Clinical trial NCT05973773: REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors)
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
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
Lead sponsor: Taiho Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2023-08-03
Enrollment: 272
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Part A and B: The rate and severity of treatment emergent AEs
timeFrame: approximately 5 years
measure: Part A and Part B: Progression-free survival (PFS) by blinded independent central review (BICR)
timeFrame: approximately 5 years
measure: Part A: The rate and severity of DLTs according to the NCI-Common Terminology Criteria of Adverse Events (CTCAE) v5.0 during Cycle 1
timeFrame: approximately 5 years
Secondary outcomes:
measure: Part A and Part B: Objective response rate (ORR)
timeFrame: approximately 5 years
measure: Part A and Part B: Disease control rate (DCR)
timeFrame: approximately 5 years
measure: Part A and Part B: Duration of response (DoR)
timeFrame: approximately 5 years
measure: Part A and Part B: Intracranial (i) Overall Response Rate (iORR)
timeFrame: approximately 5 years
measure: Part A and Part B: Intracranial duration of complete response (iDCR)
timeFrame: approximately 5 years
measure: Part A and Part B: Intracranial duration of Response (iDoR)
timeFrame: approximately 5 years
measure: Part B: Overall survival (OS)
timeFrame: approximately 5 years
measure: Pharmacokinetic (PK) parameter
timeFrame: approximately 5 years
measure: European Quality of Life 5 Dimensions, 3 Level Version (EQ-5D-3L)
timeFrame: approximately 5 years
measure: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30
timeFrame: approximately 5 years
measure: Non-small Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ )
timeFrame: approximately 5 years
Other outcomes:
measure: Pharmacokinetic (PK) parameter
timeFrame: approximately 5 years
measure: Pharmacokinetic (PK) parameter
timeFrame: approximately 5 years
measure: Pharmacokinetic (PK) parameter
timeFrame: approximately 5 years
measure: EGFR mutation status
timeFrame: approximately 5 years
Locations:
city: Henderson
country: United States
facility: Comprehensive Cancer Centers of Nevada - Henderson
state: Nevada
city: Henderson
country: United States
facility: Comprehensive Cancer Centers of Nevada - Horizon Ridge Henderson
state: Nevada
city: Henderson
country: United States
facility: Comprehensive Cancer Centers of Nevada - Southeast Henderson - Stephanie
state: Nevada
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada - Summerlin Medical Center II
state: Nevada
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada - Southwest
state: Nevada
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada - Central Valley - Twain
state: Nevada
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada - Northwest
state: Nevada
city: Canton
country: United States
facility: Gabrail Cancer and Research Center
state: Ohio
city: Toledo
country: United States
facility: The Toledo Clinic Cancer Center
state: Ohio
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven - Campus Gasthuisberg
state: Flemish Brabant
city: Gent
country: Belgium
facility: Algemeen Ziekenhuis Maria Middelares
state: Oost-Vlaaderen
city: Menen
country: Belgium
facility: Algemeen Ziekenhuis Delta - Campus Menen
state: West Flanders
city: Rosières
country: Belgium
facility: Algemeen Ziekenhuis Delta - Campus Rumbeke
state: West-Vlaanderen
city: Fortaleza
country: Brazil
facility: Centro Regional Integrado de Oncologia
state: Ceará
city: Porto Alegre
country: Brazil
facility: Hospital São Lucas da PUCRS
state: Rio Grande Do Sul
city: Itajaí
country: Brazil
facility: Clínica Neoplasias Litoral
state: Santa Catatina
city: Jaú
country: Brazil
facility: Hospital Amaral Carvalho
state: São Paulo
city: Panagyurishte
country: Bulgaria
facility: Multi-profile Hospital for Active Treatment Uni Hospital
state: Pazardzhik
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Tsaritsa Yoanna-ISUL
city: Brampton
country: Canada
facility: William Osler Health System - Brampton Civic Hospital
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Strasbourg cedex
country: France
facility: Les Hôpitaux Universitaires de Strasbourg
state: Alsace
city: Caen cedex 9
country: France
facility: Hôpital Côte De Nacre
state: Basse-Normandie
city: Paris cedex
country: France
facility: Institut Curie
state: Ile-de-France
city: Limoges
country: France
facility: Centre Hospitalier Universitaire Limoges
state: Limousin
city: Pessac
country: France
facility: Hôpital Haut-Lévêque
state: Nouvelle-Aquitaine
city: Le Mans cedex 9
country: France
facility: Centre Hospitalier Le Mans
state: Pays De La Loire
city: Villejuif
country: France
facility: Gustave Roussy
state: Val-de-Marne
city: Boulogne-Billancourt
country: France
facility: Hôpital Ambroise-Paré
state: Île-de-France
city: Hamburg
country: Germany
facility: Asklepios Klinik Altona
state: Hamburg (Hansestadt)
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen und Marburg - Gießen
state: Hessen
city: München
country: Germany
facility: LMU Klinikum - Campus Innenstadt
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Athens
country: Greece
facility: General Hospital for Thoracic Diseases Sotiria
state: Attica
city: Piraeus
country: Greece
facility: Metropolitan General
state: Attica
city: Patra
country: Greece
facility: University General Hospital of Patras
state: Peloponnese
city: Peiraias
country: Greece
facility: Metropolitan Hospital
state: Pireas
city: Larissa
country: Greece
facility: University General Hospital of Larissa
state: Thessaly
city: Thessaloniki
country: Greece
facility: BioClinic Thessaloniki
city: Afula
country: Israel
facility: Emek Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Jerusalem
country: Israel
