Basket Study of Neratinib in Participants With Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations

Study Overview
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Brief Summary
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This is an open-label, multicenter, multinational, Phase 2 basket study exploring the efficacy and safety of neratinib as monotherapy or in combination with other therapies in participants with HER (EGFR, HER2) mutation-positive solid tumors.

Detailed Description
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This is an open-label, multicenter, multinational, Phase 2 basket study exploring the efficacy and safety of neratinib as monotherapy or in combination with other therapies in participants with HER (EGFR, HER2) mutation-positive solid tumors. The study has a basket design and includes several cohorts, either defined by an actionable somatic mutation or by actionable mutation and tumor histology, including HER2 mutant breast, HER2 mutant cervical, HER2 mutant salivary gland, and EGFR Exon 18 mutant Non-small cell lung cancers. The trial will consist of a screening period, a treatment period, and an end of treatment visit occurring when neratinib is discontinued for any reason, a safety follow-up visit occurring 28 days after the last dose of neratinib and a survival follow-up period.

Official Title
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An Open-Label, Phase 2 Basket Study of Neratinib in Patients With Solid Tumors With Somatic Activating HER Mutations

Conditions
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Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations

Intervention / Treatment
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* Drug: Neratinib
* Drug: Fulvestrant
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent Histologically confirmed cancers for which no curative therapy exists Documented HER2 or EGFR exon 18 mutation Participants must agree and commit to use appropriate methods of contraception as outlined in the protocol At least one measurable lesion, defined by RECIST v1.1 Exclusion Criteria: Participants harboring ineligible somatic HER2 mutations Prior treatment with any HER2-directed tyrosine kinase inhibitor (e.g., lapatinib, afatinib, dacomitinib, neratinib) is excluded with the following exception: patients with EGFR exon 18 mutated NSCLC who may have received afatinib, osimertinib, or other pan HER or EGFR TKIs remain eligible Participants who are receiving any other anticancer agents Symptomatic or unstable brain metastases Women who are pregnant or breast-feeding There are additional inclusion and exclusion criteria. The study center will determine if criteria for participation are met.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neratinib monotherapy<br>Neratinib monotherapy in HER2 mutated cancers including cervical, salivary gland, and lung cancers containing EGFR exon 18 mutations. | Drug: Neratinib<br>* 240 mg administered orally, once daily with food, continuously in 28 day cycles<br>* Other names: Nerlynx;|
| Experimental: Neratinib and Trastuzumab<br>Neratinib and Trastuzumab in HER2 mutated (TNBC, HR-negative) breast cancers. | Drug: Neratinib<br>* 240 mg administered orally, once daily with food, continuously in 28 day cycles<br>* Other names: Nerlynx;Drug: Trastuzumab<br>* Initial dose of 8 mg/kg of trastuzumab administered IV on Day 1, followed by 6 mg/kg IV once every 3 weeks thereafter<br>* Other names: Herceptin;|
| Experimental: Neratinib, Fulvestrant and Trastuzumab (Randomized)<br>Neratinib, Fulvestrant and Trastuzumab or Fulvestrant and Trastuzumab or Fulvestrant alone in HER2 mutated (HR-positive with prior CDK4/6i) breast cancers. | Drug: Neratinib<br>* 240 mg administered orally, once daily with food, continuously in 28 day cycles<br>* Other names: Nerlynx;Drug: Fulvestrant<br>* 500 mg administered as two 5 mL injections on Days 1, 15, and 29; then once every 4 weeks thereafter month, then Day 1 of every 4 week cycle<br>* Other names: Faslodex;Drug: Trastuzumab<br>* Initial dose of 8 mg/kg of trastuzumab administered IV on Day 1, followed by 6 mg/kg IV once every 3 weeks thereafter<br>* Other names: Herceptin;|
| Experimental: Neratinib, Fulvestrant and Trastuzumab (Non-Randomized)<br>Neratinib, Fulvestrant and Trastuzumab in HER2 mutated (HR-positive with CDK4/6i naïve) breast cancers. | Drug: Neratinib<br>* 240 mg administered orally, once daily with food, continuously in 28 day cycles<br>* Other names: Nerlynx;Drug: Fulvestrant<br>* 500 mg administered as two 5 mL injections on Days 1, 15, and 29; then once every 4 weeks thereafter month, then Day 1 of every 4 week cycle<br>* Other names: Faslodex;Drug: Trastuzumab<br>* Initial dose of 8 mg/kg of trastuzumab administered IV on Day 1, followed by 6 mg/kg IV once every 3 weeks thereafter<br>* Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (Breast, Cervical Cohorts) | Percentage of participants who are confirmed by independent central review to have achieved complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (HR+, HER2 negative metastatic breast cancer, and metastatic cervical cancer cohorts) | From enrollment date to first confirmed Complete or Partial Response, whichever came earlier, up to 18 months | 
| Objective Response Rate - First Tumor Assessment (Other Cohorts) | Percentage of participants who achieve CR or PR per RECIST v1.1, or other defined response criteria, at the first scheduled tumor assessment (all other cohorts) | From enrollment date to first Complete or Partial Response, whichever came earlier, up to 8 or 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Number of months between first dose date and the first date on which recurrence, progression, or death due to any cause, is documented, censored at the last tumor assessment or at the initiation of new anticancer therapy | From enrollment date until the date of first documented progression, or date of death from any cause, whichever came first, assessed up to 18 months | 
| Confirmed Objective Response Rate (Other Cohorts) | Percentage of participants who are confirmed by independent central review to have achieved CR or PR according to RECIST v1.1 (all other cohorts) | From enrollment date to first confirmed Complete or Partial Response, whichever came earlier, up to 18 months | 
| Objective Response Rate - First Tumor Assessment (Breast, Cervical Cohorts) | Percentage of participants who achieve CR or PR according to RECIST v1.1, or other defined response criteria, at the first scheduled tumor assessment (HR+, HER2 negative metastatic breast cancer, and metastatic cervical cancer cohorts) | From enrollment date to first Complete or Partial Response, whichever came earlier, up to 8 or 9 weeks | 
| Clinical Benefit Rate (CBR) | Percentage of participants with CR + PR + stable disease ≥16, or ≥24 weeks for breast cancer, from the date of enrollment | From enrollment date to first documented response or stable disease ≥16, or ≥24 weeks for breast cancer, assessed up to 18 months | 
| Duration of Response (DOR) | Time from which measurement criteria are met for confirmed overall response of CR or PR (whichever status is recorded first) until the first date of documented disease progression | From first response to first disease progression or death, assessed up to 18 months | 
| Overall Survival (OS) | Time from Cycle 1 Day 1 to death due to any cause | From enrollment date to death, assessed up to two years | 
| Incidence of Treatment-Emergent Adverse Events | Treatment-emergent and serious adverse events that occurred on or after first dose of investigational product and up to 28 days after the last dose | From first dose through 28 days after the last dose, assessed up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neratinib, Nerlynx, Breast, Solid Tumors, Cancer, HER2 mutations, EGFR mutations, Fulvestrant, Trastuzumab, Cervical, Salivary, ERBB2, Exon 18, Metastatic, HR Positive, Lung, Non-Small Cell Lung Cancer (NSCLC)