A Study to Assess the Efficacy and Safety of Zipalertinib Versus Placebo for Adjuvant Treatment in Participants With Stage IB-IIIA NSCLC With Uncommon EGFR Mutations, Following Complete Tumor Resection
- Conditions
- NSCLC, Stage IBNSCLC, Stage IIIA
- Interventions
- Registration Number
- NCT07128199
- Lead Sponsor
- Taiho Oncology, Inc.
- Brief Summary
The purpose of this study is to compare the efficacy of zipalertinib combined standard with adjuvant chemotherapy versus placebo combined standard with adjuvant chemotherapy in participants with early stage (stage IB-IIIA) resected non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor mutation (EGFRmt).
- Detailed Description
This study will evaluate zipalertinib, a novel EGFR tyrosine kinase inhibitor (TKI) in combination with standard platinum-based adjuvant chemotherapy versus placebo in combination with chemotherapy in participants with resected stage IB-IIIA NSCLC harboring uncommon EGFRmt.
Approximately 360 participants will be randomized 1:1 to:
Arm A: Platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed) in combination with zipalertinib 100 milligrams (mg) twice daily (BID), followed by zipalertinib 100 mg BID alone OR
Arm B: Platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed) in combination with placebo BID, followed by placebo BID alone.
The duration of 1 treatment cycle will be 21 days. An independent data monitoring committee (IDMC) will be established to monitor interim safety data.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 360
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Histologically confirmed diagnosis of primary NSCLC on predominantly non-squamous histology.
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Documented EGFRmt status as determined by local testing performed at a clinical laboratory improvement amendment (CLIA) certified (United States [US]) or accredited (outside of the US) local laboratory, defined as either one of the following EGFRmt:
- exon20 insertion mutations (ex20ins) or
- other uncommon, non-ex20ins EGFRmt (eg, G719X, L861Q, or S768I)
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Magnetic resonance imaging (MRI) or computed tomography (CT) scan of the brain done prior to surgery. Participants in whom this was not done prior to surgery may still be enrolled if appropriate imaging (i.e., MRI or CT of the brain) is performed prior to randomization.
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Complete surgical resection of the primary NSCLC is mandatory. All gross disease must have been removed at the end of surgery. All surgical margins of resection must be negative for tumor. Resection may be accomplished by open thoracotomy or video associated thoracic surgery (VATS) techniques.
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Classified post-operatively as either Stage IB, IIA, IIB, or IIIA according to the tumor nodes metastasis (TNM) staging system for lung cancer (American Joint Committee on Cancer [AJCC] 9th edition).
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Complete recovery from surgery at the time of randomization.
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Eastern cooperative oncology group performance status (ECOG PS) of 0 or 1.
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Archival tumor tissue available for submission, with minimum quantity sufficient to evaluate EGFRmt status and, where possible, other biomarkers.
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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.
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Treatment with any of the following within the time frame specified:
- Zipalertinib (TAS6417/CLN-081) or any other EGFR inhibitor at any time.
- Pre-operative or post-operative or planned radiation therapy for the current lung cancer.
- Any prior systemic anticancer therapy (e.g., neoadjuvant chemotherapy), including investigational therapy, for treatment of NSCLC.
- Major surgery (including primary tumor surgery, excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
- All prescribed medication, over-the-counter medication, vitamin preparations and other food supplements, or herbal medications that are strong or moderate cytochrome p450 (CYP) 3A4 inducers or inhibitors within 7 days prior to first dose.
- Treatment with an investigational drug within five half-lives of the compound or any of its related material, if known.
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Has received only segmentectomies or wedge resections.
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Past medical history of interstitial lung disease (ILD)/pneumonitis, drug-induced ILD/pneumonitis or any evidence of clinically active ILD/pneumonitis.
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Impaired cardiac function or clinically significant cardiac disease.
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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 significant bowel resection).
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Participants with a history of any other cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer, other cancers curatively treated with no evidence of disease for >5 years following the end of treatment and which, in the opinion of the treating physician, do not have a substantial risk of recurrence of the prior malignancy.
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Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is unstable or not controlled with treatment. Screening not required.
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Active bleeding disorders.
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Known:
a. Hypersensitivity: i. To the ingredients in zipalertinib/placebo or any drugs similar in structure or class. ii. To platinum-containing drugs (i.e., cisplatin, carboplatin), pemetrexed, or any known excipients of these drugs. b. Contraindications to platinum-containing drugs (i.e., cisplatin, carboplatin) or pemetrexed according to the respective local labels.
