Evaluation of Trastuzumab in Combination With Lapatinib or Pertuzumab in Combination With Trastuzumab-Emtansine to Treat Patients With HER2-positive Metastatic Colorectal Cancer (HERACLES)
|ClinicalTrials.gov Identifier: NCT03225937|
Recruitment Status : Active, not recruiting
First Posted : July 21, 2017
Last Update Posted : October 30, 2018
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.
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Colorectal Cancer||Drug: Trastuzumab, Lapatinib Drug: Pertuzumab, trastuzumab-emtansine||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||54 participants|
|Intervention Model:||Sequential Assignment|
|Intervention Model Description:||two sequential cohorts: cohort A (lapatinib + trastuzumab); cohort B (pertuzumab + trastuzumab-emtansine).|
|Masking:||None (Open Label)|
|Official Title:||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|
|Study Start Date :||August 2012|
|Estimated Primary Completion Date :||December 2018|
|Estimated Study Completion Date :||June 2019|
Experimental: Cohort A
Trastuzumab and lapatinib
Drug: Trastuzumab, Lapatinib
Patients enrolled in Cohort A will receive lapatinib 1000 mg daily per os + trastuzumab 4 mg/kg iv load, followed by 2 mg/kg iv weekly. Patients will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever come first.
Experimental: Cohort B
Pertuzumab and Trastuzumab-emtansine
Drug: Pertuzumab, trastuzumab-emtansine
Patients enrolled in Cohort B will receive pertuzumab 840 mg iv load, followed by 420 mg iv Q3weeks + trastuzumab-emtansine 3.6 mg/kg iv on day 1 of each subsequent 3 week cycle.
Patients will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever come first.
- 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 ]
- Description of the frequency and severity of Adverse Events based on the NCI -CTCAE V4.0 [ Time Frame: 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: 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 ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03225937
|Fondazione del Piemonte per l'Oncologia - IRCCS|
|Candiolo, Please Select, Italy, 10060|
|AOU Policlinico S. Orsola Malpighi|
|Grande Ospedale Metropolitano Niguarda|
|Milano, Italy, 20162|
|Seconda Università di Napoli|
|Istituto Oncologico Veneto - IRCCS|
|AOU Città della Salute e della Scienza di Torino|
|Study Chair:||Salvatore Siena, MD||Grande Ospedale Metropolitano Niguarda - Milano|