Study to evaluate the efficacy and safety of cetuximab plus irinotecan compared to investigator's choice therapy in patients with metastatic colorectal cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Associacio Per A La Recerca Oncologica

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Oct 2020 → 19 Jun 2025

Decision date (initial)

2024-10-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518728-59-00

EudraCT number

2020-000443-31

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective of the study is to evaluate the efficacy, in terms of overall response
rate (ORR), of a rechallenge strategy with cetuximab and irinotecan in comparison to
investigator's choice of treatment, excluding anti-EGFR therapy, as third-line treatment in
patients with RAS, BRAF and EGFR-ECD wild-type mCRC genomically selected by liquid
biopsy.

Secondary objectives 7

1. To evaluate the efficacy, in terms of disease control rate (DCR), of cetuximab plus irinotecan rechallenge in comparison to the investigator's choice of treatment in the third-line setting.
2. To evaluate the duration of disease control (DDC) with cetuximab plus irinotecan rechallenge in comparison to the investigator's choice of treatment in the third-line setting.
3. To evaluate the time to treatment failure (TTF) with cetuximab plus irinotecan rechallenge in comparison to the investigator's choice of treatment in the third-line setting.
4. To evaluate the efficacy, in terms of PFS, of cetuximab plus irinotecan rechallenge in comparison to the investigator's choice of treatment in the third-line setting.
5. To evaluate the efficacy, in terms of OS, of cetuximab plus irinotecan rechallenge in comparison to the investigator's choice of treatment in the third-line setting.
6. To evaluate the safety profile of cetuximab plus irinotecan treatment and of the investigator´s choice of treatment in the third-line setting in patients previously treated with a non-anti-EGFR therapy as second-line treatment after cetuximab-based first-line treatment.
7. To evaluate the emergence/expression level/levels of additional potential biomarkers, related to treatment resistance, in ctDNA and tissue.

Conditions and MedDRA coding

metastatic colorectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Written informed consent before any study procedure is performed.
2. Men and women aged 18 years or older.
3. Histologically confirmed mCRC.
4. RAS wild-type (KRAS and NRAS exon 2,3,4) status in a tissue-based test determined by a local assay before starting first-line treatment.
5. Patients must have received two prior regimens of standard chemotherapy for mCRC and must have been refractory to or failed (includes intolerance) to those regimens. ▪ Prior standard chemotherapy may not have included TAS-102 or regorafenib, but must have included all of the following agents: ▪ AntiEGFR monoclonal antibodies (cetuximab or panitumumab) in the firstline setting ▪ Fluoropyrimidines, irinotecan and oxaliplatin (+/- an anti-VEGF pathway inhibitor approved for treatment of mCRC). Reintroduction of a chemotherapeutic regimen will not be considered as a new line of treatment.
6. Patients with “acquired” resistance to antiEGFR monoclonal antibodies (cetuximab or panitumumab), defined as: ▪ Response to first-line antiEGFR-based treatment (defined as CR, PR or SD lasting ≥16 weeks). ▪ Documented progression to first-line antiEGFR-based treatment within 4 weeks after the last administration of cetuximab or panitumumab.
7. Recovery of any toxicity related to second-line treatment to grade ≤1 according to NCICTCAE version 5.0 at screening, with the exception of grade 2 alopecia or grade 2 neuropathy.
8. Triple negative mutation status defined as no detection of clonal mutations in extended RAS (KRAS and NRAS exon 2,3,4), BRAF V600E and EGFR-ECD (V441, S464, G465 and S492) as assessed in liquid biopsy testing for screening before third-line treatment initiation assessed by the central laboratory. Note: A centralized genomic analysis will be performed. For this purpose, peripheral blood will be collected and sent to the central laboratory for detecting RAS, BRAF V600E, and EGFR-ECD mutations on ctDNA by Oncomine CRC NGS analysis.
9. At least one measurable lesion, defined as one or more target lesions according to RECIST, version 1.1.
10. ECOG performance status of 0-1
11. Adequate bone marrow (hemoglobin ≥9.0 g/dL, neutrophil count > 1.0 x 109/L and platelet > 50 x 109/L), renal (serum creatinine <2 x upper limit of normal [ULN] and/or bilirubin <2.5 x UNL) and hepatic function (ALT and AST < 2.5 x ULN, ≤ 5 x ULN if liver metastases are present).
12. Absence of any psychological, familial, sociological or geographical circumstance potentially hampering compliance with the study protocol.
13. Life expectancy >12 weeks, as determined by the investigator.

