REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors)

NCT05973773 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: TAS6417-3012023-503575-21
• Study Type: interventional
• Target: 285
• Locations: 22 countries
• Sites: 128

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of zipalertinib in combination with standard first-line platinum-based chemotherapy compared to chemotherapy alone, in patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations.

Conditions

Advanced or Metastatic NSCLS With Exon 20 Insertion Mutation

Keywords

Exon 20 insertion mutation; NSCLC; phase 3; Lung disease; Carcinoma, Non-Small-Cell Lung; CLN-081; TAS6417; EGFR

Outcome Measures

Primary Outcomes (3)

• Part A and B: The rate and severity of treatment emergent AEs

  approximately 5 years

• Part A and Part B: Progression-free survival (PFS) by blinded independent central review (BICR)

  approximately 5 years

• Part A: The rate and severity of DLTs according to the NCI-Common Terminology Criteria of Adverse Events (CTCAE) v5.0 during Cycle 1

  approximately 5 years

Secondary Outcomes (11)

• Part A and Part B: Objective response rate (ORR)

  approximately 5 years

• Part A and Part B: Disease control rate (DCR)

  approximately 5 years

• Part A and Part B: Duration of response (DoR)

  approximately 5 years

• Part A and Part B: Intracranial (i) Overall Response Rate (iORR)

  approximately 5 years

• Part A and Part B: Intracranial duration of complete response (iDCR)

  approximately 5 years

Other Outcomes (4)

• Pharmacokinetic (PK) parameter

  approximately 5 years

• Pharmacokinetic (PK) parameter

  approximately 5 years

• Pharmacokinetic (PK) parameter

  approximately 5 years

Study Arms (2)

Part A (Safety Lead in)

EXPERIMENTAL

Part A: Safety Lead-In Approximately 6-12 patients will receive zipalertinib administered at an initial dose of zipalertinib PO BID (Dose Level 1) in combination with pemetrexed and carboplatin or cisplatin on a 21-day cycle. Patients may continue to receive study treatment until documentation of progressive disease (PD) or until other withdrawal criteria are met, whichever comes first.

Drug: TAS6417

Part B

EXPERIMENTAL

Enrollment into the Phase 3 portion of the study will begin following completion of Part A. Approximately 260 patients will be randomized on a 1:1 basis to receive pemetrexed and a platinum agent (either carboplatin or cisplatin) with or without zipalertinib on a 21-day cycle. Carboplatin or cisplatin will be administered for 4 cycles. Patients may continue to receive zipalertinib (experimental study arm) and pemetrexed (both study arms) until documentation of PD or until other withdrawal criteria are met, whichever comes first.

Drug: TAS6417

Interventions

TAS6417 DRUG

oral tablets

Also known as: Zipalertinib, CLN-081

Part A (Safety Lead in); Part B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

