14.085 | 60.55 years STANDARD_DEVIATION 10.256 |
| Age, Customized ≥ 40 to < 60 years | 11 Participants | 5 Participants | 16 Participants |
| Age, Customized < 40 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Customized ≥ 60 years | 19 Participants | 6 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 11 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 29 Participants | 10 Participants | 39 Participants |
| Sex: Female, Male Female | 14 Participants | 5 Participants | 19 Participants |
| Sex: Female, Male Male | 16 Participants | 7 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 26 / 30 | 8 / 12 |
| other Total, other adverse events | 30 / 30 | 12 / 12 |
| serious Total, serious adverse events | 23 / 30 | 9 / 12 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs)
The investigator rated the severity of each AE according to the NCI CTCAE Version 4.03 and according to the following: Grade 1: The AE is transient and easily tolerated by the subject (mild). Grade 2: The AE causes the subject discomfort and interrupts the subject's usual activities (moderate). Grade 3/4: The AE causes considerable interference with the subject's usual activities and may be incapacitating or life-threatening (severe). Grade 5: The AE resulted in death of the subject (severe). The maximum severity AE for each participant is reported. A serious adverse event was defined as an AE meeting any of the following: * Death * Life-threatening * Resulted in hospitalization or prolongation of hospitalization * Resulted in congenital abnormality * Resulted in persistent or significant disability or incapacity * Was an important medical event requiring medical intervention to prevent a serious outcome. Relationship to study drug was assessed by the Investigator.
Time frame: From the first dose of study drug until 100 days after the last dose of study drug; median duration of treatment was 65 days and 53 days in each cohort respectively.
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Drug-related serious adverse event | 13 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | AE leading to treatment interruption | 18 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Drug-related Grade 3 adverse event | 9 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | AE leading to dose reduction | 0 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Grade 4 adverse event | 1 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Drug-related AE leading to study drug withdrawal | 9 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Drug-related Grade 4 adverse event | 3 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Drug-related AE leading to treatment interruption | 17 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Grade 3 adverse event | 11 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Drug-related AE leading to dose reduction | 0 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Drug-related Grade 5 adverse event | 4 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Any adverse event | 30 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Grade 5 adverse event | 14 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Drug-related adverse event | 29 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | Serious adverse event | 23 Participants |
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Adverse Events (AEs) | AE leading to study drug withdrawal | 12 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Serious adverse event | 9 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Drug-related serious adverse event | 6 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Grade 3 adverse event | 7 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Grade 4 adverse event | 1 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Grade 5 adverse event | 4 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Drug-related Grade 3 adverse event | 10 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Drug-related Grade 4 adverse event | 1 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Drug-related Grade 5 adverse event | 0 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | AE leading to study drug withdrawal | 6 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | AE leading to treatment interruption | 8 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | AE leading to dose reduction | 1 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Drug-related AE leading to study drug withdrawal | 4 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Drug-related AE leading to treatment interruption | 8 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Drug-related AE leading to dose reduction | 0 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Any adverse event | 12 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Adverse Events (AEs) | Drug-related adverse event | 12 Participants |
Primary
Number of Participants With Dose-limiting Toxicities (DLT)
Dose-limiting toxicities were defined as any of the following in the 12-week DLT-evaluation period, graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03: * Grade 4 thrombocytopenia (or Grade 3 thrombocytopenia with bleeding) lasting more than 7 days and/or requiring platelet transfusion * Grade 4 neutropenia lasting more than 7 days, and/or requiring hematopoietic growth factor rescue, or any febrile neutropenia (Grade 3 or 4 neutropenia with concurrent fever ≥ 38.3°C) * Grade 4 anemia unrelated to underlying disease * Clinically significant Grade 3 or 4 non-hematologic laboratory abnormality that did not resolve to Grade 0/1 or baseline within 7 days * Grade 3 or 4 non-laboratory adverse event (AE), except fatigue, asthenia, nausea, or other manageable constitutional symptom
Time frame: Up to 12 weeks
Population: DLT-evaluable participants were those who completed 4 cycles treatment during the DLT period or stopped treatment earlier due to DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rovalpituzumab Tesirine and Nivolumab | Number of Participants With Dose-limiting Toxicities (DLT) | 1 Participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Number of Participants With Dose-limiting Toxicities (DLT) | 3 Participants |
Secondary
Duration of Response (DOR)
Duration of overall response is defined as the time from the date of first documented CR or PR, assessed by central radiology review and based on RECIST v. 1.1, to the documented date of progressive disease (PD) or death, whichever occurred first. Participants who neither progressed nor died were censored at the last evaluable disease assessment. Duration of response was evaluated using Kaplan-Meier methodology. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 0.5 cm, or the unequivocal progression of non-target lesions, or the appearance of one or more new lesions.
Time frame: Cohort 1: at Week 6, Week 13, and every 8 weeks thereafter; Cohort 2: at Week 6, Week 12, Week 18 and every 8 weeks thereafter, to the end of follow-up; median duration on follow-up was 31.7 and 48.0 weeks in each cohort respectively.
Population: The analysis includes participants in the Efficacy Analysis Set with a best overall response of unconfirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rovalpituzumab Tesirine and Nivolumab | Duration of Response (DOR) | 3.8 months |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Duration of Response (DOR) | 3.3 months |
Secondary
Objective Response Rate (ORR)
Treatment response was assessed by radiographic tumor evaluations conducted by a central radiology review. Objective response rate (ORR) is defined as the percentage of participants whose best overall response is either a confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria for Solid Tumors (RECIST) v1.1. Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. Partial response (PR): A ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR or PR must have been confirmed at least 4 weeks (28 days) from the initial determination per RECIST v 1.1.
Time frame: Cohort 1: at Week 6, Week 13, and every 8 weeks thereafter; Cohort 2: at Week 6, Week 12, Week 18, and every 8 weeks thereafter, to the end of follow-up; median duration on follow-up was 31.7 and 48.0 weeks in each cohort respectively.
Population: The Efficacy Analysis Set includes participants who received at least one dose of study drug, had a target lesion identified at Baseline, and either had at least 1 post-dose tumor assessment or discontinued treatment due to AE, progressive disease (PD) or death.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rovalpituzumab Tesirine and Nivolumab | Objective Response Rate (ORR) | 27.6 percentage of participants |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Objective Response Rate (ORR) | 36.4 percentage of participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from the first dose date to death for any reason. Participants who were still alive were censored at the last known alive date. Overall survival was evaluated using Kaplan-Meier methodology.
Time frame: From first dose of study drug to the end of follow-up; median duration on follow-up was 31.7 and 48.0 weeks in each cohort respectively.
Population: The Full Analysis Set includes participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rovalpituzumab Tesirine and Nivolumab | Overall Survival (OS) | 7.4 months |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Overall Survival (OS) | 11.0 months |
Secondary
Progression-free Survival (PFS)
Progression-free survival is defined as the time from the first dose date to the documented date of PD or death, whichever occurred first, based on central radiology review according to RECIST v 1.1. Progression-free survival was evaluated using Kaplan-Meier methodology. Participants who neither progressed nor died were censored at the last evaluable disease assessment. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 0.5 cm, or the unequivocal progression of non-target lesions, or the appearance of one or more new lesions.
Time frame: From first dose of study drug to the end of follow-up; median duration on follow-up was 31.7 and 48.0 weeks in each cohort respectively.
Population: Efficacy Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rovalpituzumab Tesirine and Nivolumab | Progression-free Survival (PFS) | 4.8 months |
| Rovalpituzumab Tesirine and Nivolumab + Ipilimumab | Progression-free Survival (PFS) | 4.1 months |