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

Phase 1

Terminated

Conditions: Small Cell Lung Cancer

Interventions: Drug: Ipilimumab
Drug: Nivolumab
Drug: Rovalpituzumab tesirine

Registration Number: NCT03026166

Lead Sponsor: AbbVie

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 42

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Rovalpituzumab Tesirine and Nivolumab + Ipilimumab 1 mg/kg	Nivolumab	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.
Rovalpituzumab Tesirine and Nivolumab + Ipilimumab 3 mg/kg	Nivolumab	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.
Rovalpituzumab Tesirine and Nivolumab	Nivolumab	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.
Rovalpituzumab Tesirine and Nivolumab + Ipilimumab 1 mg/kg	Ipilimumab	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.
Rovalpituzumab Tesirine and Nivolumab + Ipilimumab 3 mg/kg	Ipilimumab	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.
Rovalpituzumab Tesirine and Nivolumab	Rovalpituzumab tesirine	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.
Rovalpituzumab Tesirine and Nivolumab + Ipilimumab 1 mg/kg	Rovalpituzumab tesirine	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.
Rovalpituzumab Tesirine and Nivolumab + Ipilimumab 3 mg/kg	Rovalpituzumab tesirine	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.

Trial Locations

Locations (35): University Cancer & Blood Cent /ID# 161028
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Athens, Georgia, United States
University of Chicago /ID# 161006
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Chicago, Illinois, United States
Clinica Universitar de Navarra - Pamplona /ID# 165165
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Pamplona, Navarra, Comunidad, Spain
Hospital Universitario Fundacion Jimenez Diaz /ID# 165164
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Madrid, Spain
Virginia Cancer Institute /ID# 161025
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Richmond, Virginia, United States
Hospital Genl Gregorio Maranon /ID# 165162
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Madrid, Spain
Hospital Universitario Madrid /ID# 165163
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Madrid, Spain
Hosp Univ Quiron Dexues /ID# 165166
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Barcelona, Spain
The University of Kansas Clini /ID# 162915
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Fairway, Kansas, United States
Ucsd /Id# 161030
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La Jolla, California, United States
Washington University-School of Medicine /ID# 161011
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Saint Louis, Missouri, United States
Memorial Sloan Kettering Cancer Center /ID# 161010
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New York, New York, United States
Duke University Medical Center /ID# 161009
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Durham, North Carolina, United States
University of Wisconsin Clinic /ID# 161013
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Madison, Wisconsin, United States
Hopital La Timone /ID# 165171
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Marseille, France
Lungenfachklinik Immenhausen /ID# 165181
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Immenhausen, Germany
KH Martha-Maria Halle Dolau /ID# 165180
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Halle (Saale), Sachsen-Anhalt, Germany
Centro di Riferimento Oncologi /ID# 165174
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Aviano, Italy
Institut Sainte Catherine /ID# 165172
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Avignon, France
CHRU de Brest - Hospital Morva /ID# 165170
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Brest Cedex, France
Oregon Health and Science University /ID# 161029
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Portland, Oregon, United States
CHU de Besancon - Jean Minjoz /ID# 165173
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Besancon, Doubs, France
Institut Gustave Roussy /ID# 165168
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Villejuif, Val-de-Marne, France
Medical University of South Carolina /ID# 161007
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Charleston, South Carolina, United States
Lungen Clinic Grosshansdorf /ID# 165182
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Grosshansdorf, Germany
Istituto Clinico Humanitas /ID# 165176
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Rozzano, Milano, Italy
Istituto Europeo di Oncologia /ID# 165175
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Milan, Italy
AO Univ di Modena /ID# 165177
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Modena, Italy
Rutgers Cancer Institute of NJ /ID# 161032
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New Brunswick, New Jersey, United States
Vanderbilt University Med Ctr /ID# 162916
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Nashville, Tennessee, United States
Florida Hospital /ID# 161017
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Orlando, Florida, United States
Centre Oscar Lambret /ID# 165169
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Lille, Hauts-de-France, France
Asklepios Fachkliniken M. Gaut /ID# 165183
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Gauting, Germany
Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele /ID# 165178
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Catania, Italy
Tennessee Oncology, PLLC /ID# 161012
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Nashville, Tennessee, United States