Inclusion- 1. Provide written informed consent. 2. ≥18 years of age (or meets the country's regulatory definition for legal adult age, whichever is greater). 3. Pathologically confirmed, locally advanced or metastatic nonsquamous NSCLC 4. Has not received any prior systemic treatment for their locally advanced or metastatic nonsquamous NSCLC. Prior adjuvant/neoadjuvant treatment received \>6 months prior to first dose of study treatment is allowed for early-stage NSCLC. Prior monotherapy with an approved EGFR TKI (ie, gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib) as nonstandard first-line therapy for the treatment of locally advanced or metastatic disease is allowed if all of the following criteria are met: 1. Treatment duration did not exceed 8 weeks; 2. Lack of disease response was documented (radiographically) by an increase in tumor burden (a copy of the computerized tomography \[CT\] report showing increase in tumor burden from baseline should be submitted); 3. Associated toxicities have resolved to baseline; and 4. The EGFR TKI was discontinued at least 2 weeks or 4 half-lives prior to randomization, whichever is longer. Prior therapy with EGFR TKI agents targeting exon20ins mutations including amivantamab, mobocertinib, sunvozertinib, furmonertinib, and poziotinib is not allowed. 5. Documented EGFR mutation status, as determined by local testing performed at a CLIA certified (US) or accredited (outside of the US) local laboratory, defined as follows: 1. Part A: EGFR ex20ins or other uncommon single or compound EGFR mutation 2. Part B: EGFR ex20ins mutation 6. Archival tumor tissue available for submission, with minimum quantity sufficient to evaluate EGFR mutation status and, where possible, other biomarkers. Patients with insufficient tissue (details provided in laboratory manual) may be eligible following discussion with the sponsor; a fresh biopsy will not be required. 7. Patients with brain metastasis(es) who have previously received definitive local treatment and have stable central nervous system (CNS) disease (defined as being neurologically stable and off corticosteroid for at least 2 weeks prior to enrollment) are eligible. If brain metastases are diagnosed on screening imaging, the patient may be rescreened for eligibility after definitive treatment. b. Asymptomatic brain metastases ≤2 cm in size can be eligible for inclusion if, in the opinion of the Investigator, immediate definitive treatment is not indicated. 8. At least one measurable lesion as determined per RECIST 1.1 for patients enrolling to Part B. Patients enrolling to Part A may be enrolled without measurable disease. 9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 10. Adequate organ function, as defined by the laboratory value 11. Have a life expectancy of at least 3 months as assessed by the investigator. 12. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to administration of the first dose of study treatment. Female patients are not considered to be of childbearing potential if they are postmenopausal (no menses for 12 months without an alternative medical cause) or permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). 13. Both males and females of reproductive potential must agree to use effective birth control during the study prior to the first dose and for 6 months after the last dose of study treatment or longer, based on local requirements. Exclusion - 1. Is currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study. 2. Prior treatment with any of the following within the specific time frame specified: 1. Zipalertinib (TAS6417/CLN-081) at any time. 2. Thoracic radiotherapy ≤28 days, palliative radiation of nonthoracic disease ≤14 days, or palliative radiation of a single lesion ≤7 days prior to first dose of study treatment. 3. Major surgery (excluding placement of vascular access) ≤28 days prior to first dose of study treatment. 4. All prescribed medication, over-the-counter medication, vitamin preparations and other food supplements, or herbal medications that are strong or moderate CYP3A4 inducers or inhibitors within 7 days prior to first dose. 3. Have any unresolved toxicity of Grade ≥2 from previous anticancer treatment in the neoadjuvant or adjuvant setting, except for Grade 2 alopecia or skin pigmentation. Patients with other chronic but stable Grade 2 toxicities may be allowed to enroll after agreement between the investigator and Sponsor. 4. Past medical history of interstitial lung disease, treatment-related pneumonitis (any grade), or any evidence of clinically active interstitial lung disease. 5. Impaired cardiac function or clinically significant cardiac disease, including any of the following: 1. History of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification . 2. Serious cardiac arrhythmias requiring treatment. 3. Resting corrected QT interval (QTc) \>470 msec calculated using Fridericia's formula (QTcF). 6. Unable to swallow tablets or has any disease or condition that may significantly affect gastrointestinal (GI) absorption of zipalertinib (such as inflammatory bowel disease, malabsorption syndrome, or prior GI resection). 7. History of another primary malignancy ≤2 years prior to the date of first dose of study treatment unless at least one of the following criteria are met: 1. Adequately treated basal or squamous cell carcinoma of the skin 2. Cancer of the breast or cervix in situ 3. Previously treated malignancy, if all treatment for that malignancy was completed at least 2 years prior to first dose of study treatment, and no current evidence of disease 4. Concurrent malignancy determined to be clinically stable and not requiring tumor directed treatment 8. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is unstable or not controlled with treatment. 9. History of COVID-19 infection within 4 weeks prior to enrolment and/or have persistent, clinically significant pulmonary symptoms related to prior COVID-19 infection. 10. Active bleeding disorders. 11. Known hypersensitivity to the ingredients in zipalertinib or any drugs similar in structure or class. To platinum-containing drugs (ie, cisplatin, carboplatin), pemetrexed, or any known excipients of these drugs. b. Contraindications toning drugs (ie, cisplatin, carboplatin) or pemetrexed according to the respective local labels. 12. History of leptomeningeal disease and spinal cord compression. 13. Is unable or unwilling to take dexamethasone, folic acid, and/or vitamin B12 supplementation during treatment with pemetrexed. 14. Is pregnant or lactating or planning to become pregnant 15. The patient is, in the investigator's opinion, unable or unwilling to comply with the trial procedures.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Taiho Oncology, Inc.: lead

Study Sites (128)