facility: Hadassah University Hospital Ein Kerem
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Tel aviv
country: Israel
facility: Assuta Hospital - Ramat HaHayal
city: Meldola
country: Italy
facility: Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST
state: Forlì-Cesena
city: Milan
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele
city: Modena
country: Italy
facility: Azienda Ospedaliero - Universitaria di Modena
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Ravenna
country: Italy
facility: Azienda Unità Sanitaria Locale della Romagna
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona
city: Nagoya
country: Japan
facility: Aichi Cancer Center
state: Aiti [Aichi]
city: Hirosaki-Shi
country: Japan
facility: Hirosaki University Hospital
state: Aomori
city: Fukuoka-shi
country: Japan
facility: Kyushu Cancer Center
state: Hukuoka
city: Sagamihara
country: Japan
facility: Kitasato University Hospital
state: Kanagawa
city: Yokohama
country: Japan
facility: Kanagawa Cardiovascular and Respiratory Center
state: Kanagawa
city: Kumamoto-Shi
country: Japan
facility: Saiseikai Kumamoto Hospital
state: Kumamoto
city: Sendai
country: Japan
facility: Sendai Kousei Hospital
state: Miyagi
city: Okayamashi
country: Japan
facility: Okayama University Hospital
state: Okayama
city: Hirakata
country: Japan
facility: Kansai Medical University Hospital
state: Osaka
city: Sakai-Shi
country: Japan
facility: National Hospital Organization Kinki-Chuo Chest Medical Center
state: Osaka
city: Koto
country: Japan
facility: Cancer Institute Hospital of JFCR
state: Tokyo
city: Shinjuku-Ku
country: Japan
facility: Keio University Hospital
state: Tokyo
city: Kanazawa
country: Japan
facility: Kanazawa University Hospital
city: Osaka
country: Japan
facility: Osaka City General Hospital
city: Osaka
country: Japan
facility: Osaka Prefectural Hospital Organization - Osaka International Cancer Institute
city: Suwon-si
country: Korea, Republic of
facility: Catholic University of Korea Saint Vincent's Hospital
state: Gyeonggi-do
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
state: Gyeonggi-do
city: Jinju
country: Korea, Republic of
facility: Gyeongsang National University Hospital
state: Gyeongsangnamdo [Kyongsangnam-do]
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
state: Incheon Gwang'yeogsi [Inch'on-Kwangyokshi]
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
state: Seoul Teugbyeolsi [Seoul-T'ukpyolshi]
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
state: Seoul Teugbyeolsi [Seoul-T'ukpyolshi]
city: Mirador
country: Mexico
facility: Clínica Integral Internacional de Oncología S de RL de CV
state: Puebla
city: Veracruz
country: Mexico
facility: FAICIC Clínical Research
city: Nijmegen
country: Netherlands
facility: Radboud Universitair Medisch Centrum
state: Gelderland
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
state: Noord-Holland
city: Quezon City
country: Philippines
facility: St. Luke's Medical Center - Quezon City
state: Metropolitan Manila
city: Muntinlupa
country: Philippines
facility: Asian Hospital and Medical Center
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie
state: Lubelskie
city: Łódź
country: Poland
facility: Instytut MSF
state: Lódzkie
city: Pozna?
country: Poland
facility: Wielkopolskie Centrum Pulmonologii i Torakochirurgii im. Eugenii i Janusza Zeylandów
state: Wielkopolskie
city: Cluj-Napoca
country: Romania
facility: Medisprof
state: Cluj
city: Craiova
country: Romania
facility: Centrul de Oncologie Sf Nectarie
state: Dolj
city: Timişoara
country: Romania
facility: Oncocenter - Oncologie Clinica
state: Timis
city: Suceava
country: Romania
facility: Clinica SIGMedical
city: Singapore
country: Singapore
facility: Icon Cancer Centre - Mount Alvernia
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Singapore
country: Singapore
facility: Oncocare Cancer Centre
city: Singapore
country: Singapore
facility: Icon Cancer Centre Mount Elizabeth
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
state: La Coruña
city: Barcelona
country: Spain
facility: Clínica Mi Tres Torres
city: Barcelona
country: Spain
facility: Hospital Quirónsalud Barcelona
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Jaén
country: Spain
facility: Hospital Universitario de Jaén
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Madrid
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Málaga - Hospital General
city: Bang Phlat
country: Thailand
facility: Faculty of Medicine Siriraj Hospital
state: Bangkok
city: Pathum Wan
country: Thailand
facility: King Chulalongkorn Memorial Hospital
state: Bangkok
city: Krung Thep Maha Nakhon
country: Thailand
facility: Navamindradhiraj University - Faculty of Medicine Vajira Hospital
state: Khet Dusit
city: Adana
country: Turkey
facility: T.C. Saglik Bakanligi Adana Sehir Egitim ve Arastirma Hastanesi
city: Adana
country: Turkey
facility: Medical Park Seyhan Hastanesi
city: Ankara
country: Turkey
facility: Hacettepe Üniversitesi Kanser Enstitüsü
city: Ankara
country: Turkey
facility: Memorial Ankara Hastanesi
city: Edirne
country: Turkey
facility: Trakya Üniversitesi Sa?l?k Ara?t?rma ve Uygulama Merkezi
city: Etlik
country: Turkey
facility: Ankara Il Saglik Mudurlugu SBU Gulhane Egitim Ve Arastirma Hastanesi
city: Istanbul
country: Turkey
facility: Bagcilar Medipol Mega Universite Hastanesi
city: Istanbul
country: Turkey
facility: T.C. Saglik Bakanligi - Istanbul Il Saglik Mudurlugu - Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi
city: Çankaya
country: Turkey
facility: T.C. Saglik Bakanligi Ankara Bilkent Sehi?r Hastanesi?
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
state: England
city: Torquay
country: United Kingdom
facility: Torbay and South Devon NHS Foundation Trust
state: England
Study officials:
References: