MM-398-01-03-04

Ipsen Bioscience Inc.

One Main Street, Cambridge, Massachusetts, United States, 02142

Medical Director, Ipsen Bioscience, Inc, clinical.trials@ipsen.com

Medical Director, Ipsen Bioscience, Inc, clinical.trials@ipsen.com

No

No

No

Final

14 Sep 2023

No

Yes

27 Jul 2023

No

Part 1: - To describe the safety and tolerability of irinotecan liposome injection monotherapy administered every 2 weeks - To determine the irinotecan liposome injection monotherapy dose (85 milligrams/meter square [mg/m^2] or 70 mg/m^2 administered every 2 weeks) for Part 2 of this study. Part 2: - To compare overall survival (OS) following treatment with irinotecan liposome injection with OS following treatment with intravenous (i.v.) topotecan.

The study was conducted under the provisions of the Declaration of Helsinki, in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice and in compliance with independent ethics committee or institutional review board, and informed consent regulations. This study adhered to the United States of America Food and Drug Administration regulations and all applicable local regulations.

25 Apr 2018

No

Yes

Australia: 7

Belgium: 10

Brazil: 14

China: 34

France: 7

Germany: 8

Hungary: 20

Italy: 3

Korea, Republic of: 22

Poland: 16

Romania: 21

Russian Federation: 62

Serbia: 39

Spain: 82

Taiwan: 17

Türkiye: 20

Ukraine: 47

United States: 62

491

167

0

0

0

0

0

0

301

190

0

Overall study (overall period)

Randomised - controlled

Yes

Irinotecan liposome

ONIVYDE

Concentrate for solution for injection/infusion

Intravenous use

Irinotecan liposome injection was administered at a dose of 85 mg/m^2 i.v. over 90 minutes, every 2 weeks in a 6-week cycle until protocol-defined discontinuation criteria was met.

Irinotecan liposome

ONIVYDE

Concentrate for solution for injection/infusion

Intravenous use

Irinotecan liposome injection was administered at a dose of 70 mg/m^2 i.v. over 90 minutes, every 2 weeks in a 6-week cycle until protocol-defined discontinuation criteria was met.

Irinotecan liposome

ONIVYDE

Concentrate for solution for injection/infusion

Intravenous use

Irinotecan liposome injection was administered at a dose of 70 mg/m^2 i.v. over 90 minutes, every 2 weeks in a 6-week cycle until protocol-defined discontinuation criteria was met.

Topotecan

HYCAMTIN

Injection

Intravenous use

Topotecan was administered at an initial dose of 1.5 mg/m^2 i.v. over 30 minutes daily for 5 consecutive days, every 3 weeks in a 6-week cycle until protocol-defined discontinuation criteria was met.

Part 1: Irinotecan Liposome Injection 85 mg/m^2

Part 1: Irinotecan Liposome Injection 70 mg/m^2

Part 2: Irinotecan Liposome Injection 70 mg/m^2

Part 2: Topotecan 1.5 mg/m^2

Part 1: Irinotecan Liposome Injection 85 mg/m^2

Part 1: Irinotecan Liposome Injection 70 mg/m^2

Part 2: Irinotecan Liposome Injection 70 mg/m^2

Part 2: Topotecan 1.5 mg/m^2

An adverse event (AE) was any untoward medical occurrence in a participant following or during exposure to a study treatment, whether or not causally related to the study treatment. An undesirable medical condition could be symptoms, signs or abnormal results of an investigation. An SAE was any AE that: resulted in death; was life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability or incapacity; resulted in congenital anomaly or birth defect; or was medically important. A TEAE was any AE that occurred or worsened on or after the day of first dose of study treatment and within 30 days after discontinuation of study treatment. Part 1: Safety population included all enrolled participants who were treated with at least 1 dose of irinotecan liposome injection.

Primary

The TEAEs were reported from the time of first study treatment administration (Day 1) up to 30 days after the date of last study treatment administration, approximately 680 days

A TEAE was considered as DLT if it occurred during the safety evaluation period (i.e. first 28 days of treatment or 14 days after the second dose of study treatment if there was a treatment delay due to non-DLT related reasons) and were deemed related to the study treatment by the investigator. The determination of whether an AE was considered a Dose Limiting Toxicity was made by the Safety Review Committee (SRC) comprising the Part 1 Investigators and the Medical Monitor(s) of the Sponsor. Part 1: Safety population included all enrolled participants who were treated with at least 1 dose of irinotecan liposome injection.

Primary

From the start of the first study treatment administration (Day 1) up to 14 days after the second dose of study treatment administration, a maximum of 42 days

The OS was defined as the time from randomization date to the date of death from any cause. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive. The OS was calculated using Kaplan-Meier technique. Following end of treatment participant and/or family was contacted by telephone every month to assess vital status. Part 2: The ITT population included all randomized participants.

Primary

From date of randomization (within 7 days before start of study treatment) until death. Assessed up to Part 2 primary analysis data cut-off (DCO) date of 08 February 2022 (approximately 900 days)

Part 2: Irinotecan Liposome Injection 70 mg/m^2 v Part 2: Topotecan 1.5 mg/m^2

461

Pre-specified

1.11

2-sided

The ORR was defined as the percentage of participants with a best overall response (BOR) characterized as either a complete response (CR) or partial response (PR) recorded from date of first dose of study treatment until documented PD or death. ORR analysis was based on BOR using RECIST v1.1 per investigator assessment. Per RECIST v1.1, CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions; and overall response = CR + PR. Per protocol, participants had computed tomography (CT)-scans and brain magnetic resonance imaging (MRI) every 6 weeks to measure tumor lesion size. This was continued throughout treatment until progressive disease (PD) or commencement of new anti-neoplastic therapy. Part 1: Safety population included all enrolled participants who were treated with at least 1 dose of irinotecan liposome injection.

Secondary

RECIST assessments performed at Baseline (within 28 days before start of study treatment), every 6 weeks post first dose and treatment pause, 30 days after discontinuation of study treatment, then every month thereafter, approximately maximum of 1177 days

The PFS was defined as time from first dose of study treatment to the first documented objective PD using RECIST v1.1 or death due to any cause, whichever occurs first. Per RECIST 1.1, progression is defined as at least 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The PFS was calculated using Kaplan-Meier technique. Per protocol, participants had CT-scans and brain MRI every 6 weeks to measure tumor lesion size. This was continued throughout treatment until PD or commencement of new anti-neoplastic therapy. Part 1: Safety population included all enrolled participants who were treated with at least 1 dose of irinotecan liposome injection. 99999=Upper limit of CI was not estimable due to insufficient number of participants with events at study closure.

Secondary

RECIST assessments performed at Baseline (within 28 days before start of study treatment), every 6 weeks post first dose and treatment pause, 30 days after discontinuation of study treatment, then every month thereafter, approximately maximum of 1177 days

The OS was defined as the time from first dose of study treatment to the date of death from any cause. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive. The OS was calculated using Kaplan-Meier technique. Following end of treatment participant and/or family was contacted by telephone every month to assess vital status. Part 1: Safety population included all enrolled participants who were treated with at least 1 dose of irinotecan liposome injection. 99999=Upper limit of CI was not estimable due to insufficient number of participants with events at study closure.

Secondary

From Baseline (Day 1) until death. Assessed up to Part 1 DCO date of 11 August 2021 (approximately 1177 days)

The PFS was defined as time from randomization to first documented objective PD using RECIST 1.1 (or response assessment in neuro-oncology brain metastases [RANO-BM] criteria for central nervous system [CNS] lesions) as assessed by blinded independent central review (BICR) or death due to any cause, whichever occurred first. Per RECIST 1.1, progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The PFS was calculated using Kaplan-Meier technique. Per protocol, participants had CT-scans and brain MRI every 6 weeks to measure tumor lesion size. This was continued throughout treatment until PD or commencement of new anti-neoplastic therapy. Part 2: The ITT population included all randomized participants.

Secondary

RECIST assessments performed at Baseline (within 28 days before start of study treatment), every 6 weeks post first dose and treatment pause, 30 days after discontinuation of study treatment, then every month thereafter, approximately maximum of 900 days

Part 2: Irinotecan Liposome Injection 70 mg/m^2 v Part 2: Topotecan 1.5 mg/m^2

461

Pre-specified

0.96

2-sided

The ORR was defined as percentage of participants with a BOR characterized as either a CR or PR, recorded from randomization until documented PD or death relative to the total number of participants. ORR analysis was based on BOR assessed by BICR using Response evaluation criteria in solid tumors (RECIST) v1.1. Per RECIST v1.1, CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions; and overall response = CR + PR. Per protocol, participants had CT-scans and brain MRI every 6 weeks to measure tumor lesion size. This was continued throughout treatment until PD or commencement of new anti-neoplastic therapy. Part 2: The ITT population included all randomized participants.

Secondary

RECIST assessments performed at Baseline (within 28 days before start of study treatment), every 6 weeks post first dose and treatment pause, 30 days after discontinuation of study treatment, then every month thereafter, approximately maximum of 900 days

Part 2: Irinotecan Liposome Injection 70 mg/m^2 v Part 2: Topotecan 1.5 mg/m^2

461

Pre-specified

22.29

2-sided

The DoR was defined as time from the first documented objective response (CR or PR, whichever was earlier) to the date of first documented PD or death due to any cause. The DoR analysis was based on BOR assessed by BICR using RECIST v1.1. Per RECIST v1.1, CR is disappearance of all target lesions and PR is >=30% decrease in the sum of the longest diameter of target lesions. The DoR was calculated using Kaplan-Meier technique. Per protocol, participants had CT-scans and brain MRI every 6 weeks to measure tumor lesion size. This was continued throughout treatment until PD or commencement of new anti-neoplastic therapy. Part 2: The ITT population included all randomized participants. Only participants with objective response were analyzed.

Secondary

RECIST assessments performed at Baseline (within 28 days before start of study treatment), every 6 weeks post first dose and treatment pause, 30 days after discontinuation of study treatment, then every month thereafter, approximately maximum of 900 days

Time to OR as per RECIST v1.1 Criteria according to BICR was defined as time from the date of randomization to the date of first documented objective tumor response (CR or PR, whichever was first). Per RECIST v1.1, CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesion. Participants with a new anti-cancer therapy prior to OR were censored at the last tumor assessment prior to new anti-cancer therapy. Per protocol, participants had CT-scans and brain MRI every 6 weeks to measure tumor lesion size. This was continued throughout treatment until PD or commencement of new anti-neoplastic therapy. Part 2: The ITT population included all randomized participants. Only participants with objective response were analyzed. 99999=Upper limit of CI was not estimable due to insufficient number of participants with events at study closure.

Secondary

RECIST assessments performed at Baseline (within 28 days before start of study treatment), every 6 weeks post first dose and treatment pause, 30 days after discontinuation of study treatment, then every month thereafter, approximately maximum of 900 days

The EORTC QLQ-LC13 is a lung cancer specific module used in conjunction with EORTC QLQ-C30 and covers typical symptoms of lung cancer (cough, pain, dyspnea, sore mouth, peripheral neuropathy, hair loss). Scores range from 0-100 and a high score represents a high level of symptomatology/problems/worse QoL. Baseline was defined as the last non-missing measurement taken prior to reference start date. Change from baseline in dyspnea scale was calculated regardless of premature study treatment discontinuation. Participants completed these questionnaires on an electronic tablet every 6 weeks during treatment and it was continued until PD or commencement of new anti-neoplastic therapy. Part 2: The ITT population included all randomized participants. Only participants analyzed at Week 12 are reported.

Secondary

Baseline (Day 1) and Week 12

The EORTC QLQ-LC13 is a lung cancer specific module used in conjunction with EORTC QLQ-C30 and covers typical symptoms of lung cancer (cough, pain, dyspnea, sore mouth, peripheral neuropathy, hair loss). Score ranges from 0-100 scale and a high score represents a high level of symptomatology/problems/worse QoL. Baseline was defined as the last non-missing measurement taken prior to reference start date. Change from baseline in cough scale was calculated regardless of premature study treatment discontinuation. Participants completed these questionnaires on an electronic tablet every 6 weeks during treatment and it was continued until PD or commencement of new anti-neoplastic therapy. Part 2: The ITT population included all randomized participants. Only participants analyzed at Week 12 are reported.

Secondary

Baseline (Day 1) and Week 12

TEAEs: From the time of first study treatment administration (Day 1) up to 30 days after the date of last study treatment administration, approximately 680 days for Part 1 and 1452 days for Part 2. All-Cause Mortality: approximately 1919 days

Part 1:Safety population: All enrolled participants treated with at least 1 dose of irinotecan liposome injection. Part 2: Safety population: All randomized participants treated with at least 1 dose of study treatment. AEs are coded using MedDRA version 26.0. During all study visits, participants were asked to report any AE since prior study visit.

26.0

Part 1: Irinotecan Liposome Injection 85 mg/m^2

Part 1: Irinotecan Liposome Injection 70 mg/m^2

Part 2: Irinotecan Liposome Injection 70 mg/m^2

Part 2: Topotecan 1.5 mg/m^2