Comprehensive Cancer Centers of Nevada - Henderson

Henderson, Nevada, 89052, United States

Location

Comprehensive Cancer Centers of Nevada - Horizon Ridge Henderson

Henderson, Nevada, 89052, United States

Location

Comprehensive Cancer Centers of Nevada - Southeast Henderson - Stephanie

Henderson, Nevada, 89074, United States

Location

Comprehensive Cancer Centers of Nevada - Summerlin Medical Center II

Las Vegas, Nevada, 89144, United States

Location

Comprehensive Cancer Centers of Nevada - Southwest

Las Vegas, Nevada, 89148, United States

Location

Comprehensive Cancer Centers of Nevada - Central Valley - Twain

Las Vegas, Nevada, 89169, United States

Location

Comprehensive Cancer Centers of Nevada - Northwest

Las Vegas, Nevada, 89218, United States

Location

Gabrail Cancer and Research Center

Canton, Ohio, 44718, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Universitair Ziekenhuis Leuven - Campus Gasthuisberg

Leuven, Flemish Brabant, 3000, Belgium

Location

Algemeen Ziekenhuis Maria Middelares

Ghent, Oost-Vlaaderen, 9000, Belgium

Location

Algemeen Ziekenhuis Delta - Campus Menen

Menen, West Flanders, 8930, Belgium

Location

Algemeen Ziekenhuis Delta - Campus Rumbeke

Rosières, West-Vlaanderen, 8800, Belgium

Location

Centro Regional Integrado de Oncologia

Fortaleza, Ceará, 60335-480, Brazil

Location

Hospital Mãe de Deus - Centro Integrado de Oncologia

Porto Alegre, Rio Grande do Sul, 90110-270, Brazil

Location

Hospital São Lucas da PUCRS

Porto Alegre, Rio Grande do Sul, 90610-000, Brazil

Location

Clínica Neoplasias Litoral

Itajaí, Santa Catatina, 88301, Brazil

Location

Hospital Amaral Carvalho

Jaú, São Paulo, 17210-180, Brazil

Location

BC Cancer Vancouver

Vancouver, British Columbia, V5Z 4E6, Canada

Location

William Osler Health System - Brampton Civic Hospital

Brampton, Ontario, L6R 3J7, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

CentroEstudiosClinicosSAGA

Santiago, Region de Santiago, 7500653, Chile

Location

Hospital Clínico Universidad de Chile

Independencia, Santiago Metropolitan, 8380494, Chile

Location

Instituto Oncológico Fundación Arturo López Pérez

Providencia, Santiago Metropolitan, 7500921, Chile

Location

Les Hôpitaux Universitaires de Strasbourg

Strasbourg, Alsace, 67091, France

Location

Hôpital Côte De Nacre

Caen, Basse-Normandie, 14033, France

Location

Centre Hospitalier Universitaire Limoges

Limoges, Limousin, 87042, France

Location

Hôpital Haut-Lévêque

Pessac, Nouvelle-Aquitaine, 33604, France

Location

Centre Hospitalier Le Mans

Le Mans, Pays de la Loire Region, 72037, France

Location

Gustave Roussy

Villejuif, Val-de-Marne, 94805, France

Location

CH Cornouaille Quimper

Quimper, 29000, France

Location

Hôpital Ambroise-Paré

Boulogne-Billancourt, Île-de-France Region, 92100, France

Location

Institut Curie

Paris, Île-de-France Region, 75248, France

Location

Asklepios Klinik Altona

Hamburg, Hamburg (Hansestadt), 22763, Germany

Location

Universitätsklinikum Gießen und Marburg - Gießen

Giessen, Hesse, 35392, Germany

Location

LMU Klinikum - Campus Innenstadt

München, 80337, Germany

Location

Universitätsklinikum Regensburg

Regensburg, 93053, Germany

Location

General Hospital for Thoracic Diseases Sotiria

Athens, Attica, 11527, Greece

Location

Metropolitan General

Piraeus, Attica, 18547, Greece

Location

University General Hospital of Patras

Patra, Peloponnese, 26504, Greece

Location

Metropolitan Hospital

Piraeus, Pireas, 185 47, Greece

Location

University General Hospital of Larissa

