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Study of Trastuzumab-emtansine in Patients With HER2-positive Metastatic Colorectal Cancer Progressing After Trastuzumab and Lapatinib. (RESCUE)

Primary Purpose

Metastatic Colorectal Cancer

Status
Unknown status
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Trastuzumab emtansine
Sponsored by
Fondazione del Piemonte per l'Oncologia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring HER2 AMPLIFICATION

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Histological/confirmed adenocarcinoma of the colon or rectum with metastatic disease not amenable to salvage surgery.
  2. Progression (PD) during or after therapy with anti-HER2 therapy including those in HERACLES trial cohort A (trastuzumab and lapatinib) within the HERACLES - A trial.
  3. ECOG PS < 2
  4. Measurable disease as defined by RECIST 1.1 criteria
  5. Adequate hematological function as defined by: ANC >= 1.5 x 10^9/L, platelet count >=100 x 10^9/L, hemoglobin >= 10 g/dL.
  6. Adequate renal function, as defined by: creatinine >= 1.5 x UNL

  7. Adequate hepatobiliary function, as defined by the following baseline liver function tests:

    1. total serum bilirubin >=1.5 upper normal limit (UNL) (unless documented Gilbert's syndrome )
    2. alanine aminotransferase (ALT), aspartate aminotransferase (AST) >= 2.5xUNL
    3. alkaline phosphatase (AP) >= 2.5xUNL; if total alkaline phosphatase (AP) > 2.5xUNL, alkaline phosphatase liver fraction must be >= 2.5xUNL
  8. Adequate contraception for all fertile patients
  9. Negative pregnancy test.

Exclusion Criteria:

  1. Symptomatic brain metastases
  2. Active infection
  3. Interval from last anti HER2 therapy < 2 weeks. Patients in treatment with T-DM1 (provided by third-parties) may be eligible for immediate treatment if not in progression at the time of protocol entry.
  4. Prior chemotherapy <4 weeks.
  5. 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; or serious cardiac arrhythmia requiring medication, baseline Left Ventricular Ejection Fraction (LVEF) ≤ 55% measured by echocardiography (ECHO)
  6. Major surgery in the two weeks prior to entering the clinical trial
  7. Concurrent treatment with any other anti-cancer therapy
  8. Patient unable to comply with the study protocol owing to psychological, social or geographical reasons
  9. Pregnant and lactating women
  10. Men and women of childbearing potential who are not using an effective method of contraception
  11. Participation in another clinical trial
  12. 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).

Sites / Locations

  • Fondazione del Piemonte per l'Oncologia
  • Grande Ospedale Metropolitano NiguardaRecruiting
  • IOV - Istituto Oncologico Veneto

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

HERACLES RESCUE

Arm Description

Patients will receive trastuzumab-emtansine, iv 3,6 mg/kg every 21 days. Patients will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever come first

Outcomes

Primary Outcome Measures

Objective Response Rate according to RECIST 1.1 criteria

Secondary Outcome Measures

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

Full Information

First Posted
January 24, 2018
Last Updated
October 29, 2018
Sponsor
Fondazione del Piemonte per l'Oncologia
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1. Study Identification

Unique Protocol Identification Number
NCT03418558
Brief Title
Study of Trastuzumab-emtansine in Patients With HER2-positive Metastatic Colorectal Cancer Progressing After Trastuzumab and Lapatinib.
Acronym
RESCUE
Official Title
Open-label, Phase II Study of Trastuzumab Emtansine in Patients With HER2-positive Metastatic Colorectal Cancer Progressing After Trastuzumab and Lapatinib: HERACLES RESCUE. (HER2 Amplification for Colo-rectaL Cancer Enhanced Stratification - REchallenge With her2 Selective Cytotoxic Uptake of Emtansine)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Unknown status
Study Start Date
July 8, 2015 (Actual)
Primary Completion Date
June 2019 (Anticipated)
Study Completion Date
June 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fondazione del Piemonte per l'Oncologia

