Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory

NCT05576896 | Recruiting Phase 2 DMC FDA Drug

• 5 other identifiers: NU 22I05Northwestern UniversityIRB#P30CA060553NCI-2022-08532
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase II, open label, single-arm trial study of adding hydroxychloroquine to encorafenib and cetuximab in patients with metastatic BRAF V600E colon cancer with progression on at least 1 prior line of therapy. We hypothesize that autophagy is a major mechanism of resistance to BRAF inhibition in stage IV BRAF V600E colorectal cancer, and that the addition of hydroxychloroquine to standard encorafenib and cetuximab therapy will help overcome this resistance.

Conditions

Stage IV Colorectal Cancer Positive for BRAF V600E Mutation; Colorectal Cancer; Colorectal Cancer Stage IV

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  To determine the ORR by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 criteria for the combination of encorafenib, cetuximab, and hydroxychloroquine. This will be assessed based on RECIST1.1 criteria by cross-sectional imaging done every 2 cycles.

  Within 30 days (+/- 7 days) of coming off treatment

Secondary Outcomes (5)

• Progression-Free Survival (PFS)

  Up to 18 months after end of treatment

• Overall Survival (OS)

  Up to 18 months after end of treatment

• Duration of Response (DoR)

  Up to 18 months after end of treatment

• Duration of Stable Disease (DoSD)

  Up to 18 months after end of treatment

• Adverse Events

  Up to 18 months after end of treatment

Study Arms (1)

Treatment (Hydroxychloroquine)

EXPERIMENTAL

Drug: Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab

Interventions

Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab DRUG

Prior to starting therapy, patients will have a pretreatment cross-sectional scan. Patients will then begin with encorafenib 300 mg daily starting with Cycle 1 day 1; then patients will receive IV cetuximab weekly, with 400 mg/m2 on C1D1 as a loading dose and 250 mg/m2 on all other days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Treatment (Hydroxychloroquine)

Eligibility Criteria

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

You may qualify if:

• Patients must have histologically confirmed stage IV colorectal cancer positive for BRAF V600E mutation and on at least 1 prior line of systemic therapy and have not had any previous BRAF inhibitor therapy Patients must have measurable disease as defined by RECIST 1.1 See Section 7 for the evaluation of measurable disease. Baseline imaging scan will be used.
• Patients must have discontinued prior chemotherapy or targeted therapy at least 14 days prior to D1 of starting study treatment (E+C). Note: patients are allowed to start standard of care treatment with Encorafenib and Cetuximab/panitumumab (prior to registration for up to 14 days).
• Patients must be at least 18 years of age.
• Patients must exhibit an ECOG performance status of 0 or 1.\[Refer Appendix 1\]
• Patients must have adequate organ and bone marrow function as defined below. If laboratory values are outside these thresholds at screening, repeat labs can be done within a 14 day window. If lab values meet criteria at screening as delineated below, they do not need to be repeated:
• Leukocytes (WBC) ≥ 3,000/mcL
• Absolute neutrophil count (ANC) ≥ 1,500/mcL
• Hemoglobin (Hgb) ≥ 9 g/dL NOTE: Transfusions will be allowed to achieve this, but no more than 2 units of pRBC in the prior 4 weeks.
• Platelets (PLT) ≥ 100,000/mcL Transfusions will be allowed to achieve this, but no more than 2 units of platelet transfusion in the prior 2 weeks
• Total bilirubin ≤ 1.5 x Institutional upper limit of normal (ULN)
• AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN, or \< 5x ULN in presence of liver metastases.
• Creatinine, OR 1.5x ULN OR Glomerular filtration rate (GFR) eGFR is estimated GFR calculated by the C-G formula \> 50 mL/min/1.73 m2 Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ULN = upper limit of normal.
• For patients with a known history of Human immunodeficiency virus (HIV), infected patients on effective anti-retroviral therapy must have an undetectable viral load.
• For patients with a known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy ≤ 14 days prior to planned treatment start date. Note: patients are allowed to start standard of care treatment with Encorafenib and Cetuximab (prior to registration for up to 14 days). Patients who are receiving any other investigational agents for at least 28 days before the first dose of study treatment i.e. C1D1 (which is start of E+C)
• Patients receiving treatment with any of the following are not eligible:
• Cyclical chemotherapy within a period of time that was shorter than the cycle length for that treatment prior to C1D1(E+C treatment)
• Biologic therapy except bevacizumab or aflibercept, continuous or intermittent small molecule therapeutics, within a period of time that is \< 5 half-lives or \< 28 days prior to starting study treatment
• Bevacizumab or aflibercept therapy \< 21 days prior to starting study treatment
• Radiation therapy including \> 30% of the bone marrow. Note: Palliative radiation is allowed at the time of enrollment Patients with leptomeningeal disease or metastases causing spinal cord compression that are symptomatic or untreated or not stable for ≥ 90 days (must be documented by imaging) or requiring corticosteroids. Subjects on a stable dose of corticosteroids \> 28 days of no more than prednisone 10 mg daily or the equivalent, or who have been off of corticosteroids for at least 7 days before C1D1 (E+C), can be enrolled with approval of the medical monitor. Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to hydroxychloroquine, encorafenib, or cetuximab.
• Patients using any medications that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 \< 7 days prior to the start of study treatment. \[Refer Appendix 6\] Note: Grapefruit/ grapefruit juice and Seville oranges and starfruit are to be avoided during treatment. Patients with known history of acute or chronic pancreatitis. Patients with history or current evidence of severe eye disease ( e.g. Retinal Vein Occlusion (RVO) or current risk factors for RVO including uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) Patients with history of thromboembolic or cerebrovascular events ≤ 90 days prior to C1D1 (start of E+C treatment), including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli. Concurrent neuromuscular disorder that is associated with the potential of elevated Creatine Kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). Patients with known history of Gilbert's syndrome or is known to have any of the following genotypes: UGT1A1\*6/\*6, UGT1A1\*28/\*28, or UGT1A1\*6/\*28. Patients with known psoriasis or porphyria. Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following:
• History of acute myocardial infection, acute coronary syndromes (including unstable angina, coronary artery bypass graft (CABG), coronary angioplasty or stenting) within 6 months prior to C1D1 (start of E+C treatment)
• Ongoing or active infection requiring systemic treatment
• Symptomatic congestive heart failure (i.e. Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality \<6 months prior to C1D1 (start of E+C treatment), EXCEPT for atrial fibrillation or paroxysmal supraventricular tachycardia
• Uncontrolled arterial hypertension despite medical treatment Female patients who are pregnant or nursing. Patients with psychiatric illness/social situations that would limit compliance with study requirements.

Sponsors & Collaborators

• Northwestern University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Hydroxychloroquine; encorafenib; Cetuximab; Panitumumab

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

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Devalingam Mahalingam, MD, PhD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Study Coordinator

CONTACT

3126951301; cancer@northwestern.edu

Study Design

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

Study Record Dates

• First Submitted: October 10, 2022
• First Posted: October 13, 2022
• Study Start: October 10, 2022
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2028
• Last Updated: October 20, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)