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Is unable or unwilling to take dexamethasone, folic acid, and/or vitamin B12 supplementation during treatment with pemetrexed.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Zipalertinib Cisplatin Participants will receive adjuvant platinum-based chemotherapy consisting of cisplatin 75 milligrams per square meter (mg/m\^2) or carboplatin (area under concentration \[AUC\] 5 milligrams per milliliter per minute mg/mL/min) plus pemetrexed 500 mg/m\^2, administered via intravenous (IV) infusion, on 21-day cycle, in combination with zipalertinib 100 mg, orally, twice daily (BID). After completion of chemotherapy, participants will continue on zipalertinib monotherapy 100 mg, orally, BID on 21-day cycle, until the participant meets any of the treatment discontinuation criteria. Zipalertinib Carboplatin Participants will receive adjuvant platinum-based chemotherapy consisting of cisplatin 75 milligrams per square meter (mg/m\^2) or carboplatin (area under concentration \[AUC\] 5 milligrams per milliliter per minute mg/mL/min) plus pemetrexed 500 mg/m\^2, administered via intravenous (IV) infusion, on 21-day cycle, in combination with zipalertinib 100 mg, orally, twice daily (BID). After completion of chemotherapy, participants will continue on zipalertinib monotherapy 100 mg, orally, BID on 21-day cycle, until the participant meets any of the treatment discontinuation criteria. Zipalertinib Pemetrexed Participants will receive adjuvant platinum-based chemotherapy consisting of cisplatin 75 milligrams per square meter (mg/m\^2) or carboplatin (area under concentration \[AUC\] 5 milligrams per milliliter per minute mg/mL/min) plus pemetrexed 500 mg/m\^2, administered via intravenous (IV) infusion, on 21-day cycle, in combination with zipalertinib 100 mg, orally, twice daily (BID). After completion of chemotherapy, participants will continue on zipalertinib monotherapy 100 mg, orally, BID on 21-day cycle, until the participant meets any of the treatment discontinuation criteria. Zipalertinib TAS6417 Participants will receive adjuvant platinum-based chemotherapy consisting of cisplatin 75 milligrams per square meter (mg/m\^2) or carboplatin (area under concentration \[AUC\] 5 milligrams per milliliter per minute mg/mL/min) plus pemetrexed 500 mg/m\^2, administered via intravenous (IV) infusion, on 21-day cycle, in combination with zipalertinib 100 mg, orally, twice daily (BID). After completion of chemotherapy, participants will continue on zipalertinib monotherapy 100 mg, orally, BID on 21-day cycle, until the participant meets any of the treatment discontinuation criteria. Placebo Cisplatin Participants will receive adjuvant platinum-based chemotherapy consisting of cisplatin 75 mg/m\^2 or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m\^2, administered via IV infusion, on 21-day cycle, in combination with zipalertinib matching-placebo 100 mg, orally, BID. After completion of chemotherapy, participants will continue on zipalertinib matching-placebo monotherapy 100mg, orally, BID on 21-day cycle, until the participant meets any of the treatment discontinuation criteria. Placebo Carboplatin Participants will receive adjuvant platinum-based chemotherapy consisting of cisplatin 75 mg/m\^2 or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m\^2, administered via IV infusion, on 21-day cycle, in combination with zipalertinib matching-placebo 100 mg, orally, BID. After completion of chemotherapy, participants will continue on zipalertinib matching-placebo monotherapy 100mg, orally, BID on 21-day cycle, until the participant meets any of the treatment discontinuation criteria. Placebo Pemetrexed Participants will receive adjuvant platinum-based chemotherapy consisting of cisplatin 75 mg/m\^2 or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m\^2, administered via IV infusion, on 21-day cycle, in combination with zipalertinib matching-placebo 100 mg, orally, BID. After completion of chemotherapy, participants will continue on zipalertinib matching-placebo monotherapy 100mg, orally, BID on 21-day cycle, until the participant meets any of the treatment discontinuation criteria. Placebo Zipalertinib Matching-placebo Participants will receive adjuvant platinum-based chemotherapy consisting of cisplatin 75 mg/m\^2 or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m\^2, administered via IV infusion, on 21-day cycle, in combination with zipalertinib matching-placebo 100 mg, orally, BID. After completion of chemotherapy, participants will continue on zipalertinib matching-placebo monotherapy 100mg, orally, BID on 21-day cycle, until the participant meets any of the treatment discontinuation criteria.
- Primary Outcome Measures
Name Time Method Disease-free Survival (DFS) as Assessed by the Investigator Up to 5 years
- Secondary Outcome Measures
Name Time Method Disease-free Survival Rate At 2, 3 and 5 years Overall Survival (OS) Up to 5 years Overall Survival Rate At 2, 3 and 5 years DFS of Central Nervous System (cDFS) Up to 5 years Number of Participants With Treatment Emergent Adverse Events (TEAEs) Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) Up to 5 years Number of Participants with Clinically Significant Changes in Clinical Laboratory Parameters Up to 5 years Number of Participants with Clinically Significant Changes in Vital Signs Up to 5 years Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters Up to 5 years Number of Participants With Change in Left Ventricular Ejection Fraction (LVEF) Evaluated Using Electrocardiography (ECHO) and Multigated Acquisition (MUGA) Scan Up to 5 years Change in EuroQuality of Life-5 Dimensional 3-Level (EQ-5D-3L) Baseline, up to 5 years EQ-5D-3L is a standardized measure of the participant's health-related quality of life (QoL). EQ-5D is a 5-item questionnaire that assesses 5 domains including 1. mobility, 2. self-care, 3. usual activities, 4. pain/discomfort and 5. anxiety/depression. Each dimension has 3 levels ranging from no problems to extreme problems. Higher scores indicate improvement in status of health. The responses will be used to derive overall score using a visual analog scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).
Change From Baseline in European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) Scores Up to 5 years EORTC QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items and a score ranging from 0 to 100 is calculated. A higher score on the global health status/quality of life scale indicates a better level of functioning, and positive changes from baseline indicate improvement.