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

Randomized, Controlled, Open-label, Phase 3, Global Multi - Center Trial to Assess the Efficacy and Safety of Zipalertinib Plus Chemotherapy Versus Chemotherapy Alone, in Patients With Previously Untreated, Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer (NSCLC) With Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion (ex20ins) Mutations

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced or Metastatic NSCLS With Exon 20 Insertion Mutation
• Intervention / Treatment: Drug: TAS6417

Detailed Description

This study will evaluate the efficacy and safety of zipalertinib in combination with standard chemotherapy with pemetrexed and a platinum agent (either carboplatin or cisplatin) in patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC harboring EGFR ex20ins mutations.

The study will be conducted in two parts:

• Part A: Safety lead-in to determine the recommended dose of zipalertinib in combination with standard chemotherapy pemetrexed and a platinum agent (either carboplatin or cisplatin) to be studied in Part B of the study.
• Part B: Randomized, controlled, open-label, multinational Phase 3 study to assess the efficacy and safety of zipalertinib in combination with standard chemotherapy with pemetrexed and a platinum agent (either carboplatin or cisplatin) compared to standard chemotherapy alone. Patients randomized to the chemotherapy-only treatment arm in Part B may receive treatment with zipalertinib as monotherapy after BICR-assessed progressive disease (PD) is documented (optional "crossover arm").

An independent data monitoring committee (IDMC) will be established to monitor interim safety Data.

A treatment cycle is defined as 21 days for both parts of the study.

Part A: Safety Lead-In The primary objective of Part A is to determine the recommended dose of zipalertinib administered in combination with pemetrexed and a platinum agent (either carboplatin or cisplatin) to be studied in the Phase 3 portion of this study.

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. Patients will be enrolled using a rolling-6 design,35 and the determination of the dose of zipalertinib to be used in Part B of the study will be informed by the incidence of dose-limiting toxicities (DLTs) observed during Cycle 1.

Part B: Phase 3 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.

• Study Type: Interventional
• Enrollment (Actual): 285
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Flemish Brabant
    • Leuven, Flemish Brabant, Belgium, 3000
      • Universitair Ziekenhuis Leuven - Campus Gasthuisberg
  • Oost-Vlaaderen
    • Ghent, Oost-Vlaaderen, Belgium, 9000
      • Algemeen Ziekenhuis Maria Middelares
  • West Flanders
    • Menen, West Flanders, Belgium, 8930
      • Algemeen Ziekenhuis Delta - Campus Menen
  • West-Vlaanderen
    • Rosières, West-Vlaanderen, Belgium, 8800
      • Algemeen Ziekenhuis Delta - Campus Rumbeke
• Brazil
  • Ceará
    • Fortaleza, Ceará, Brazil, 60335-480
      • Centro Regional Integrado de Oncologia
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90610-000
      • Hospital Sao Lucas Da Pucrs
    • Porto Alegre, Rio Grande do Sul, Brazil, 90110-270
      • Hospital Mãe de Deus - Centro Integrado de Oncologia
  • Santa Catatina
    • Itajaí, Santa Catatina, Brazil, 88301
      • Clínica Neoplasias Litoral
  • São Paulo
    • Jaú, São Paulo, Brazil, 17210-180
      • Hospital Amaral Carvalho
• Bulgaria
  • Sofia, Bulgaria, 4500
    • University Multiprofile Hospital for Active Treatment Tsaritsa Yoanna-ISUL
  • Pazardzhik
    • Panagyurishte, Pazardzhik, Bulgaria, 1527
      • Multi-profile Hospital for Active Treatment Uni Hospital
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer Vancouver
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • William Osler Health System - Brampton Civic Hospital
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
• Chile
  • Region de Santiago
    • Santiago, Region de Santiago, Chile, 7500653
      • CentroEstudiosClinicosSAGA
  • Santiago Metropolitan
    • Independencia, Santiago Metropolitan, Chile, 8380494
      • Hospital Clínico Universidad de Chile
    • Providencia, Santiago Metropolitan, Chile, 7500921
      • Instituto Oncológico Fundación Arturo López Pérez
• France
  • Quimper, France, 29000
    • CH Cornouaille Quimper
  • Alsace
    • Strasbourg, Alsace, France, 67091
      • Les Hôpitaux Universitaires de Strasbourg
  • Basse-Normandie
    • Caen, Basse-Normandie, France, 14033
      • Hôpital Côte De Nacre
  • Limousin
    • Limoges, Limousin, France, 87042
      • Centre Hospitalier Universitaire Limoges
  • New Aquitaine
    • Pessac, New Aquitaine, France, 33604
      • Hôpital Haut-Lévêque
  • Pays de la Loire Region
    • Le Mans, Pays de la Loire Region, France, 72037
      • Centre Hospitalier Le Mans
  • Val-de-Marne
    • Villejuif, Val-de-Marne, France, 94805
      • Gustave Roussy
  • Île-de-France Region
    • Boulogne-Billancourt, Île-de-France Region, France, 92100
      • Hôpital Ambroise-Paré
    • Paris, Île-de-France Region, France, 75248
      • Institut Curie
• Germany
  • München, Germany, 80337
    • LMU Klinikum - Campus Innenstadt
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg
  • Hamburg (Hansestadt)
    • Hamburg, Hamburg (Hansestadt), Germany, 22763
      • Asklepios Klinik Altona
  • Hesse
    • Giessen, Hesse, Germany, 35392
      • Universitätsklinikum Gießen und Marburg - Gießen
• Greece
  • Thessaloniki, Greece, 54622
    • Bioclinic Thessaloniki
  • Attica
    • Athens, Attica, Greece, 11527
      • General Hospital for Thoracic Diseases Sotiria
    • Piraeus, Attica, Greece, 18547
      • Metropolitan General
  • Peloponnese
    • Patra, Peloponnese, Greece, 26504
      • University General Hospital of Patras
  • Pireas
    • Piraeus, Pireas, Greece, 185 47
      • Metropolitan Hospital
  • Thessaly
    • Larissa, Thessaly, Greece, 41110
      • University General Hospital of Larissa
• Israel
  • Afula, Israel, 18101
    • Emek Medical Center
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center
  • Jerusalem, Israel, 9112001
    • Hadassah University Hospital Ein Kerem
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center
  • Tel Aviv, Israel, 69710
    • Assuta Hospital - Ramat HaHayal
• Italy
  • Milan, Italy, 20132
    • Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele
  • Modena, Italy, 41224
    • Azienda Ospedaliero - Universitaria di Modena
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San Matteo
  • Ravenna, Italy, 48121
    • Azienda Unità Sanitaria Locale della Romagna
  • Roma, Italy, 1444
    • IRCCS Istituto Nazionale Tumori Regina Elena
  • Verona, Italy, 37126
    • Azienda Ospedaliera Universitaria Integrata Verona
  • Forli-Cesena
    • Meldola, Forli-Cesena, Italy, 47014
      • Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST
  • Forlì-Cesena
    • Meldola, Forlì-Cesena, Italy, 47014
      • Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST
  • Genoa
    • Genova, Genoa, Italy, 16132
      • Istituto Nazionale per la Ricerca sul Cancro
• Japan
  • Kanazawa, Japan, 920-8641
    • Kanazawa University Hospital
  • Osaka, Japan, 534-0021
    • Osaka City General Hospital
  • Osaka, Japan, 541-8567
