A Study of Zipalertinib and Chemotherapy Compared With Chemotherapy Alone in Patients With Advanced Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion.

Study Overview
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Brief Summary
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The purpose of this study is to will 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
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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. 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 300 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.

Official Title
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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

Conditions
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Advanced or Metastatic NSCLS With Exon 20 Insertion Mutation

Intervention / Treatment
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* Drug: TAS6417


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent. ≥18 years of age (or meets the country's regulatory definition for legal adult age, whichever is greater). Pathologically confirmed, locally advanced or metastatic nonsquamous NSCLC Has not received any prior systemic treatment for their locally advanced or metastatic nonsquamous NSCLC. Prior adjuvant/neoadjuvant treatment for advanced or metastatic disease >6 months prior to first dose of study treatment is allowed for early-stage NSCLC. Documented EGFR mutation status, as determined by local testing performed at a CLIA certified or equivalent laboratory, defined as follows: Part A: ex20ins or other common single or compound EGFR mutation Part B: ex20ins EGFR mutation 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. Patients with previously treated brain metastasis(es) and stable CNS disease (defined as being neurologically stable and receiving a stable or decreasing corticosteroid dose at time of enrollment) are eligible. 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. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.10. Adequate organ function, as defined by the laboratory value Have a life expectancy of at least 3 months as assessed by the investigator. 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). 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 Criteria: 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. Prior treatment with any of the following within the specific time frame specified: Zipalertinib (TAS6417/CLN-081) at any time. 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. Major surgery (excluding placement of vascular access) ≤28 days prior to first dose of study treatment. 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. Past medical history of interstitial lung disease, treatment-related pneumonitis (any grade), or any evidence of clinically active interstitial lung disease. Impaired cardiac function or clinically significant cardiac disease, including any of the following: History of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification (Appendix A). Serious cardiac arrhythmias requiring treatment. Resting corrected QT interval (QTc) >470 msec calculated using Fridericia's formula (QTcF). Unable to swallow tablets/capsules 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). 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: Adequately treated basal or squamous cell carcinoma of the skin Cancer of the breast or cervix in situ 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 Concurrent malignancy determined to be clinically stable and not requiring tumor directed treatment Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is unstable or not controlled with treatment. 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. Active bleeding disorders. Known hypersensitivity to the ingredients in zipalertinib or any drugs similar in structure or class. Is unable or unwilling to take dexamethasone, folic acid, and/or vitamin B12 supplementation during treatment with pemetrexed. Is pregnant or lactating. The patient is, in the investigator's opinion, unable or unwilling to comply with the trial procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A (Safety Lead in)<br>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<br>* oral tablets/capsules<br>* Other names: CLN-081;|
| Experimental: Part B<br>Part B: Phase 3 Enrollment into the Phase 3 portion of the study will begin following completion of Part A. Approximately 300 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<br>* oral tablets/capsules<br>* Other names: CLN-081;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exon 20 insertion mutation, NSCLC, Lung disease, Carcinoma, Non-Small-Cell Lung, CLN-081, TAS6417, EGFR, phase 3