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

• ClinicalTrials.gov Identifier: NCT01953926
• Recruitment Status: Terminated
• First Posted: October 1, 2013
• Results First Posted: March 12, 2024
• Last Update Posted: March 12, 2024
• Sponsor: Puma Biotechnology, Inc.
• Information provided by (Responsible Party): Puma Biotechnology, Inc.

Tracking Information

• First Submitted Date: September 26, 2013
• First Posted Date: October 1, 2013
• Results First Submitted Date: December 21, 2023
• Results First Posted Date: March 12, 2024
• Last Update Posted Date: March 12, 2024
• Actual Study Start Date: September 30, 2013
• Actual Primary Completion Date: January 2, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 12, 2024)

• Confirmed Objective Response Rate (ORR) by Independent Central Review (Breast Cancer With Prior CDK46i Cohort) [ Time Frame: 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
• Confirmed Objective Response Rate (ORR) by Investigator Review (Cervical Cancer Cohort) [ Time Frame: 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
• Objective Response Rate (ORR) at First Assessment by Investigator Review (All Other Cohorts) [ Time Frame: 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

• Original Primary Outcome Measures (submitted: September 26, 2013): Objective Response Rate at 8 weeks (ORR8) [ Time Frame: 8 weeks ]

Current Secondary Outcome Measures (submitted: February 12, 2024)

• Confirmed Objective Response Rate (ORR) by Investigator Review (Breast Cancer With Prior CDK46i Cohort) [ Time Frame: 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
• Confirmed Objective Response Rate (ORR) by Investigator Review (All Other Cohorts) [ Time Frame: 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.
• Duration of Response (DOR) by Independent Central Review (Breast Cancer With Prior CDK46i Cohort) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.
• Progression-Free Survival (PFS) by Investigator Review (All Cohorts) [ Time Frame: 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 [ Time Frame: 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

Original Secondary Outcome Measures (submitted: September 26, 2013)

• Overall Response Rate (ORR) [ Time Frame: Estimated 6 months ]
• Progression-free survival (PFS) [ Time Frame: Estimated 18 months ]
• Clinical Benefit Rate (CBR) [ Time Frame: 16 weeks ]
  Clinical benefit rate (CBR) is defined as the percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD) ≥16 weeks from the date of enrollment
• Duration of Response (DOR) [ Time Frame: Estimated 1 year ]
  Duration of response (DOR) is defined as the time from which measurement criteria are met for CR or PR (whichever status is recorded first) until the first date of documented disease progression.
• Overall survival (OS) [ Time Frame: Estimated 2 years ]
• Safety (Adverse Events [AEs] and Serious Adverse Events [SAEs]) [ Time Frame: From consent through 28 days following treatment completion (estimated 6 months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Basket Study of Neratinib in Participants With Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations
• Official Title: An Open-Label, Phase 2 Basket Study of Neratinib in Patients With Solid Tumors With Somatic Activating HER Mutations
• 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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations

Intervention

• Drug: Neratinib
  240 mg administered orally, once daily with food, continuously in 28 day cycles
  Other Name: Nerlynx
• Drug: Fulvestrant
  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
  Other Name: Faslodex
• Drug: Trastuzumab
  Initial dose of 8 mg/kg of trastuzumab administered IV on Day 1, followed by 6 mg/kg IV once every 3 weeks thereafter
  Other Name: Herceptin
• Drug: Paclitaxel
  80mg/m^2 administered IV on Days 1, 8, and 15 of every 4 week cycle
  Other Name: Taxol

Study Arms

• Experimental: Neratinib monotherapy

  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.

  Intervention: Drug: Neratinib
• Experimental: Neratinib and 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.

  Interventions:

  • Drug: Neratinib
  • Drug: Trastuzumab
• Experimental: Neratinib, Fulvestrant and Trastuzumab (Randomized)
  Neratinib, Fulvestrant and Trastuzumab or Fulvestrant and Trastuzumab or Fulvestrant alone in HER2 mutated (HR-positive with prior CDK4/6i) breast cancers.
  Interventions:

  • Drug: Neratinib
  • Drug: Fulvestrant
  • Drug: Trastuzumab
• Experimental: Neratinib, Fulvestrant and Trastuzumab (Non-Randomized)
  Neratinib, Fulvestrant and Trastuzumab in HER2 mutated (HR-positive with or without CDK4/6i) breast cancers.
  Interventions:

  • Drug: Neratinib
  • Drug: Fulvestrant
  • Drug: Trastuzumab
• Experimental: Neratinib and Paclitaxel
  Neratinib and Paclitaxel in HER2 mutated bladder/urinary tract cancers.
  Interventions:

  • Drug: Neratinib
  • Drug: Paclitaxel
• Experimental: Neratinib and Fulvestrant
  Neratinib and Fulvestrant in HER2 mutated (HR-positive) breast cancers.
  Interventions:

