Study of Irinotecan Liposome Injection (ONIVYDE®) in Patients With Small Cell Lung Cancer

Small Cell Lung Cancer Clinical Trial

— RESILIENT  

Official title:

RESILIENT: A Randomized, Open Label Phase 3 Study of Irinotecan Liposome Injection (ONIVYDE®) Versus Topotecan in Patients With Small Cell Lung Cancer Who Have Progressed on or After Platinum-based First-Line Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03088813
• Other study ID #: MM-398-01-03-04
• Secondary ID: 2017-004261-26
• Status: Completed
• Phase: Phase 3
• Start date: April 25, 2018
• Est. completion date: July 27, 2023

Study information

• Verified date: September 2023
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A randomized, open label phase 3 study of irinotecan liposome injection (ONIVYDE®) versus topotecan in patients with small cell lung cancer who have progressed on or after platinum-based first-line therapy

The study was conducted in two parts:

1. Dose determination of irinotecan liposome injection

2. A randomized, efficacy study of irinotecan liposome injection versus topotecan

Description:

The study was conducted in two parts:

Part 1: Open-label dose-finding study of irinotecan liposome injection. 30 patients were planned to be enrolled.

Part 1 Primary Objectives:

• Describe the safety and tolerability of irinotecan liposome injection monotherapy administered every 2 weeks

• Determine the optimal irinotecan liposome injection monotherapy dose for Part 2 of this study

Part 2: A randomized, efficacy study of irinotecan liposome injection versus intravenous (IV) topotecan.

Approximately 450 patients were planned to be enrolled in part 2.

Part 2 objectives: To compare overall survival following treatment with irinotecan liposome injection with overall survival following treatment with IV topotecan.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 491
• Est. completion date: July 27, 2023
• Est. primary completion date: February 8, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• At least 18 years of age.

• Able to understand and provide an informed consent

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Life expectancy >12 weeks

• Histopathologically or cytologically confirmed small cell lung cancer

• Evaluable disease as defined by RECIST Version 1.1 guidelines (patients with non measurable lesions only are eligible).

• Radiologically confirmed progression on or after first-line platinum based chemotherapy (carboplatin or cisplatin), or chemo-radiation including platinum-based chemotherapy for treatment of limited or extensive stage Small Cell Lung Cancer (SCLC). In addition to platinum-based regimen, one line of immunotherapy as monotherapy or in combination, in first or in second line setting is allowed.

• Recovered from the effects of any prior chemotherapy, surgery, radiotherapy or other anti-neoplastic therapy (recovered to Grade 1 or better, with the exception of alopecia, peripheral neuropathy, or ototoxicity).

• Adequate bone marrow reserves

• Adequate hepatic function

• Adequate renal function

• Electrocardiogram during the Screening period without any clinically significant findings, per investigator's assessment

• Patients with certain types of asymptomatic CNS metastases that meet ALL the following criteria are eligible.

1. Patients with asymptomatic CNS metastases prior to enrollment

2. Prior radiation for CNS metastatic disease is completed =4 weeks prior to enrollment

3. CNS metastases that are stable or have decreased according to the post radiation follow-up scan that is conducted at least 4 weeks after completion of radiation treatment for CNS lesion.

4. Patients have discontinued corticosteroids or are on stable low-dose steroids (prednisone or equivalent 10 mg daily or less) for at least 1 week after completion of radiation for CNS lesion prior to enrollment.

Exclusion Criteria

• Any medical or social condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results

• Pregnant or breast feeding;

• Patients with large cell neuroendocrine lung carcinoma.

• Patients who have received prior topoisomerase I inhibitor treatment, retreatment with platinum-based regimen, antibody-drug conjugates or molecular targeted agents, more than one line of immunotherapy, or any other additional regimen of prior cytotoxic chemotherapy.

• Patients with the symptomatic Central Nervous System (CNS) metastasis and/or who have developed new or progressive brain metastasis within 3 months following prophylactic and/or therapeutic cranial radiation (whole brain stereotactic radiation).

• Patients with carcinomatous meningitis.

• Unable to discontinue the use of strong CYP3A4 or UGT1A1 inhibitors at least 1 week or strong CYP3A4 inducers at least 2 weeks prior to receiving the first dose of irinotecan liposome injection.

• Have a previous or concurrent cancer that is distinct in primary (non-pulmonary) site or SCLC histology

• Investigational therapy administered within 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is less, prior to the first scheduled day of dosing in this study.

• Severe cardiovascular and pulmonary diseases

• New York Heart Association Class III or IV congestive heart failure, ventricular arrhythmias, or uncontrolled blood pressure.

• Active infection

• Known hypersensitivity to any of the components of irinotecan liposome injection, other liposomal products, or topotecan.

• Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > grade 1.

Related Conditions & MeSH terms

• Lung Neoplasms
• Small Cell Lung Cancer
• Small Cell Lung Carcinoma

Intervention

Drug:
• Irinotecan liposome injection
IV
• Topotecan
IV

Locations

Country	Name	City	State
Australia	Border Medical Oncology Research Unit	Albury	New South Wales
Australia	South West Healthcare	Warrnambool	Victoria
Australia	Southern Medical Day Care Centre	Wollongong
Australia	Princess Alexandra Hospital	Woolloongabba
Belgium	AZ Klina	Brasschaat
Belgium	UZ Leuven	Leuven
Belgium	Centre Hospitalier de l'Ardenne	Libramont
Belgium	AZ Sint-Maarten	Mechelen
Brazil	Hospital de Cancer de Barretos, Fundacoa Pio X II	Barretos
Brazil	Hospital de Caridade de Ijuí	Ijuí
Brazil	Oncobio Servicos de Saude	Nova Lima
Brazil	HGB - Hospital Giovanni Battista - Mãe de Deus Center	Porto Alegre
Brazil	Hospital Nossa Senhora da Conceição	Porto Alegre
Brazil	INCA - Instituto Nacional de Câncer	Rio De Janeiro
Brazil	CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia	Santo André
Brazil	Fundação Faculdade Regional de Medicina de São José do Rio Preto	São José Do Rio Preto
China	Beijing Cancer Hospital	Beijing
China	The First Affiliated Hospital of Bengbu Medical College	Bengbu
China	The First Hospital of Jilin University	Changchun
China	West China Hospital, Sichuan University	Chengdu
China	Guangdong Provincial People's Hospital	Guangzhou
China	Zhejiang Cancer Hospital	Hangzhou
China	Tongji Hospital	Hubei
China	Linyi Cancer Hospital	Linyi
China	Henan Cancer Hospital	Zhengzhou
France	CHU Brest - Hôpital Morvan	Brest
France	Hôpital Nord - CHU Marseille	Marseille
France	Institut de Cancérologie de la Loire	Saint-Priest-en-Jarez
France	Centre Hospitalier de Saint-Quentin	Saint-Quentin
Germany	Universitaetsklinikum Freiburg	Freiburg
Germany	Evangelisches Krankenhaus Hamm GmbH	Hamm
Germany	Universitaetsklinikum Heidelberg	Heidelberg
Germany	Pius-Hospital Oldenburg	Oldenburg
Hungary	Semmelweis Egyetem	Budapest
Hungary	Bekes Megyei Kozponti Korhaz Pandy Kalman Tagkorhaza	Gyula
Hungary	Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet	Szolnok
Hungary	Tudogyogyintezet Torokbalint	Törökbálint
Hungary	Zala Megyei Szent Rafael Korhaz	Zalaegerszeg
Italy	Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori	Meldola
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano
Italy	Azienda Sanitaria Universitaria Integrata di Udine	Udine
Korea, Republic of	Chungbuk National University Hospital	Cheongju-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Korea, Republic of	The Catholic University of Korea, St. Vincent's Hospital	Suwon
Poland	KO-MED Centra Kliniczne Biala Podlaska	Biala Podlaska
Poland	Szpitale Pomorskie spólka z ograniczona odpowiedzialnoscia	Gdynia
Poland	SP Zespol Gruzlicy i Chorob Pluc w Olsztynie	Olsztyn
Poland	Przychodnia Med-Polonia Sp. z o.o.	Poznan
Poland	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego	Poznan
Romania	S.C Gral Medical S.R.L	Bucuresti
Romania	Institutul Oncologic "Prof. Dr. Ion Chiricuta" Cluj-Napoca	Cluj-Napoca
Romania	S.C Medisprof S.R.L	Cluj-Napoca
Romania	S.C Centrul de Oncologie Sf. Nectarie S.R.L	Craiova
Romania	S.C Radiotherapy Center Cluj S.R.L	Floresti
Romania	Oncomed SRL	Timisoara
Russian Federation	SBIH of Arkhangelsk region "Arkhangelsk Clinical Oncological Dispensary"	Arkhangel'sk
Russian Federation	"VitaMed" LLC	Moscow
Russian Federation	BHI of Omsk region "Clinical Oncology Dispensary"	Omsk
Russian Federation	SBHI of Kaluga Region "Kaluga regional clinical oncology dispensary"	Saint Petersburg
Russian Federation	SPb SBIH "City Clinical Oncological Dispensary"	Saint Petersburg
Russian Federation	SBIH of Yaroslavl region "Regional Clinical Oncological Hospital"	Yaroslavl
Serbia	Clinical Center Kragujevac	Belgrad
Serbia	Clinical Center "Bezanijska kosa"	Belgrade
Serbia	Oncomed System	Belgrade
Serbia	Institute for Pulmonary Diseases of Vojvodina	Sremska Kamenica
Serbia	General Hospital Uzice	Užice
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	ICO l'Hospitalet - Hospital Duran i Reynals	L'Hospitalet De Llobregat	Barcelona
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Regional Universitario de Malaga	Málaga
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Tri-Service General Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital, Linkou	Taoyuan
Turkey	Baskent University Adana Application and Research Center	Adana
Turkey	Trakya University Medical Faculty	Edirne
Turkey	Istanbul Medeniyet Uni Goztepe Training&Res Hosp	Istanbul
Turkey	Istanbul University Cerrahpasa - Cerrahpasa Medical Faculty	Istanbul
Turkey	Inonu Uni. Med. Fac.	Malatya
Turkey	Namik Kemal University	Tekirdag
Ukraine	CI Chernivtsi RC Oncological Dispensary	Chernivtsi
Ukraine	CI Dnipropetrovsk CMCH #4 of Dnipropetrovsk RC Dept of Chemotherapy SI Dnipropetrovsk MA of MOHU	Dnipro
Ukraine	Communal Non-profit Enterprise Regional Center of Oncology	Kharkiv
Ukraine	Communal Enterprise Kremenchuk Regional Oncology Dispensary of Poltava Regional Council	Kremenchuk
Ukraine	CI Kryvyi Rih Oncological Dispensary of DRC	Kryvyi Rih
Ukraine	Treatment-Prevention Institution Volyn Regional Oncological Dispensary	Luts'k
Ukraine	Odesa Regional Oncologic Dispensary	Odesa
Ukraine	RCI Sumy Regional Clinical Oncological Dispensary	Sumy
Ukraine	CCCH City Oncological Center SHEI Uzhgorod NU	Uzhgorod
Ukraine	Medical Clinic Innovacia, LLC	Vyshhorod
United States	University of Maryland Medical Group	Baltimore	Maryland
United States	Southern Maine Health Care	Biddeford	Maine
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Charleston Hematology Oncology Associates, PA	Charleston	South Carolina
United States	Case Western Reserve University	Cleveland	Ohio
United States	National Jewish Health	Denver	Colorado
United States	Rocky Mountain Cancer Centers	Denver	Colorado
United States	Henry Ford Hospital	Detroit	Michigan
United States	North Shore Hematology Oncology Associates, PC	East Setauket	New York
United States	Florida Cancer Specialists (South Region)	Fort Myers	Florida
United States	Cancer & Hematology Centers of Western Michigan	Grand Rapids	Michigan
United States	Greenville Hospital System University Medical Center	Greenville	South Carolina
United States	Sparrow Regional Cancer Center	Lansing	Michigan
United States	Northwest Georgia Oncology Centers	Marietta	Georgia
United States	Tri County Hematology & Oncology Associates, Inc	Massillon	Ohio
United States	Tennessee Oncology	Nashville	Tennessee
United States	Cancer Treatment Centers of America-Georgia	Newnan	Georgia
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Illinois Cancer Care, PC	Peoria	Illinois
United States	Florida Cancer Specialists	Saint Petersburg	Florida
United States	MultiCare Health System Institute for Research and Innovation	Spokane	Washington
United States	Summit Cancer Treatment Center	Spokane	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Ipsen

