STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer

NCT07213570 | Recruiting Phase 2

• 2 other identifiers: STREAM-22024-519669-23-00
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators hypothesize that patients with mCRC RAS-mutant eligible for a second line treatment with good prognostic features, identified as single metastatic site, long progression free survival (PFS) in first line treatment, might benefit from a personalized approach, with less intensive treatment with regorafenib as part of a continuum-of-care strategy aimed at ensuring quality of life and extending survival.

Conditions

Colorectal Cancer Metastatic

Keywords

metastatic colorectal cancer; liquid biopsy; Regorafenib; RAS-mutation

Outcome Measures

Primary Outcomes (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.

  up to 6 months from randomization

Secondary Outcomes (10)

• Progression free survival (PFS)

  up to 1 year last patients randomized

• Overall survival (OS)

  up to 1 year last patients randomized

• Objective Tumor Response Rate (ORR)

  up to 1 year last patients randomized

• Disease Control Rate (DCR)

  up to 1 year last patients randomized

• Progression free survival 2 (PFS2)

  up to 1 year last patients randomized

Study Arms (2)

Regorafenib for ARM A - experimental arm

EXPERIMENTAL

Regorafenib will be administered following a dose-escalation strategy: starting dose 80 mg/day orally with weekly escalation, per 40 mg increment up to 160 mg/day regorafenib); if no significant drug-related adverse events occurred for 21 days of a 28-day cycle. The following cycle will be administered at highest tolerated dose from cycle 1 (up to 160 mg), as per current guidelines and clinical practice. Treatment will continue until disease progression, unacceptable toxic effects, motivated decision to stop the treatment by the treating physician, or refusal or withdrawal of consent by the patient.

Drug: Regorafenib (BAY73-4506)

Standard treatment for ARM B - calibration arm

ACTIVE COMPARATOR

Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria.

Drug: standard second line treatment, at discretion of the investigator

Interventions

Regorafenib (BAY73-4506) DRUG

Regorafenib will be administered following a dose-escalation strategy: starting dose 80 mg/day orally with weekly escalation, per 40 mg increment up to 160 mg/day regorafenib); if no significant drug-related adverse events occurred for 21 days of a 28-day cycle. The following cycle will be administered at highest tolerated dose from cycle 1 (up to 160 mg), as per current guidelines and clinical practice. Treatment will continue until disease progression, unacceptable toxic effects, motivated decision to stop the treatment by the treating physician, or refusal or withdrawal of consent by the patient. Every cycle will be administered every 28 days (four weeks) +/- 3 days.

Regorafenib for ARM A - experimental arm

standard second line treatment, at discretion of the investigator DRUG

Combination treatment may include: 5FU/LFA, capecitabine, oxaliplatin, irinotecan, bevacizumab, aflibercept

Standard treatment for ARM B - calibration arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent to study procedures and to correlative studies.
• Either sex aged ≥ 18.
• Histologically proven of colorectal adenocarcinoma.
• Diagnosis of metastatic disease.
• RAS mutant at initial diagnosis assessed at local centers according with a validated method defined by EMA and known MMR/MSI status.
• Achieved a PFS in first line \> 6 months with chemotherapy in combination to antiangiogenic treatment OR with one metastatic site at study entry
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry.
• Imaging-documented measurable disease, according to RECIST 1.1 criteria.
• Estimated life expectancy of more than 12 weeks
• 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.
• 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.
• 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).
• Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range.
• Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory. Additional analysis of polymorphisms uridine diphosphate-glycosyltransferase 1 (UGT1A1) enzyme is recommended but not mandatory.

You may not qualify if:

• 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.
• Any contraindication to regorafenib.
• Not received immunotherapy if dMMR or MSI-H.
• Major surgical intervention within 4 weeks prior to enrollment.
• Pregnancy and breast-feeding.
• Any brain metastasis.
• 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.
• 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.
• Participation in any interventional drug or medical device study within 30 days prior to treatment start.
• 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.
• Complete deficiency of activity of dihydropyrimidine dehydrogenase (DPYD)

Sponsors & Collaborators

• National Cancer Institute, Naples: lead

Study Sites (1)

Istituto Nazionale Tumori | "Fondazione Pascale"

Naples, Italy, Italy

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

regorafenib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Central Study Contacts

Antonio Avallone, MD

CONTACT

003908117770357; a.avallone@istitutotumori.na.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2025
• First Posted: October 9, 2025
• Study Start: October 16, 2025
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: December 17, 2025

Record last verified: 2025-09

Locations

IT (1)