Evaluation of Trastuzumab in Combination With Lapatinib or Pertuzumab in Combination With Trastuzumab-Emtansine to Treat Patients With HER2-positive Metastatic Colorectal Cancer

NCT03225937 | Unknown Phase 2

• 2 other identifiers: 004-IRCC-10IIS-122012-002128-33
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 7

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.

Conditions

Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate according to RECIST 1.1 criteria

  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 (2)

• 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

Study Arms (2)

Cohort A

EXPERIMENTAL

Trastuzumab and lapatinib

Drug: Trastuzumab, Lapatinib

Cohort B

EXPERIMENTAL

Pertuzumab and Trastuzumab-emtansine

Drug: Pertuzumab, trastuzumab-emtansine

Interventions

Trastuzumab, Lapatinib DRUG

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.

Cohort A

Pertuzumab, trastuzumab-emtansine DRUG

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.

Cohort B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological/confirmed adenocarcinoma of the colon or rectum with metastatic disease not amenable to salvage surgery.
• Pathology mandatory requirements: the original tumour specimen must be KRAS WT and SISH/FISH positive or IHC 3+ positive in more than 50% cells. Note: for immunohistochemistry a positive staining (3+) is defined as an intense membrane staining which can be circumferential, basolateral, or lateral of the tumor cells. the original paraffin block or a minimum of 15 polarized unstained slides from the original paraffin block must be made available to the Pathology Core within 15 days from registration.
• Age ≥18
• ECOG PS 0-1
• Measurable disease as defined by RECIST 1.1 criteria.
• Progression (PD) while on, or within 6 months from therapy with approved standard drugs.
• Unless otherwise contraindicated patients should have received and failed the following previous therapies for mCRC: fluoropyrimidines, oxaliplatin, irinotecan, cetuximab or panitumumab containing regimens. Bevacizumab is allowed
• Adequate haematological function as defined by: ANC \> 1.5 x 109/L, platelet count \>100 x 109/L, haemoglobin \> 10 g/dL
• Adequate renal function, as defined by: creatinine \< 1.5 x UNL
• Adequate hepatobiliary function, as defined by the following baseline liver function tests: total serum bilirubin \<1.5 upper normal limit (UNL); alanine aminotransferase (ALT), aspartate aminotransferase (AST) \< 2.5xUNL; alkaline phosphatase (AP) \< 2.5xUNL, if total alkaline phosphatase (AP) \> 2.5xUNL, alkaline phosphatase liver fraction must be \< 2.5xUNL
• Adequate contraception for all fertile patients
• Negative pregnancy test

You may not qualify if:

• Subjects meeting any of the following criteria must not be enrolled in the study:
• Radiotherapy ≤ 4 weeks prior to enrolment.
• Other chemotherapy or biological therapy treatment ≤ 4 weeks prior to enrolment.
• Symptomatic brain metastases.
• Active infection.
• Gastro-intestinal abnormalities, inability to take oral medication, any condition affecting absorption.
• Impaired cardiac function including any of the following: uncontrolled hypertension (systolic \>150 mmHg and/or diastolic \> 100 mmHg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication; unstable angina; chronic heart failure (CHF) of New York Heart Association (NYHA) Grade II or higher (See Appendix 4); or serious cardiac arrhythmia requiring medication, baseline Left Ventricular Ejection Fraction (LVEF) ≤ 55% measured by echocardiography (ECHO).
• Major surgery in the two weeks prior to entering the clinical trial.
• Concurrent treatment with any other anti-cancer therapy.
• History of another neoplastic disease (except basal cell carcinoma of the skin or uterine cervix carcinoma in situ adequately treated), unless in remission for ≥ 5 years.
• Patient unable to comply with the study protocol owing to psychological, social or geographical reasons.
• Pregnant and lactating women.
• Patients with history of hypersensitivity to either IP or excipients.
• Men and women of childbearing potential who are not using an effective method of contraception.
• Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).

Sponsors & Collaborators

• Fondazione del Piemonte per l'Oncologia: lead

Study Sites (7)

Fondazione del Piemonte per l'Oncologia - IRCCS

Candiolo, Please Select, 10060, Italy

Location

AOU Policlinico S. Orsola Malpighi

Bologna, Italy

Location

Grande Ospedale Metropolitano Niguarda

Milan, 20162, Italy

Location

Seconda Università di Napoli

Napoli, Italy

Location

Istituto Oncologico Veneto - IRCCS

Padua, Italy

Location

Campus Biomedico

Roma, Italy

Location

AOU Città della Salute e della Scienza di Torino

Torino, Italy

Location

Related Publications (3)

• Valtorta E, Martino C, Sartore-Bianchi A, Penaullt-Llorca F, Viale G, Risio M, Rugge M, Grigioni W, Bencardino K, Lonardi S, Zagonel V, Leone F, Noe J, Ciardiello F, Pinto C, Labianca R, Mosconi S, Graiff C, Aprile G, Frau B, Garufi C, Loupakis F, Racca P, Tonini G, Lauricella C, Veronese S, Truini M, Siena S, Marsoni S, Gambacorta M. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol. 2015 Nov;28(11):1481-91. doi: 10.1038/modpathol.2015.98. Epub 2015 Oct 9.

  PMID: 26449765 BACKGROUND

• Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, Zagonel V, Leone F, Depetris I, Martinelli E, Troiani T, Ciardiello F, Racca P, Bertotti A, Siravegna G, Torri V, Amatu A, Ghezzi S, Marrapese G, Palmeri L, Valtorta E, Cassingena A, Lauricella C, Vanzulli A, Regge D, Veronese S, Comoglio PM, Bardelli A, Marsoni S, Siena S. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016 Jun;17(6):738-746. doi: 10.1016/S1470-2045(16)00150-9. Epub 2016 Apr 20.

  PMID: 27108243 RESULT

• Sartore-Bianchi A, Lonardi S, Martino C, Fenocchio E, Tosi F, Ghezzi S, Leone F, Bergamo F, Zagonel V, Ciardiello F, Ardizzoni A, Amatu A, Bencardino K, Valtorta E, Grassi E, Torri V, Bonoldi E, Sapino A, Vanzulli A, Regge D, Cappello G, Bardelli A, Trusolino L, Marsoni S, Siena S. Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial. ESMO Open. 2020 Sep;5(5):e000911. doi: 10.1136/esmoopen-2020-000911.

  PMID: 32988996 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Trastuzumab; Lapatinib; pertuzumab; Ado-Trastuzumab Emtansine

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Salvatore Siena, MD

  Grande Ospedale Metropolitano Niguarda - Milano

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: two sequential cohorts: cohort A (lapatinib + trastuzumab); cohort B (pertuzumab + trastuzumab-emtansine).

Study Record Dates

• First Submitted: June 13, 2017
• First Posted: July 21, 2017
• Study Start: August 1, 2012
• Primary Completion: December 1, 2018
• Study Completion: June 1, 2019
• Last Updated: October 30, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will not share

Locations

IT (7)