Open-Label, Phase II Study of Trastuzumab in Combination With Lapatinib (Cohort A) or Pertuzumab in Combination With Trastuzumab-emtansine (Cohort B) in Patients With HER2-positive Metastatic Colorectal Cancer: the HERACLES (HER2 Amplification for Colo-rectaL Cancer Enhanced Stratification)Trial
Overview
- Phase
- Phase 2
- Intervention
- Trastuzumab, Lapatinib
- Conditions
- Metastatic Colorectal Cancer
- Sponsor
- Fondazione del Piemonte per l'Oncologia
- Enrollment
- 54
- Locations
- 7
- Primary Endpoint
- Objective Response Rate according to RECIST 1.1 criteria
- Last Updated
- 7 years ago
Overview
Brief Summary
This is a Phase II multi-center 2-sequential cohorts trial, designed to assess the objective response rate of two anti HER2 combination in advanced disease CRC patients harbouring an amplified HER2 tumor assessed according to HERACLES Diagnostic Criteria by FISH/SISH.
Cohort A: monoclonal antibody trastuzumab, used in combination with the small molecule tyrosine kinase inhibitor lapatinib.
Cohort B, monoclonal antibody pertuzumab, used in combination with the antibody drug conjugate trastuzumab-emtansine.
Please note that cohort A accrual has been closed and endpoint already reached.
Detailed Description
Investigators identified HER2 amplification as a potential onco-driver and marker of de novo resistance to anti-EGFR therapy in mCRC patients for which other known genetic alterations conferring resistance to anti EGFR antibodies were excluded. Exploiting direct transfer xenografts of mCRC surgical samples in mice (xenopatients), investigators conducted a multi-arm study in HER2-amplified xenopatients showing that combinations of the dual EGFR/HER2 inhibitor lapatinib and the anti-HER2 moAb trastuzumab induced long-lasting tumor regressions, while monotherapy with lapatinib led to stabilization and monotherapy with trastuzumab was ineffective. On these findings investigators designed the HERACLES trial. HERACLES is an open-label Phase II, 2-sequential cohorts trial, assessing the response rate (ORR) of Trastuzumab combined Lapatinib (Cohort A) or Pertuzumab combined with trastuzumab-emtansine (Cohort B), in metastatic colorectal patients harboring an amplified HER2 tumors . HER2 positivity is centrally established by immunohistochemistry (IHC) and Silver In Situ Hybridization (SISH). To be HER2 eligible the original tumor, or the biopsied metastasis (whichever is last available), must be IHC 3+ or 2+ in more than 50% of cells, confirmed by SISH or FISH with a HER2:CEP17 ratio ≥ 2.0. For IHC a positive staining (3+) is defined as an intense membrane staining which can be circumferential, basolateral, or lateral of the tumor cells.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Cohort A
Trastuzumab and lapatinib
Intervention: Trastuzumab, Lapatinib
Cohort B
Pertuzumab and Trastuzumab-emtansine
Intervention: Pertuzumab, trastuzumab-emtansine
Outcomes
Primary Outcomes
Objective Response Rate according to RECIST 1.1 criteria
Time Frame: Time Frame: every 8 weeks (cohort A) or every 9 weeks (cohort B) from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
Secondary Outcomes
- Description of the frequency and severity of Adverse Events based on the NCI -CTCAE V4.0(Time Frame: weekly (cohort A) or every 21 days (cohort B) from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months)
- Progression Free Survival(Time Frame: every 8 weeks (cohort A) or every 9 weeks (cohort B) from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months)