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a phase II, open label, multicenter study. Patients with advanced colon rectal cancer (CRC) harboring an amplified HER2 that have been previously treated and progressed with an aNti-HER2 treatment, will be treated with the anti HER2 antibody conjugate trastuzumab emtansine (TDM1). Patients will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death. Main objective of the study is the evaluation of objective response rate according to RECIST 1.1 criteria. Disease control rate, defined as the sum of complete, partial and stable disease patients over total patient, followed by response duration, time to progression and safety are secondary endpoints.
Detailed Description
In metastatic colorectal cancer, HER2 amplified patients relapsing after initial long-lasting response to the anti HER combination of trastuzumab + lapatinib, HER2 gene amplification, and the ensuing high levels of HER2 expression on the tumor surface, persist in spite of the tumor progression as determined by HER2 amplified ctDNA levels measured at progression and HER2 IHC findings on rebiopsies of resistant tumors. These findings offer an unexpected 'precision chemotherapy' rescue potential, in spite of progression under anti HER2 treatment and were confirmed experimentally in a HER2 amplified mCRC PDX (metastatic ColoRectal Carcinoma Patient Derived Xenografts), model generated from the viable biopsy of a relapsing HERACLES patient. In this model a randomized trial comparing TDM1 to pertuzumab versus control (6 animal per arm), showed that T-DM1, but not pertuzumab treated animals achieved tumor disappearance. The results of this experiment confirm the principle strength of targeted toxins which is based on their bipartite structure, with one component binding to a disease-specific cell-surface target molecule and the other conferring cytotoxicity, once internalized. In this case HER2 amplification confer to the tumor the characteristics of a 'molecular sponge' for TDM1 with the trastuzumab moiety targeting the still over-abundant HER2 bound to the cell-surface of anti HER2 resistant tumor cell clusters, thus allowing for a 'surgical' delivery of the emtansine cytotoxicity moiety. Given the good predictability of mCRC PDXs model, as testified by HERACLES TRIAL results (NCT03225937), investigators believe that this activity signal should be tested in the clinic. It is therefore proposed a proof-of-concept trial of T-DM1 in HER2 amplified mCRC patients progressing or relapsing after trastuzumab-lapatinib treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer
Keywords
HER2 AMPLIFICATION

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
13 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
HERACLES RESCUE
Arm Type
Experimental
Arm Description
Patients will receive trastuzumab-emtansine, iv 3,6 mg/kg every 21 days. Patients will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever come first
Intervention Type
Drug
Intervention Name(s)
Trastuzumab emtansine
Primary Outcome Measure Information:
Title
Objective Response Rate according to RECIST 1.1 criteria
Time Frame
every 9 weeks from date of enrollment until the date of first documented progression or date of death for any cause, whichever came first, assessed up to 48 months
Secondary Outcome Measure Information:
Title
Description of the frequency and severity of Adverse Events based on the NCI -CTCAE V4.0
Time Frame
every 21 days from date of enrollment until the date of first documented progression or date of death for any cause, whichever came first, assessed up to 48 months
Title
Progression Free Survival
Description
Progression Free Survival
Time Frame
every 9 weeks from date of enrollment until the date of first documented progression or date of death for any cause, whichever came first, assessed up to 48 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histological/confirmed adenocarcinoma of the colon or rectum with metastatic disease not amenable to salvage surgery. Progression (PD) during or after therapy with anti-HER2 therapy including those in HERACLES trial cohort A (trastuzumab and lapatinib) within the HERACLES - A trial. ECOG PS < 2 Measurable disease as defined by RECIST 1.1 criteria Adequate hematological function as defined by: ANC >= 1.5 x 10^9/L, platelet count >=100 x 10^9/L, hemoglobin >= 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) (unless documented Gilbert's syndrome ) 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. Exclusion Criteria: Symptomatic brain metastases Active infection Interval from last anti HER2 therapy < 2 weeks. Patients in treatment with T-DM1 (provided by third-parties) may be eligible for immediate treatment if not in progression at the time of protocol entry. Prior chemotherapy <4 weeks. 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; 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 Patient unable to comply with the study protocol owing to psychological, social or geographical reasons Pregnant and lactating women Men and women of childbearing potential who are not using an effective method of contraception Participation in another clinical trial 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).
Facility Information:
Facility Name
Fondazione del Piemonte per l'Oncologia
City
Candiolo
ZIP/Postal Code
10060
Country
Italy
Individual Site Status
Completed
Facility Name
Grande Ospedale Metropolitano Niguarda
City
Milano
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Salvatore Siena, MD
Email
salvatore.siena@ospedaleniguarda.it
Facility Name
IOV - Istituto Oncologico Veneto
City
Padova
Country
Italy
Individual Site Status
Completed

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Study of Trastuzumab-emtansine in Patients With HER2-positive Metastatic Colorectal Cancer Progressing After Trastuzumab and Lapatinib.

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