Efficacy And Safety Of Hydroxychloroquine Combined With Methotrexate, Capecitabine And Bevacizumab Vs. Regorafenib In Participants With Refractory Metastatic Colorectal Cancer With Mutations In RAS Genes

NCT06949982 | Recruiting Phase 2

• 1 other identifier: 1.0
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate efficacy and safety of hydroxychloroquine combined with methotrexate, capecitabine and bevacizumab versus regorafenib in participants with refractory metastatic colorectal cancer with mutations in KRAS or NRAS genes. The hypotheses of this study are that a combination of hydroxychloroquine, methotrexate, capecitabine, and bevacizumab (compared to regorafenib) prolongs progression-free survival and overall survival, and also increases rates of objective responses and disease control.

Conditions

Metastatic Colorectal Cancer (mCRC); Colorectal Neoplasms

Keywords

Refractory metastatic colorectal cancer; Hydroxychloroquine; Regorafenib; KRAS mutation; NRAS mutation

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  objective response rate (ORR) was defined as the proportion of participants whose best overall outcome included a confirmed complete response (CR) or partial response (PR), assessed by the investigator using RECIST version 1.1 criteria. PR corresponds to a minimum 30% reduction in the total diameter of target lesions compared to the baseline measurements. CR indicates the total disappearance of all identified target lesions. Additionally, any pathological lymph nodes (classified as target or non-target) must shrink to a short axis measurement below 10 millimeters (mm).

  From randomization until the first documentation of best overall response (up to 24 months)

• Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  Progression-free survival (PFS) was defined as the time from randomization to the initial occurrence of documented disease progression (PD) or death from any cause, whichever occurs earlier. According to RECIST 1.1 criteria, PD was characterized by at least a 20% enlargement in the total diameter of target lesions compared to the smallest sum recorded during the study, along with an absolute increase of 5 mm or more. The development of any new lesions was also classified as PD.

  From randomization until the first documentation of objective progression or death, whichever comes first (up to 24 months)

Secondary Outcomes (4)

• Overall Survival (OS)

  From randomization until the first documentation of objective progression or death, whichever comes first (up to 24 months)

• Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  From randomization until the first documentation of objective progression or death, whichever comes first (up to 24 months)

• Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  From randomization until the first documentation of objective progression or death, whichever comes first (up to 24 months)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

  From start of study drug administration up to approximately 38 months

Study Arms (2)

experimental group x-MAP

EXPERIMENTAL

This patient cohort will receive systemic therapy with the x-MAP regimen (hydroxychloroquine + methotrexate + capecitabine + bevacizumab) until disease progression or unacceptable toxicity.

Combination Product: experimental group x-MAP

comparator arm

ACTIVE COMPARATOR

This group of patients will receive systemic therapy (regorafenib) according to local standards.

Drug: Regorafenib (BAY 73-4506)

Interventions

experimental group x-MAP COMBINATION_PRODUCT

hydroxychloroquine 200 mg TID PO+ methotrexate 2.5 mg BID twice a week PO+ capecitabine 1000 mg/m2 PO BID for 14 days+ bevacizumab 7.5 mg/m2 IV on day 1, every 3 weeks.

experimental group x-MAP

Regorafenib (BAY 73-4506) DRUG

Regorafenib 160 mg PO daily on days 1-21, every 28 days OR 1st cycle: Regorafenib 80 mg PO daily on days 1-7, followed by 120 mg PO daily on days 8-14, followed by 160 mg PO daily on days 15-21, every 28 days, 2nd and subsequent cycles: Regorafenib 160 mg PO daily on days 1-21, every 28 days

comparator arm

Eligibility Criteria

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

You may qualify if:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Provide written informed consent
• Age ≥ 18 years
• Histologically confirmed diagnosis of colorectal cancer (CRC) with distant metastases.
• Presence of mutations in the KRAS or NRAS gene.
• Participants must have previously treated for metastatic colorectal cancer and experienced disease progression during receiving at least 2 lines of systemic chemotherapy in combination with antiangiogenic agents.
• Patient has previously received oxaliplatin- and irinotecan-containing regimens and developed resistance to these chemotherapeutic agents.

You may not qualify if:

• Presence of clinically significant cardiovascular disease: severe or unstable ischemic heart disease, history of myocardial infarction, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias.
• Stroke and/or transient ischemic attack within 6 months prior to screening;
• Uncontrolled hypertension
• History of previous malignancies except non-melanoma skin cancers, or in situ cervical or breast cancer unless a complete remission was achieved at least 2 years prior to randomization AND no additional therapy is required during the study period. Patients having hepatic involvement of cancer should be excluded as per investigator assessment.
• Patients with CNS metastases are eligible only if the metastases are adequately treated.
• Absolute neutrophil count (ANC) \<1.5×109/L, platelet count \<100×109/L, or hemoglobin \<9.0 g/dL.
• Serum total bilirubin \>1.5 × the upper limit of normal (ULN). Participants with Gilbert syndrome, bilirubin \<2 X ULN, and normal AST/ALT are eligible;
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 × ULN;
• Serum creatinine \>1.5 × ULN.
• History of a thromboembolic event
• Presence of any allergic reactions to components of the study drugs
• Concomitant medications with a known risk of causing QT prolongation and/or Torsades de Pointes.
• Any anti-cancer systemic therapy, radiation therapy
• Women who are pregnant or lactating;
• Presence of unresolved adverse events of grade 2 or higher toxicity, according to CTCAE v5.0 criteria, from prior therapy (except for alopecia or neurotoxicity grade≤2).

Sponsors & Collaborators

• Sergey Orlov, MD: lead

Study Sites (1)

First Pavlov State Medical University

Saint Petersburg, Sankt-Peterburg, 197022, Russia

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

Sergey V. Orlov, Professor

CONTACT

+79811957915; orloff-sv@mail.ru

Aram A. Musaelyan, PhD

CONTACT

+79990263455; a.musaelyan8@gmail.com

Study Design

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

Model Details: A parallel design is a type of clinical trial in which participants are allocated to two treatment groups: one group receives exclusively one intervention, while the other receives exclusively a different intervention. Randomization in such studies ensures the accuracy of outcomes and reduces the risk of bias.

Study Record Dates

• First Submitted: April 14, 2025
• First Posted: April 29, 2025
• Study Start: March 17, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): October 1, 2027
• Last Updated: May 4, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

RU (1)