Exclusion criteria 13

1. Patients who decline or are unable to understand, provide or are unwilling to sign an informed consent form.
2. Failure to perform screening examinations.
3. Second-line treatment with anti-EGFR therapy.
4. Pregnant or nursing (lactating) women; women of childbearing potential (premenopausal or less than 12 months of amenorrhea post-menopause) who have not undergone surgical sterilization and who are sexually active that are unwilling to use adequate contraception (such as oral contraceptives, intrauterine contraceptive device or barrier method with spermicide or surgical sterilization) during the study and until 3 months after last dose of study treatment administration.
5. Previous or concurrent second malignancy with exception of basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or other solid tumors with no evidence of recurrence in the last 5 years.
6. Patients with known, untreated central nervous system (CNS) or leptomeningeal metastases, or spinal cord compression; patients with any of these metastases not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required.
7. Patients with MSI-high (MSI-H) tumors.
8. Suspected or known allergy or intolerance to any components of the study treatment.
9. History of grade 3/4 infusion reactions to cetuximab or panitumumab monoclonal antibodies.
10. Unable or unwilling to complete all required screening and/or follow-up assessments.
11. Patients under ongoing treatment with an investigational medication or medical device or participation in another investigational study within the previous 4 weeks.
12. Patients with active alcohol or drug addiction or any other condition that, in the investigator's opinion, would interfere with their ability to comply with the study requirements.
13. Patients with any concurrent condition that, in the investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the study is the ORR, defined as the percentage of patients achieving a CR or PR as the best overall response, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer 2009) from randomization to disease progression, death, or premature withdrawal from study treatment due to any reason, including unacceptable toxicity, whichever is first, in both study arms.

Secondary endpoints 7

1. DCR, defined as the percentage of patients achieving CR, PR or SD, as the best overall response according to RECIST v1.1, from randomization to disease progression, death, or premature withdrawal from study treatment, whichever is first, in both study arms.
2. DDC, defined as the time elapsed from first CR, PR or SD to first observed progression or death from any cause, among patients achieving CR, PR or SD, in both study arms.
3. TTF, defined as the time elapsed from randomization to the end date of study treatment for any reason (including but not limited to disease progression or unacceptable toxicity) or date of progressive disease, whichever occurs first, in both study arms.
4. PFS, defined as the time elapsed from randomization to the date of first observed progression or death due to any cause, whichever is first, in both study arms.
5. OS, defined as the time elapsed from randomization to the date of death due to any cause, in both study arms.
6. The safety profile of cetuximab plus irinotecan treatment and of the investigator´s choice of treatment in the third-line setting will be measured based on all AEs (serious and nonserious) experienced since randomization, classified and graded according to NCICTCAE version 5.0 (Cho 2019), and any abnormal findings on physical examination, vital signs, laboratory results, electrocardiogram (ECG) and imaging tests through the study.
7. Emergence/expression level of additional potential biomarker related to treatment resistance including but not limited to MAPKs pathway mutations, alternative receptor activation, PIK3CA mutations (ctDNA), as well as immunologic characteristics in peripheral blood and tumor tissue (primary tumor or metastases) during the screening period (before treatment initiation), at week 8 after randomization and at the end-of-treatment visit in both study arms.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Associacio Per A La Recerca Oncologica

Sponsor organisation

Associacio Per A La Recerca Oncologica

Address

Calle Vilarrubias 20

City

Sabadell

Postcode

08202

Country

Spain

Scientific contact point

Organisation

Associacio Per A La Recerca Oncologica

Contact name

Joaquim Bellmunt

Public contact point

Organisation

Associacio Per A La Recerca Oncologica

Contact name

Joaquim Bellmunt

Third parties 3

Locations

1 EU/EEA country · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications