Regorafenib as second-line treatment of patients with RAS-mutant advanced colorectal cancer: a multicentre, phase 2 study - STREAM-2

Overview

Sponsor-declared trial summary

Key facts

Sponsor

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Sep 2025 → ongoing

Decision date (initial)

2025-06-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To assess the anti-tumor efficacy of regorafenib as second line treatment in mCRC RAS-mutant patients, eligible to a second line treatment, and with good prognostic features, measured as progression-free survival rate at 6 months

Secondary objectives 2

1. To assess the antitumor activity, the toxicity profile and quality of life in patients treated with regorafenib
2. To assess the efficacy and anti-tumor activity of standard treatment and its toxicity profile and quality of life, measured as progression-free survival (PFS), overall survival (OS), objective tumor response rate (ORR), disease control rate (DCR), adverse event frequency, time toxicity and questionnaire on quality of life and financial toxicity

Conditions and MedDRA coding

Patients with metastatic colorectal cancer (mCRC) RAS-mutant

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Written informed consent to study procedures and to correlative studies.
2. Either sex aged ≥ 18
3. Histologically proven of colorectal adenocarcinoma
4. Diagnosis of metastatic disease.
5. RAS mutant at initial diagnosis assessed at local centers according with a validated method defined by EMA and known MMR/MSI status
6. Achieved a PFS in first line > 6 months with chemotherapy in combination to antiangiogenic treatment OR with one metastatic site at study entry
7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry
8. Imaging-documented measurable disease, according to RECIST 1.1 criteria.
9. Estimated life expectancy of more than 12 weeks
10. Adequate bone marrow hematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL.
11. Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 2 (in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5 X ULN
12. Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula)
13. Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range.
14. Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory. Additional analysis of polymorphisms uridine diphosphate-glycosyltransferase 1 (UGT1A1) enzyme is recommended but not mandatory

Exclusion criteria 11

1. Prior malignancy within five years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
2. Any contraindication to regorafenib.
3. Not received immunotherapy if dMMR or MSI-H
4. Major surgical intervention within 4 weeks prior to enrollment.
5. Pregnancy and breast-feeding.
6. Any brain metastasis.
7. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study.
8. History of poor co-operation, non-compliance with medical treatment, unreliability or any condition that may impair the patient's understanding of the Informed consent form.
9. Participation in any interventional drug or medical device study within 30 days prior to treatment start.
10. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment
11. Complete deficiency of activity of dihydropyrimidine dehydrogenase (DPYD).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression Free Survival rate at 6 months in the two arms. Progression Free Survival rate at 6 months(PFS rate at 6-months) is defined as the rate of assessable patients alive and not progressed after 6 months from study initiation (i.e randomization) to the first documentation of objective disease progression by RECIST 1.1 criteria, or death due to any cause, whichever occurs first.

Secondary endpoints 10

1. Progression free survival (PFS) calculated as the time from randomization until the date of death from any cause until the date of the first observation of disease progression or death due to any cause, whichever occurs first. PFS will be censored at the time of the last available tumor assessment documenting absence of progressive disease for patients alive at the time of analysis.
2. Overall survival (OS) calculated as the time from randomization until the date of death from any cause. OS will be censored at the last date the patient was known to be alive for patients alive at the time of analysis
3. Objective Tumor Response Rate (ORR) assessed according to RECIST criteria 1.1, as the proportion of patients achieving complete or partial response relative to total enrolled patients.
4. Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response.
5. Progression free survival 2 (PFS2) calculated as the time from registration to progression from subsequent line of treatment or death without progression, whichever occurred first.
6. Overall Toxicity rate defined as adverse events graded according NCI CTCAE v 5.0. as the proportion of patients experiencing any grade AE accordingly to the NCI Common Terminology Criteria of Adverse Events (NCI CTC-AE) Version 5, relative to the total of patients receiving at least one cycle of treatment.AE will be listed individually by the patient and summarized overall (severity grades 1-4) and for grade ≥3 by treatment received.
7. Quality of life (QoL) investigated through the EORTC QOL-C30 and CR29 questionnaires at baseline (prior to treatment start, once eligibility is confirmed) and every 8 weeks from randomization until disease progression, treatment failure or death.
8. PRO-CTCAE questionnaires will be administered at the same time points with items dedicated in particular to Hand-Foot Syndrome and Hand-Foot skin reactions, diarrhea and neuropathy, to better evaluate the effect of two different strategies of treatment on the health-related QoL.
9. Time/toxicity defined as time spent coordinating treatments and in-visits to a health care facility (including travel and waiting), seeking urgent/emergent care for side effects, hospitalizations, and follow-up tests and rehabilitation (measured as Days with Physical Health Care System Contact
10. Financial toxicity assessed through the PROFFIT questionnaire at baseline (prior to treatment start, once eligibility is confirmed) and every 8 weeks from randomization until disease progression, treatment failure or death.

Investigational products

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

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Sponsor organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Address

Via Mariano Semmola 52

City

Naples

Postcode

80131

Country

Italy

Scientific contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Antonio Avallone

Public contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Antonio Avallone

Locations

1 EU/EEA country · 9 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 33 files

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

Application history

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