Larissa, Thessaly, 41110, Greece

Location

BioClinic Thessaloniki

Thessaloniki, 54622, Greece

Location

Emek Medical Center

Afula, 18101, Israel

Location

Shaare Zedek Medical Center

Jerusalem, 9103102, Israel

Location

Hadassah University Hospital Ein Kerem

Jerusalem, 9112001, Israel

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 6423906, Israel

Location

Assuta Hospital - Ramat HaHayal

Tel Aviv, 69710, Israel

Location

Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST

Meldola, Forli-Cesena, 47014, Italy

Location

Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST

Meldola, Forlì-Cesena, 47014, Italy

Location

Istituto Nazionale per la Ricerca sul Cancro

Genova, Genoa, 16132, Italy

Location

Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele

Milan, 20132, Italy

Location

Azienda Ospedaliero - Universitaria di Modena

Modena, 41224, Italy

Location

Fondazione IRCCS Policlinico San Matteo

Pavia, 27100, Italy

Location

Azienda Unità Sanitaria Locale della Romagna

Ravenna, 48121, Italy

Location

IRCCS Istituto Nazionale Tumori Regina Elena

Roma, 1444, Italy

Location

Azienda Ospedaliera Universitaria Integrata Verona

Verona, 37126, Italy

Location

Aichi Cancer Center

Nagoya, Aiti [Aichi], 464-8681, Japan

Location

Hirosaki University Hospital

Hirosaki-Shi, Aomori, 036-8563, Japan

Location

Kyushu Cancer Center

Fukuoka, Hukuoka, 811-1395, Japan

Location

Kitasato University Hospital

Sagamihara, Kanagawa, 252-0375, Japan

Location

Kanagawa Cardiovascular and Respiratory Center

Yokohama, Kanagawa, 236-0051, Japan

Location

Saiseikai Kumamoto Hospital

Kumamoto, Kumamoto, 861-4163, Japan

Location

Sendai Kousei Hospital

Sendai, Miyagi, 980-0873, Japan

Location

Okayama University Hospital

Okayama, Okayama-ken, 700-8558, Japan

Location

Kansai Medical University Hospital

Hirakata, Osaka, 573-1191, Japan

Location

National Hospital Organization Kinki-Chuo Chest Medical Center

Sakai-Shi, Osaka, 591-8555, Japan

Location

Cancer Institute Hospital of JFCR

Koto, Tokyo, 135-8550, Japan

Location

Keio University Hospital

Shinjuku-Ku, Tokyo, 160-8582, Japan

Location

Kanazawa University Hospital

Kanazawa, 920-8641, Japan

Location

Osaka City General Hospital

Osaka, 534-0021, Japan

Location

Osaka Prefectural Hospital Organization - Osaka International Cancer Institute

Osaka, 541-8567, Japan

Location

Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcalde"

Guadalajara, Jalisco, 44280, Mexico

Location

Actualidad Basada en la Investigación del Cáncer

Guadalajara, Jalisco, 44680, Mexico

Location

Health Pharma Professional Research S.A. De C.V

Mexico City, Mexico City, 3100, Mexico

Location

Clínica Integral Internacional de Oncología S de RL de CV

Mirador, Puebla, 72530, Mexico

Location

Investigacion Medica Galerias

Aguascalientes, 20124, Mexico

Location

FAICIC Clínical Research

Veracruz, 91900, Mexico

Location

Radboud Universitair Medisch Centrum

Nijmegen, Gelderland, 6525 GA, Netherlands

Location

Antoni Van Leeuwenhoek Ziekenhuis

Amsterdam, North Holland, 1066 CX, Netherlands

Location

Vrije Universiteit Medisch Centrum

Amsterdam, North Holland, 1081 HV, Netherlands

Location

St. Luke's Medical Center - Quezon City

Quezon City, Metropolitan Manila, 1112, Philippines

Location

The Medical City

Pasig, National Capital Region, 1605, Philippines

Location

Asian Hospital and Medical Center

City of Muntinlupa, 1780, Philippines

Location

Wielkopolskie Centrum Pulmonologii i Torakochirurgii im. Eugenii i Janusza Zeylandów

Pozna?, Greater Poland Voivodeship, 60-569, Poland

Location

Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie

Lublin, Lublin Voivodeship, 20-954, Poland

Location

Instytut MSF

Lodz, Lódzkie, 90-302, Poland

Location

Medisprof

Cluj-Napoca, Cluj, 400641, Romania

Location

Centrul de Oncologie Sf Nectarie

Craiova, Dolj, 200746, Romania

Location

Oncocenter - Oncologie Clinica

Timișoara, Timiș County, 300166, Romania

Location

Clinica SIGMedical

Suceava, 720214, Romania

Location

National Cancer Centre Singapore

Singapore, 168583, Singapore

Location

Icon Cancer Centre - Mount Alvernia

Singapore, 228510, Singapore

Location

Tan Tock Seng Hospital

Singapore, 30433, Singapore

Location

Oncocare Cancer Centre

Singapore, 308900, Singapore

Location

Icon Cancer Centre Mount Elizabeth

Singapore, 574623, Singapore

Location

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, South Korea

Location

Catholic University of Korea Saint Vincent's Hospital

Suwon, Gyeonggi-do, 16247, South Korea

Location

Ajou University Hospital

Suwon, Gyeonggi-do, 16499, South Korea

Location

Gyeongsang National University Hospital

Jinju, Gyeongsangnamdo [Kyongsangnam-do], 52727, South Korea

Location

Inha University Hospital

Incheon, Incheon Gwang'yeogsi [Inch'on-Kwangyokshi], 22332, South Korea

Location

Korea University Anam Hospital

Seoul, Seoul Teugbyeolsi [Seoul-T'ukpyolshi], 02841, South Korea

Location

Korea University Guro Hospital

Seoul, Seoul Teugbyeolsi [Seoul-T'ukpyolshi], 08308, South Korea

Location

Complejo Hospitalario Universitario A Coruña

A Coruña, La Coruña, 15006, Spain

Location

Clínica Mi Tres Torres

Barcelona, 08017, Spain

Location

Hospital Quirónsalud Barcelona

Barcelona, 08023, Spain

Location

Hospital Clinic de Barcelona

Barcelona, 08036, Spain

Location

Hospital Universitario de Jaén

Jaén, 23007, Spain

Location

MD Anderson Cancer Center Madrid

Madrid, 28033, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, 28040, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Regional Universitario de Málaga - Hospital General

Málaga, 29010, Spain

Location

Faculty of Medicine Siriraj Hospital

Bang Phlat, Bangkok, 10700, Thailand

Location

King Chulalongkorn Memorial Hospital

Pathum Wan, Bangkok, 10330, Thailand

Location

Navamindradhiraj University - Faculty of Medicine Vajira Hospital

Bangkok, Khet Dusit, 10300, Thailand

Location

T.C. Saglik Bakanligi Adana Sehir Egitim ve Arastirma Hastanesi

Adana, 01060, Turkey (Türkiye)

Location

Medical Park Seyhan Hastanesi

Adana, 01120, Turkey (Türkiye)

Location

Hacettepe Üniversitesi Kanser Enstitüsü

Ankara, 06010, Turkey (Türkiye)

Location

Memorial Ankara Hastanesi

Ankara, 6520, Turkey (Türkiye)

Location

T.C. Saglik Bakanligi Ankara Bilkent Sehi?r Hastanesi?

Çankaya, 06800, Turkey (Türkiye)

Location

Trakya Üniversitesi Sa?l?k Ara?t?rma ve Uygulama Merkezi

Edirne, 22130, Turkey (Türkiye)

Location

Ankara Il Saglik Mudurlugu SBU Gulhane Egitim Ve Arastirma Hastanesi

Etlik, 06010, Turkey (Türkiye)

Location

Bagcilar Medipol Mega Universite Hastanesi

Istanbul, 34214, Turkey (Türkiye)

Location

T.C. Saglik Bakanligi - Istanbul Il Saglik Mudurlugu - Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi

Istanbul, 34722, Turkey (Türkiye)

Location

Royal Free London NHS Foundation Trust

London, England, NW3 2QG, United Kingdom

Location

Nottingham University Hospitals NHS Trust

Nottingham, England, NG5 1PB, United Kingdom

Location

Torbay and South Devon NHS Foundation Trust

Torquay, England, TQ2 7AA, United Kingdom

Location

Related Publications (1)

• Heymach JV, Yu HA, Besse B, Cheng Y, Tan DS, Wei L, Wacheck V, Nishio M. REZILIENT3: randomized phase III study of first-line zipalertinib plus chemotherapy in patients with EGFR exon 20 insertion-mutated NSCLC. Future Oncol. 2025 Feb;21(5):549-556. doi: 10.1080/14796694.2025.2457294. Epub 2025 Feb 16.

  PMID: 39957151 DERIVED

MeSH Terms

Conditions

Lung Diseases; Carcinoma, Non-Small-Cell Lung

Interventions

zipalertinib

Condition Hierarchy (Ancestors)

Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 11, 2023
• First Posted: August 3, 2023
• Study Start: December 18, 2023
• Primary Completion (Estimated): October 29, 2026
• Study Completion (Estimated): May 27, 2027
• Last Updated: March 10, 2026

Record last verified: 2026-03

Locations

KR (7); TH (3); IL (5); BR (5); JP (15); IT (9); SG (5); BE (4); CL (3); GR (6); ME (6); NL (3); FR (9); PH (3); TU (9); US (9); ES (10); PL (3); RO (4); GB (3); DE (4); CA (3)