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

Phase 2

Terminated

• Conditions: Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations
• Interventions: Drug: Neratinib; Drug: Trastuzumab; Drug: Fulvestrant; Drug: Paclitaxel

• Registration Number: NCT01953926
• Lead Sponsor: Puma Biotechnology, Inc.

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2013-09-26
• Study First Submitted QC: 2013-09-26
• Study Start: 2013-09-30
• Study First Posted: 2013-10-01
• Primary Completion: 2023-01-02
• Study Completion: 2023-01-02
• Results First Submitted: 2023-12-21
• Status Verified: 2024-02
• Results First Submitted QC: 2024-02-12
• Last Update Submitted: 2024-02-12
• Results First Posted: 2024-03-12
• Last Update Posted: 2024-03-12

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 582

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Neratinib monotherapy	Neratinib	Neratinib monotherapy in HER2 mutated cancers including cervical, salivary gland, and lung cancers containing EGFR exon 18 mutations. Cohorts closed to enrollment in prior amendments: HER2 mutant cancers including bladder/urinary, colorectal, endometrial, breast HR-positive, TNBC HR-negative, lung, gastroesophageal, biliary, and ovarian; HER3 mutant solid tumor NOS; HER4 mutant solid tumor NOS; fibrolamellar carcinoma and EGFR brain.
Neratinib, Fulvestrant and Trastuzumab (Randomized)	Neratinib	Neratinib, Fulvestrant and Trastuzumab or Fulvestrant and Trastuzumab or Fulvestrant alone in HER2 mutated (HR-positive with prior CDK4/6i) breast cancers.
Neratinib and Trastuzumab	Neratinib	Neratinib and Trastuzumab in HER2 mutated (TNBC, HR-negative) breast cancers. Cohorts closed to enrollment in in prior amendments: colorectal, lung cancer HER2 mutant.
Neratinib and Trastuzumab	Trastuzumab	Neratinib and Trastuzumab in HER2 mutated (TNBC, HR-negative) breast cancers. Cohorts closed to enrollment in in prior amendments: colorectal, lung cancer HER2 mutant.
Neratinib, Fulvestrant and Trastuzumab (Randomized)	Fulvestrant	Neratinib, Fulvestrant and Trastuzumab or Fulvestrant and Trastuzumab or Fulvestrant alone in HER2 mutated (HR-positive with prior CDK4/6i) breast cancers.
Neratinib, Fulvestrant and Trastuzumab (Randomized)	Trastuzumab	Neratinib, Fulvestrant and Trastuzumab or Fulvestrant and Trastuzumab or Fulvestrant alone in HER2 mutated (HR-positive with prior CDK4/6i) breast cancers.
Neratinib, Fulvestrant and Trastuzumab (Non-Randomized)	Neratinib	Neratinib, Fulvestrant and Trastuzumab in HER2 mutated (HR-positive with or without CDK4/6i) breast cancers.
Neratinib, Fulvestrant and Trastuzumab (Non-Randomized)	Trastuzumab	Neratinib, Fulvestrant and Trastuzumab in HER2 mutated (HR-positive with or without CDK4/6i) breast cancers.
Neratinib, Fulvestrant and Trastuzumab (Non-Randomized)	Fulvestrant	Neratinib, Fulvestrant and Trastuzumab in HER2 mutated (HR-positive with or without CDK4/6i) breast cancers.
Neratinib and Paclitaxel	Paclitaxel	Neratinib and Paclitaxel in HER2 mutated bladder/urinary tract cancers.
Neratinib and Fulvestrant	Neratinib	Neratinib and Fulvestrant in HER2 mutated (HR-positive) breast cancers.
Neratinib and Paclitaxel	Neratinib	Neratinib and Paclitaxel in HER2 mutated bladder/urinary tract cancers.
Neratinib and Fulvestrant	Fulvestrant	Neratinib and Fulvestrant in HER2 mutated (HR-positive) breast cancers.

