A phase II randomized clinical study of the combination of avelumab plus cetuximab as rechallenge strategy in pre-treated RAS/BRAF wild type metastatic colorectal cancer patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Gruppo Oncologico Dell'Italia Meridionale

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

8 Jan 2025 → ongoing

Decision date (initial)

2025-01-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-519481-44-00

EudraCT number

2021-004593-56

ClinicalTrials.gov

NCT05291156

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of the study is to evaluate the efficacy (in terms of Overall Survival - OS) of avelumab and
cetuximab combined in pre-treated RAS, BRAF wild type metastatic colorectal cancer patients compared to
cetuximab alone.

Secondary objectives 3

1. To demonstrate superiority with regard to the Objective Response Rate (ORR) of avelumab and cetuximab combined in pre-treated RAS, BRAF wild type metastatic colorectal cancer patients compared to cetuximab alone.
2. To demonstrate superiority with regard to Progression Free Survival (PFS) of avelumab and cetuximab combined in pre-treated RAS, BRAF wild type metastatic colorectal cancer patients compared to cetuximab alone
3. • To determine the safety and tolerability of avelumab and cetuximab combined in pre-treated RAS/BRAF wild type metastatic colorectal cancer patients compared to cetuximab alone

Conditions and MedDRA coding

colorectal metastatic cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Signed written informed consent before any trial-related procedure is undertaken that is not part of the standard patient management
2. Male or female subjects aged ≥ 18 years.
3. Histologically proven diagnosis of colorectal adenocarcinoma.
4. Diagnosis of metastatic disease.
5. RAS (NRAS and KRAS exon 2,3 and 4) and BRAF wild-type in liquid biopsy at initial diagnosis (according to NGS, Foundation/Roche).
6. Efficacy of a first line therapy containing anti-EGFR drug with a major response achieved (i.e. complete or partial response according to RECIST criteria v1.1).
7. Received a second line therapy.
8. More than 4 months since the last dose of anti-EGFR drug administered in first line treatment before randomization.
9. Measurable disease according to RECIST criteria v1.1.
10. ECOG PS of 0 to 1 at trial entry.
11. Estimated life expectancy of more than 12 weeks.
12. Adequate hematological function defined by white blood cell (WBC) count ≥ 2.5 × 109 /L with absolute neutrophil count (ANC) ≥ 1.5 × 109 /L, lymphocyte count ≥ 0.5 × 109 /L, platelet count ≥ 100 × 109 /L, and hemoglobin ≥ 9 g/dL (may have been transfused).
13. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and alanine aminotransferase (ALT) levels ≤ 2.5 × ULN for all subjects or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver).
14. Adequate renal function defined by an estimated creatinine clearance > 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
15. Effective contraception for both male and female subjects throughout the study and for at least 2 months after last study treatment administration if the risk of conception exists (Note: The effects of the trial drug on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use effective contraception, defined as 2 barrier methods, or 1 barrier method with a spermicide, an intrauterine device, or use of oral female contraceptive. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately).

Exclusion criteria 20

1. Any contraindication to cetuximab and/or avelumab
2. Past or current history of malignancies other than colorectal carcinoma, except for curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix.
3. Pregnancy.
4. Breastfeeding.
5. Participation in a clinical study or experimental drug treatment within 30 days before enrollment
6. Subjects receiving immunosuppressive agents (such as steroids) for any reason, should be tapered off these drugs before initiation of the trial treatment, with the exception of: - Subjects with adrenal insufficiency, who may continue corticosteroids at physiologic replacement dose, equivalent to ≤ 10 mg prednisone daily - Intranasal, inhaled, topical steroids, - Local steroid injection (e.g., intra-articular injection) - Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent - Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
7. All subjects with brain metastases, except those meeting the following criteria: - Brain metastases have been treated locally - No ongoing neurological symptoms related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
8. Prior organ transplantation, including allogeneic stem-cell transplantation
9. Significant acute or chronic infections including, among others: - Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome - Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
10. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: - Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. - Subjects requiring hormone replacement with corticosteroids are eligible if steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or equivalent prednisone per day. - Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable. - Active infection requiring systemic therapy.
11. . Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the daily dose after 14 days will be ≤ 10 mg per day of equivalent prednisone.
12. Known severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v 5 Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
13. History of hypersensitivity to Polysorbate 80 that led to unacceptable toxicity requiring treatment cessation
14. Persisting toxicity related to prior therapy of Grade > 1 NCI- CTCAE v 5.0.
15. Known alcohol or drug abuse.
16. . Clinically significant (that is active) cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication.
17. History of keratitis, ulcerative keratitis or severe dry eye. Since contact lent use is also a risk factor for keratitis and ulceration, it is not recommended
18. Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
19. Vaccination within 4 weeks of the first dose of avelumab and cetuximab and while on treatment is prohibited except for administration of inactivated vaccine (i.e. inactivated influenza vaccine).
20. Legal incapacity or limited legal capacity.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint for the trial is OS time, defined as the interval from enrollment to death for every cause

Secondary endpoints 3

1. The overall response rate (ORR) according to RECIST 1.1 defined as the proportion of patients who have a partial or complete response to therapy
2. Progression free survival (PFS) according to RECIST 1.1 defined as the time from random assignment in the clinical trial to disease progression or death from any cause.
3. Safety endpoints include AEs, assessed throughout the trial and evaluated using the NCI- CTCAE version 5.0 (CTCAE v 5.0), clinical laboratory assessments, vital signs, and electrocardiogram (ECG) parameters

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Gruppo Oncologico Dell'Italia Meridionale

Sponsor organisation

Gruppo Oncologico Dell'Italia Meridionale

Address

Viale John Fitzgerald Kennedy 50

City

Bari

Postcode

70124

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Dell'Italia Meridionale

Contact name

Fortunato Ciardiello

Public contact point

Organisation

Gruppo Oncologico Dell'Italia Meridionale

Contact name

Fortunato Ciardiello

Locations

1 EU/EEA country · 27 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

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

Documents 13 files

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

Application history

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