Basket Study of Neratinib in Participants With Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations
- Conditions
- Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations
- Interventions
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 582
- 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
- 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 + PRConfirmed 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 + PRObjective 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 + PRDuration 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
Related Research Topics
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Trial Locations
- Locations (60)
Northwestern University
🇺🇸Chicago, Illinois, United States
Istituto Europeo di Oncologia (IEO) I.R.C.C.S.
🇮🇹Milano, Italy
Gundersen Center for Cancer and Blood Disorders
🇺🇸La Crosse, Wisconsin, United States
Kaplan Medical Center
🇮🇱Rehovot, Israel
UZ Leuven
🇧🇪Leuven, Belgium
Davidoff Cancer Center, Rabin Medical Center
🇮🇱Petah Tikva, Israel
Hospital Universitario Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Hospital Universitario Madrid Sanchinarro (START Madrid)
🇪🇸Madrid, Spain
Institut Curie - Hopital Rene Huguenin
🇫🇷Saint-Cloud, Ile De France, France
Saint Francis Cancer Center-Bon Secours
🇺🇸Greenville, South Carolina, United States
Royal Free Hospital
🇬🇧London, United Kingdom
Hospital Universitario Quiron Madrid
🇪🇸Madrid, Spain
British Columbia Cancer Center
🇨🇦Vancouver, British Columbia, Canada
Hospital Clinico Universitario de Valencia
🇪🇸Valencia, Spain
Institut Gustave Roussy
🇫🇷Villejuif, Paris, France
Roswell Park Comprehensive Cancer Center
🇺🇸Buffalo, New York, United States
The West Clinic
🇺🇸Germantown, Tennessee, United States
Peter MacCallum Cancer Centre
🇦🇺East Melbourne, Victoria, Australia
Hospital Universitario Quiron Dexeus
🇪🇸Barcelona, Spain
Hospital Universitari Clinic Barcelona
🇪🇸Barcelona, Spain
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Instituto Valenciano de Oncologia
🇪🇸Valencia, Spain
Hospital Clinico Universitario San Carlos
🇪🇸Madrid, Spain
University of California, Los Angeles
🇺🇸Los Angeles, California, United States
Kaiser Permanente NoCal (STRATA)
🇺🇸Vallejo, California, United States
Winship Cancer Institute, Emory University
🇺🇸Atlanta, Georgia, United States
Metro Minnesota Community Oncology Research Consortium
🇺🇸Saint Louis Park, Minnesota, United States
UPMC Magee-Woman's Hospital, Women's Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States
University Hospital, Rigshospitalet
🇩🇰Kopenhagen, Denmark
Sheba Medical Center
🇮🇱Ramat Gan, Israel
University of California, San Diego
🇺🇸La Jolla, California, United States
City of Hope
🇺🇸Duarte, California, United States
Stanford Cancer Center
🇺🇸Palo Alto, California, United States
Mayo Clinic Florida
🇺🇸Jacksonville, Florida, United States
Washington University
🇺🇸Saint Louis, Missouri, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Institut Bergonié
🇫🇷Bordeaux, France
Azienda Socio Sanitaria Territoriale di Cremona
🇮🇹Cremona, Italy
Fondazione Policlinico Universitario Gemelli I.R.C.C.S.
🇮🇹Roma, Italy
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
AOU Citta della Salute e della Scienza di Torino
🇮🇹Torino, Italy
Yonsei University Health System, Serverance Hospital
🇰🇷Seodaemun-Gu, Seoul, Korea, Republic of
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Mayo Clinic Arizona
🇺🇸Phoenix, Arizona, United States
UCSF Helen Diller Family Comprehensive Cancer Center
🇺🇸San Francisco, California, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Vanderbilt-Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
University of Miami
🇺🇸Miami, Florida, United States
Centre Leon Berard
🇫🇷Lyon, France
University of Wisconsin Carbone Cancer Center
🇺🇸Madison, Wisconsin, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
St. Vincent's University Hospital
🇮🇪Dublin, Leinster, Ireland
Institute for Oncology and Radiology of Serbia
🇷🇸Belgrade, Serbia
University of Southern California
🇺🇸Los Angeles, California, United States
Ochsner Clinic Foundation
🇺🇸New Orleans, Louisiana, United States