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  China,  France,  Germany,  Hungary,  Italy,  Korea, Republic of,  Poland,  Romania,  Russian Federation,  Serbia,  Spain,  Taiwan,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (SAEs)	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.	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 506 days
Primary	Part 1: Number of Participants With Dose-Limiting Toxicities (DLT)	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 Adverse Event 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.	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
Primary	Part 2: Overall Survival (OS)	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.	From date of randomization (within 7 days before start of study treatment) until death. Assessed up to Part 2 DCO date of 08 February 2022 (approximately 900 days)
Secondary	Part 1: Objective Response Rate (ORR)	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.	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
Secondary	Part 1: Progression-Free Survival (PFS)	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.	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
Secondary	Part 1: OS	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.	From Baseline (Day 1) until death. Assessed up to Part 1 DCO date of 11 August 2021 (approximately 1177 days)
Secondary	Part 2: PFS	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.	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
Secondary	Part 2: ORR	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 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.	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
Secondary	Part 2: Median Duration of Response (DoR)	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.	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
Secondary	Part 2: Median Time to Objective Response (OR)	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.	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
Secondary	Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30)/Lung Cancer Supplement (LC13) Dyspnea Scale at 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). 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.	Baseline (Day 1) and Week 12
Secondary	Change From Baseline in EORTC QLQ-LC13 Cough Scale at 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.	Baseline (Day 1) and Week 12