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Metastatic Colorectal CancerPhase 2HERACLESNCT03225937

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

A Phase 2 study testing Trastuzumab, Lapatinib and Pertuzumab, trastuzumab-emtansine in people with Metastatic Colorectal Cancer, run by Fondazione del Piemonte per l'Oncologia at 7 sites in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Colorectal Cancer
What is being tested?
Trastuzumab, Lapatinib and Pertuzumab, trastuzumab-emtansine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
54 participants
Where
7 sitesItaly
Study dates
Aug 2012to Jun 2019
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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
  • Histological/confirmed adenocarcinoma of the colon or rectum with metastatic disease not amenable to salvage surgery.
  • The original tumour specimen must be RAS (KRAS exons 2 3 4; NRAS exons 2 3 4) wild type and SISH/FISH positive or IHC 2+/3+ positive in more than 50% cells.
  • 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 must have received and failed fluoropyrimidines, oxaliplatin, irinotecan -containing regimens as previous therapies for metastatic disease.
  • Patients having failed only one line of chemotherapy for their metastatic diseases are eligible if they have received:
  • FOLFOXIRI;
  • FOLFIRI after progression to adjuvant FOLFOX, occurred on treatment or within 6 months after treatment completion.
  • Treatments with bevacizumab, aflibercept or regorafenib and cetuximab or panitumumab are allowed.
  • Adequate hematological 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 hepato-biliary 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

Who cannot join

  • 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.
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  • 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.
  • Participation in another clinical trial or treatment with any investigational product within 4 weeks prior to inclusion in this study.
  • 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).
  • Patient with unresolved hypokalaemia, hypomagnesemia or hypocalcaemia
  • 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 (ie 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.
  • Participation in another clinical trial or treatment with any investigational product within 4 weeks prior to inclusion in this study.
  • 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).
  • Patient with unresolved hypokalaemia, hypomagnesemia or hypocalcaemia.

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

Italy7 sites

  • AOU Policlinico S. Orsola Malpighi

    Bologna

  • Fondazione del Piemonte per l'Oncologia - IRCCS

    Candiolo, Please Select, 10060

  • Grande Ospedale Metropolitano Niguarda

    Milan, 20162

  • Seconda Università di Napoli

    Naples

  • Istituto Oncologico Veneto - IRCCS

    Padova

  • Campus Biomedico

    Roma

  • AOU Città della Salute e della Scienza di Torino

    Torino

Other trials in Italy

About this study

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

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.

Read the 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.

Being tested
Trastuzumab, Lapatinib, Pertuzumab, trastuzumab-emtansine
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Trastuzumab, LapatinibDrug

    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.

  • Pertuzumab, trastuzumab-emtansineDrug

    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.

Study groups in NCT03225937
Study groupRoleWhat they receive
Cohort AExperimentalTrastuzumab and lapatinib
Receives: Drug: Trastuzumab, Lapatinib
Cohort BExperimentalPertuzumab and Trastuzumab-emtansine
Receives: Drug: Pertuzumab, trastuzumab-emtansine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Objective Response Rate according to RECIST 1.1 criteria

    Measured: 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)

  1. Description of the frequency and severity of Adverse Events based on the NCI -CTCAE V4.0

    Measured: 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

  2. Progression Free Survival

    Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jul 2017
  2. Study startAug 2012
  3. Primary completionDec 2018 (estimated)
  4. Study completionJun 2019 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Model description
two sequential cohorts: cohort A (lapatinib + trastuzumab); cohort B (pertuzumab + trastuzumab-emtansine).
Masking
None (open label)
Enrolment
54 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03225937
Sponsor's protocol ID
004-IRCC-10IIS-12
Other IDs
2012-002128-33
Acronym
HERACLES
Status last verified
Oct 2018
First submitted
13 Jun 2017
Last updated
30 Oct 2018
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • 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.

    PubMed 26449765

  • 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.

    PubMed 27108243

  • 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.

    PubMed 32988996

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Trastuzumab, Lapatinib and Pertuzumab, trastuzumab-emtansine in people with Metastatic Colorectal Cancer, run by Fondazione del Piemonte per l'Oncologia at 7 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 31 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 30 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03225937, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Oct 2018.

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