Primary Outcome Measures

Name	Time	Method
Confirmed Objective Response Rate (ORR) by Investigator Review (Cervical Cancer Cohort)	From enrollment date to first confirmed Complete or Partial Response, whichever came earlier, assessed up to 58 months	Percentage of participants who are confirmed by investigator review to have achieved complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (cervical cancer cohort).; Per Response Evaluation Criteria in Sold Tumors Criteria (RECISTv1.1) for target lesions and assessed by MRI or CT: Complete response(CR),Disappearance of all target lesions; Partial response(PR),\>=30% decrease in sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Confirmed Objective Response Rate (ORR) by Independent Central Review (Breast Cancer With Prior CDK46i Cohort)	From enrollment date to first confirmed Complete or Partial Response, whichever came earlier, assessed up to 58 months	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 cohorts).; Per Response Evaluation Criteria in Sold Tumors Criteria (RECISTv1.1) for target lesions and assessed by MRI or CT: Complete response(CR),Disappearance of all target lesions; Partial response(PR),\>=30% decrease in sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Objective Response Rate (ORR) at First Assessment by Investigator Review (All Other Cohorts)	From first treatment date to first Complete or Partial Response, whichever came earlier, assessed up to 8 or 9 weeks	Percentage of participants who achieve CR or PR per Response Evaluation Criteria in Sold Tumors Criteria (RECIST) v1.1, or other defined response criteria, at the first scheduled tumor assessment (all other cohorts), per RECIST (if assessed) or PERCIST.; RECISTv1.1 for target lesions and assessed by MRI or CT: Complete response(CR),Disappearance of all target lesions; Partial response(PR),\>=30% decrease in sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; PERCISTv1.0: Complete Metabolic Response - Complete resolution of 18F-FDG uptake within measurable target lesion so that it is less than mean liver activity and indistinguishable from surrounding background blood-pool levels; Partial Metabolic Response - Reduction of minimum of 30% in target measurable tumour 18F-FDG SULpeak. Absolute drop in SUL must be at least 0.8 SUL units, as well. No new lesions.; Positive Metabolic Response - Participants having either "Complete Metabolic Response" or "Part

Secondary Outcome Measures

Name	Time	Method
Confirmed Objective Response Rate (ORR) by Investigator Review (Breast Cancer With Prior CDK46i Cohort)	From enrollment date to first confirmed Complete or Partial Response, whichever came earlier, assessed up to 58 months	Percentage of participants who are confirmed by investigator 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 cohorts).; Per Response Evaluation Criteria in Sold Tumors Criteria (RECISTv1.1) for target lesions and assessed by MRI or CT: Complete response(CR),Disappearance of all target lesions; Partial response(PR),\>=30% decrease in sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Duration of Response (DOR) by Independent Central Review (Breast Cancer With Prior CDK46i Cohort)	From first response to first disease progression or death, assessed up to 58 months	Time from which measurement criteria are met for response (whichever status is recorded first) until the first date of documented disease progression or death. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
Duration of Response (DOR) by Investigator Review (All Cohorts)	From first response to first disease progression or death, assessed up to 58 months	Time from which measurement criteria are met for response (whichever status is recorded first) until the first date of documented disease progression or death. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
Clinical Benefit Rate (CBR) by Independent Central Review (Breast Cancer With Prior CDK46i Cohort)	From enrollment date to first documented response or stable disease ≥16, or ≥24 weeks for breast cancer, assessed up to 58 months	Percentage of participants with CR + PR + stable disease ≥16, or ≥24 weeks for breast cancer, from the date of enrollment.
Clinical Benefit Rate (CBR) by Investigator Review (All Cohorts)	From enrollment date to first documented response or stable disease ≥16, or ≥24 weeks for breast cancer, assessed up to 58 months	Percentage of participants with CR + PR + stable disease ≥16, or ≥24 weeks for breast cancer, from the date of enrollment.
Progression-Free Survival (PFS) by Independent Central Review (Breast Cancer With Prior CDK46i Cohort)	From enrollment date until the date of first documented progression, or date of death from any cause, whichever came first, assessed up to 58 months	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. Progression was defined by RECIST criteria for those participants with RECIST assessments; and PERCIST criteria for other participants.
Confirmed Objective Response Rate (ORR) by Investigator Review (All Other Cohorts)	From first treatment date to confirmed Complete or Partial Response, assessed up to 58 months.	Percentage of participants who achieve CR or PR per RECIST v1.1, or metabolic complete response via PERCIST v1.0.; For RECIST, A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met. PERCIST criteria were used for patients without RECIST assessments.
Progression-Free Survival (PFS) by Investigator Review (All Cohorts)	From enrollment date until the date of first documented progression, or date of death from any cause, whichever came first, assessed up to 58 months	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. Progression was defined by RECIST criteria for those participants with RECIST assessments; and PERCIST criteria for other participants.
Number of Participants With Treatment-Emergent Adverse Events	From first dose through 28 days after the last dose, assessed up to 75 months.	The safety of neratinib in patients as measured by the incidence of treatment-emergent adverse events (TEAE), including serious adverse events (SAEs), in study participants. TEAEs are any adverse event that occurred on or after first dose of investigational product and up to 28 days after the last dose

Trial Locations

Locations (60)

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Mayo Clinic Arizona; 🇺🇸 Phoenix, Arizona, United States

City of Hope; 🇺🇸 Duarte, California, United States

University of California, San Diego; 🇺🇸 La Jolla, California, United States

University of Southern California; 🇺🇸 Los Angeles, California, United States

University of California, Los Angeles; 🇺🇸 Los Angeles, California, United States

Stanford Cancer Center; 🇺🇸 Palo Alto, California, United States

UCSF Helen Diller Family Comprehensive Cancer Center; 🇺🇸 San Francisco, California, United States

Kaiser Permanente NoCal (STRATA); 🇺🇸 Vallejo, California, United States

Mayo Clinic Florida; 🇺🇸 Jacksonville, Florida, United States

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