A Study of Rovalpituzumab Tesirine Administered in Combination With Nivolumab and With or Without Ipilimumab for Adults With Extensive-Stage Small Cell Lung Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1/2 Study on the Safety of Rovalpituzumab Tesirine Administered in Combination With Nivolumab or Nivolumab and Ipilimumab for Adults With Extensive-Stage Small Cell Lung Cancer

Conditions
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Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Ipilimumab
* Drug: Nivolumab
* Drug: Rovalpituzumab tesirine


Participation Criteria
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Eligibility Criteria
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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

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rovalpituzumab Tesirine and Nivolumab<br>Participants will receive 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 will then receive maintenance therapy with 480 mg nivolumab IV once every 4 weeks from Cycle 4 until disease progression. | Drug: Nivolumab<br>* Administered by intravenous infusion<br>* Other names: Opdivo®;Drug: Rovalpituzumab tesirine<br>* Administered by intravenous infusion<br>* Other names: SC16LD6.5;|
| Experimental: Rovalpituzumab Tesirine and Nivolumab + Ipilimumab 1 mg/kg<br>Participants will receive 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 will then receive maintenance therapy with 480 mg nivolumab IV once every 4 weeks from Cycle 6 until disease progression. | Drug: Ipilimumab<br>* Administered by intravenous infusion<br>* Other names: Yervoy®;Drug: Nivolumab<br>* Administered by intravenous infusion<br>* Other names: Opdivo®;Drug: Rovalpituzumab tesirine<br>* Administered by intravenous infusion<br>* Other names: SC16LD6.5;|
| Experimental: Rovalpituzumab Tesirine and Nivolumab + Ipilimumab 3 mg/kg<br>Participants will receive 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 3 mg/kg IV every 3 weeks for 4 cycles beginning on Cycle 2 (Day 1 of Cycles 2-5). After an 8-week washout, participants will then receive maintenance therapy with 480 mg nivolumab IV once every 4 weeks from Cycle 6 until disease progression. | Drug: Ipilimumab<br>* Administered by intravenous infusion<br>* Other names: Yervoy®;Drug: Nivolumab<br>* Administered by intravenous infusion<br>* Other names: Opdivo®;Drug: Rovalpituzumab tesirine<br>* Administered by intravenous infusion<br>* Other names: SC16LD6.5;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Up to 12 weeks | 
| 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 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. | 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. | 
| 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. | 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 (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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Extensive-Stage Small Cell Lung Cancer, Nivolumab, Ipilimumab, Rovalpituzumab tesirine