    • Osaka Prefectural Hospital Organization - Osaka International Cancer Institute
  • Aiti [Aichi]
    • Nagoya, Aiti [Aichi], Japan, 464-8681
      • Aichi Cancer Center
  • Aomori
    • Hirosaki-Shi, Aomori, Japan, 036-8563
      • Hirosaki University Hospital
  • Hukuoka
    • Fukuoka, Hukuoka, Japan, 811-1395
      • Kyushu Cancer Center
  • Kanagawa
    • Sagamihara, Kanagawa, Japan, 252-0375
      • Kitasato University Hospital
    • Yokohama, Kanagawa, Japan, 236-0051
      • Kanagawa Cardiovascular and Respiratory Center
  • Kumamoto
    • Kumamoto, Kumamoto, Japan, 861-4163
      • Saiseikai Kumamoto Hospital
  • Miyagi
    • Sendai, Miyagi, Japan, 980-0873
      • Sendai Kousei Hospital
  • Okayama-ken
    • Okayama, Okayama-ken, Japan, 700-8558
      • Okayama University Hospital
  • Osaka
    • Hirakata, Osaka, Japan, 573-1191
      • Kansai Medical University Hospital
    • Sakai-Shi, Osaka, Japan, 591-8555
      • National Hospital Organization Kinki-Chuo Chest Medical Center
  • Tokyo
    • Koto, Tokyo, Japan, 135-8550
      • Cancer Institute Hospital of Jfcr
    • Shinjuku-Ku, Tokyo, Japan, 160-8582
      • Keio University Hospital
• Mexico
  • Aguascalientes, Mexico, 20124
    • Investigacion Medica Galerias
  • Veracruz, Mexico, 91900
    • FAICIC Clínical Research
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcalde"
    • Guadalajara, Jalisco, Mexico, 44680
      • Actualidad Basada en la Investigación del Cáncer
  • Mexico City
    • Mexico City, Mexico City, Mexico, 3100
      • Health Pharma Professional Research S.A. De C.V
  • Puebla
    • Mirador, Puebla, Mexico, 72530
      • Clínica Integral Internacional de Oncología S de RL de CV
• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboud Universitair Medisch Centrum
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1066 CX
      • Antoni van Leeuwenhoek Ziekenhuis
    • Amsterdam, North Holland, Netherlands, 1081 HV
      • Vrije Universiteit Medisch Centrum
• Philippines
  • City of Muntinlupa, Philippines, 1780
    • Asian Hospital and Medical Center
  • Metropolitan Manila
    • Quezon City, Metropolitan Manila, Philippines, 1112
      • St. Luke's Medical Center - Quezon City
  • National Capital Region
    • Pasig, National Capital Region, Philippines, 1605
      • The Medical City
• Poland
  • Greater Poland Voivodeship
    • Pozna?, Greater Poland Voivodeship, Poland, 60-569
      • Wielkopolskie Centrum Pulmonologii i Torakochirurgii im. Eugenii i Janusza Zeylandów
  • Lublin Voivodeship
    • Lublin, Lublin Voivodeship, Poland, 20-954
      • Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie
  • Lódzkie
    • Lodz, Lódzkie, Poland, 90-302
      • Instytut MSF
• Romania
  • Suceava, Romania, 720214
    • Clinica SIGMedical
  • Cluj
    • Cluj-Napoca, Cluj, Romania, 400641
      • Medisprof
  • Dolj
    • Craiova, Dolj, Romania, 200746
      • Centrul de Oncologie Sf Nectarie
  • Timiș County
    • Timișoara, Timiș County, Romania, 300166
      • Oncocenter - Oncologie Clinica
• Singapore
  • Singapore, Singapore, 168583
    • National Cancer Centre Singapore
  • Singapore, Singapore, 228510
    • Icon Cancer Centre - Mount Alvernia
  • Singapore, Singapore, 30433
    • Tan Tock Seng Hospital
  • Singapore, Singapore, 308900
    • Oncocare Cancer Centre
  • Singapore, Singapore, 574623
    • Icon Cancer Centre Mount Elizabeth
• South Korea
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, South Korea
      • Seoul National University Bundang Hospital
    • Suwon, Gyeonggi-do, South Korea, 16499
      • Ajou University Hospital
    • Suwon, Gyeonggi-do, South Korea, 16247
      • Catholic University of Korea Saint Vincent's Hospital
  • Gyeongsangnamdo [Kyongsangnam-do]
    • Jinju, Gyeongsangnamdo [Kyongsangnam-do], South Korea, 52727
      • Gyeongsang National University Hospital
  • Incheon Gwang'yeogsi [Inch'on-Kwangyokshi]
    • Incheon, Incheon Gwang'yeogsi [Inch'on-Kwangyokshi], South Korea, 22332
      • Inha University Hospital
  • Seoul Teugbyeolsi [Seoul-T'ukpyolshi]
    • Seoul, Seoul Teugbyeolsi [Seoul-T'ukpyolshi], South Korea, 02841
      • Korea University Anam Hospital
    • Seoul, Seoul Teugbyeolsi [Seoul-T'ukpyolshi], South Korea, 08308
      • Korea University Guro Hospital
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
  • Barcelona, Spain, 08023
    • Hospital Quironsalud Barcelona
  • Barcelona, Spain, 08017
    • Clínica Mi Tres Torres
  • Jaén, Spain, 23007
    • Hospital Universitario de Jaen
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center Madrid
  • Málaga, Spain, 29010
    • Hospital Regional Universitario de Malaga - Hospital General
  • La Coruña
    • A Coruña, La Coruña, Spain, 15006
      • Complejo Hospitalario Universitario A Coruña
• Thailand
  • Bangkok
    • Bang Phlat, Bangkok, Thailand, 10700
      • Faculty of Medicine Siriraj Hospital
    • Pathum Wan, Bangkok, Thailand, 10330
      • King Chulalongkorn Memorial Hospital