  • Drug: Neratinib
  • Drug: Fulvestrant

Publications *

• Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, Juric D, Quinn DI, Moreno V, Doger B, Mayer IA, Boni V, Calvo E, Loi S, Lockhart AC, Erinjeri JP, Scaltriti M, Ulaner GA, Patel J, Tang J, Beer H, Selcuklu SD, Hanrahan AJ, Bouvier N, Melcer M, Murali R, Schram AM, Smyth LM, Jhaveri K, Li BT, Drilon A, Harding JJ, Iyer G, Taylor BS, Berger MF, Cutler RE Jr, Xu F, Butturini A, Eli LD, Mann G, Farrell C, Lalani AS, Bryce RP, Arteaga CL, Meric-Bernstam F, Baselga J, Solit DB. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018 Feb 8;554(7691):189-194. doi: 10.1038/nature25475. Epub 2018 Jan 31. Erratum In: Nature. 2019 Feb;566(7745):E11-E12.
• Smyth LM, Piha-Paul SA, Won HH, Schram AM, Saura C, Loi S, Lu J, Shapiro GI, Juric D, Mayer IA, Arteaga CL, de la Fuente MI, Brufksy AM, Spanggaard I, Mau-Sorensen M, Arnedos M, Moreno V, Boni V, Sohn J, Schwartzberg LS, Gonzalez-Farre X, Cervantes A, Bidard FC, Gorelick AN, Lanman RB, Nagy RJ, Ulaner GA, Chandarlapaty S, Jhaveri K, Gavrila EI, Zimel C, Selcuklu SD, Melcer M, Samoila A, Cai Y, Scaltriti M, Mann G, Xu F, Eli LD, Dujka M, Lalani AS, Bryce R, Baselga J, Taylor BS, Solit DB, Meric-Bernstam F, Hyman DM. Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer. Cancer Discov. 2020 Feb;10(2):198-213. doi: 10.1158/2159-8290.CD-19-0966. Epub 2019 Dec 5.
• Shishido SN, Masson R, Xu L, Welter L, Prabakar RK, D' Souza A, Spicer D, Kang I, Jayachandran P, Hicks J, Lu J, Kuhn P. Disease characterization in liquid biopsy from HER2-mutated, non-amplified metastatic breast cancer patients treated with neratinib. NPJ Breast Cancer. 2022 Feb 18;8(1):22. doi: 10.1038/s41523-022-00390-5.
• Oaknin A, Friedman CF, Roman LD, D'Souza A, Brana I, Bidard FC, Goldman J, Alvarez EA, Boni V, ElNaggar AC, Passalacqua R, Do KTM, Santin AD, Keyvanjah K, Xu F, Eli LD, Lalani AS, Bryce RP, Hyman DM, Meric-Bernstam F, Solit DB, Monk BJ. Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial. Gynecol Oncol. 2020 Oct;159(1):150-156. doi: 10.1016/j.ygyno.2020.07.025. Epub 2020 Jul 25.
• Ulaner GA, Saura C, Piha-Paul SA, Mayer I, Quinn D, Jhaveri K, Stone B, Shahin S, Mann G, Dujka M, Bryce R, Meric-Bernstam F, Solit DB, Hyman DM. Impact of FDG PET Imaging for Expanding Patient Eligibility and Measuring Treatment Response in a Genome-Driven Basket Trial of the Pan-HER Kinase Inhibitor, Neratinib. Clin Cancer Res. 2019 Dec 15;25(24):7381-7387. doi: 10.1158/1078-0432.CCR-19-1658. Epub 2019 Sep 23.
• Hanker AB, Brewer MR, Sheehan JH, Koch JP, Sliwoski GR, Nagy R, Lanman R, Berger MF, Hyman DM, Solit DB, He J, Miller V, Cutler RE Jr, Lalani AS, Cross D, Lovly CM, Meiler J, Arteaga CL. An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer. Cancer Discov. 2017 Jun;7(6):575-585. doi: 10.1158/2159-8290.CD-16-1431. Epub 2017 Mar 8. Erratum In: Cancer Discov. 2019 Feb;9(2):303.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: March 3, 2022): 582
• Original Estimated Enrollment (submitted: September 26, 2013): 42
• Actual Study Completion Date: January 2, 2023
• Actual Primary Completion Date: January 2, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, Denmark, France, Ireland, Israel, Italy, Korea, Republic of, Serbia, Spain, United Kingdom, United States
• Removed Location Countries: Finland

Administrative Information

• NCT Number: NCT01953926
• Other Study ID Numbers: PUMA-NER-5201; 2013-002872-42 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Puma Biotechnology is committed to sharing clinical trial data and information to help physicians and patients make informed treatment decisions, and to help qualified researchers advance scientific knowledge.

In accordance with legal and regulatory requirements, Puma publishes study protocol information and clinical study results on clinical trial registries, including ClinicalTrials.gov and EU Clinical Trials Register. Puma also publishes information about clinical studies in peer-reviewed scientific journals and shares data in scientific meetings.

Puma commits to safeguarding confidentiality and patient privacy throughout the clinical trial data and information sharing process. Any patient-level data will be anonymized to protect personally identifiable information.

Qualified researchers and study participants may submit requests for other study documentation and clinical trial data to clinicaltrials@pumabiotechnology.com for consideration.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Clinical study documents and clinical trial data may be requested by qualified researchers and study participants for studies that have been completed for at least 18 months, and for which the indication of the drug has been approved in the US and/or EU, as applicable. Requests will be accepted for up to 24 months after the criteria described in this section are met.

Access Criteria

Requestors must provide organizational contact information; a detailed research plan, including outcomes; timeline for completion of the research; qualifications of the research team; funding source; and potential conflicts of interest.

Puma will not provide access to patient-level data if there is a reasonable likelihood that individual patients could be identified, or in cases where confidentiality or consent provisions prohibit transfer of data or information to third parties. Additionally, Puma will not disclose information that jeopardizes intellectual property rights or divulges confidential commercial information.

• URL: https://pumabiotechnology.com/data_sharing_policy.html

• Current Responsible Party: Puma Biotechnology, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Puma Biotechnology, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Chief Scientific Officer; Puma Biotechnology, Inc.

• PRS Account: Puma Biotechnology, Inc.
• Verification Date: February 2024