  • Khet Dusit
    • Bangkok, Khet Dusit, Thailand, 10300
      • Navamindradhiraj University - Faculty of Medicine Vajira Hospital
• Turkey (Türkiye)
  • Adana, Turkey (Türkiye), 01060
    • T.C. Saglik Bakanligi Adana Sehir Egitim ve Arastirma Hastanesi
  • Adana, Turkey (Türkiye), 01120
    • Medical Park Seyhan Hastanesi
  • Ankara, Turkey (Türkiye), 6520
    • Memorial Ankara Hastanesi
  • Ankara, Turkey (Türkiye), 06010
    • Hacettepe Üniversitesi Kanser Enstitüsü
  • Edirne, Turkey (Türkiye), 22130
    • Trakya Üniversitesi Sa?l?k Ara?t?rma ve Uygulama Merkezi
  • Etlik, Turkey (Türkiye), 06010
    • Ankara Il Saglik Mudurlugu SBU Gulhane Egitim Ve Arastirma Hastanesi
  • Istanbul, Turkey (Türkiye), 34214
    • Bagcilar Medipol Mega Universite Hastanesi
  • Istanbul, Turkey (Türkiye), 34722
    • T.C. Saglik Bakanligi - Istanbul Il Saglik Mudurlugu - Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi
  • Çankaya, Turkey (Türkiye), 06800
    • T.C. Saglik Bakanligi Ankara Bilkent Sehi?r Hastanesi?
• United Kingdom
  • England
    • London, England, United Kingdom, NW3 2QG
      • Royal Free London NHS Foundation Trust
    • Nottingham, England, United Kingdom, NG5 1PB
      • Nottingham University Hospitals Nhs Trust
    • Torquay, England, United Kingdom, TQ2 7AA
      • Torbay and South Devon NHS Foundation Trust
• United States
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Comprehensive Cancer Centers of Nevada - Henderson
    • Henderson, Nevada, United States, 89074
      • Comprehensive Cancer Centers of Nevada - Southeast Henderson - Stephanie
    • Henderson, Nevada, United States, 89052
      • Comprehensive Cancer Centers of Nevada - Horizon Ridge Henderson
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada - Central Valley - Twain
    • Las Vegas, Nevada, United States, 89144
      • Comprehensive Cancer Centers of Nevada - Summerlin Medical Center II
    • Las Vegas, Nevada, United States, 89148
      • Comprehensive Cancer Centers of Nevada - Southwest
    • Las Vegas, Nevada, United States, 89218
      • Comprehensive Cancer Centers of Nevada - Northwest
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer and Research Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A (Safety Lead in); 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; oral tablets; Other Names: CLN-081; Zipalertinib
Experimental: Part B; 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; oral tablets; Other Names: CLN-081; Zipalertinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Part A and Part B: Intracranial duration of Response (iDoR)		approximately 5 years
Part B: Overall survival (OS)		approximately 5 years
Pharmacokinetic (PK) parameter	Minimum observed concentration (Cmin)	approximately 5 years
European Quality of Life 5 Dimensions, 3 Level Version (EQ-5D-3L)	The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. This scale is numbered from 0 to 100. The higher the score the better the outcome	approximately 5 years
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30	The EORTC QLQ-C30 is a "core questionnaire" which incorporates a range of physical, emotional and social health developed to assess the quality of life of cancer patients. This scale is numbered from 30 to 130. The higher the score equates to better functioning.	approximately 5 years
Non-small Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ )	The NSCLC- SAQ was developed to incorporate the patient's perspective into evaluation of clinical benefit in advanced non-small cell lung cancer trials.. Qualitative evidence supports 7 items covering 5 symptom concepts with the total score measuring overall severity of the following NSCLC symptoms: cough, pain, dyspnea, fatigue, and appetite. Lower scores indicate lower symptom severity.	approximately 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) parameter	Minimum Plasma Concentration [Cmin]	approximately 5 years
Pharmacokinetic (PK) parameter	Maximum Plasma Concentration [Cmax]	approximately 5 years
Pharmacokinetic (PK) parameter	Area Under Curve [AUC]	approximately 5 years
EGFR mutation status	local central tests results	approximately 5 years

Collaborators and Investigators

• Sponsor: Taiho Oncology, Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2023
• Primary Completion (Estimated): October 29, 2026
• Study Completion (Estimated): May 27, 2027

Study Registration Dates

• First Submitted: July 11, 2023
• First Submitted That Met QC Criteria: July 25, 2023
• First Posted (Actual): August 3, 2023

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; EGFR; Carcinoma, Non-Small-Cell Lung; Exon 20 insertion mutation; phase 3; Lung disease; CLN-081; TAS6417
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Diseases; Carcinoma, Non-Small-Cell Lung; zipalertinib
• Other Study ID Numbers: TAS6417-301; 2023-503575-21 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes