Hydroxychloroquine + Encorafenib/Cetuximab for Colorectal Cancer

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must be taking: Encorafenib, Cetuximab

Must not be taking: CYP3A4/5 inhibitors, inducers

Disqualifiers: Chemotherapy, Radiotherapy, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: Variable, based on disease progression or toxicity

43 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Do I need to stop my current medications to join the trial?

You will need to stop any chemotherapy or targeted therapy at least 14 days before starting the trial treatment. Additionally, you cannot take medications that strongly affect certain liver enzymes (CYP3A4/5) within 7 days before starting the trial. If you are on any other medications, it's best to discuss with the trial team to see if they are allowed.

What data supports the effectiveness of the drug combination Hydroxychloroquine + Encorafenib/Cetuximab for colorectal cancer?

Research shows that the combination of encorafenib and cetuximab improved survival in patients with a specific type of colorectal cancer (BRAFV600E mutation) compared to standard treatments. Cetuximab, when used with other drugs, has also been shown to improve outcomes in colorectal cancer patients. ^{1 2 3 4 5}

What safety data exists for Hydroxychloroquine + Encorafenib/Cetuximab in humans?

The combination of encorafenib and cetuximab has been studied in patients with metastatic colorectal cancer, and common side effects include fatigue, nausea, diarrhea, skin rash, and decreased appetite. Cetuximab alone has been associated with skin rash and paronychia (nail infection). ^{1 4 5 6 7}

What makes the drug combination of Hydroxychloroquine, Encorafenib, and Cetuximab unique for colorectal cancer?

This drug combination is unique because it targets colorectal cancer with a specific BRAF V600E mutation, using a combination of a BRAF inhibitor (Encorafenib) and an epidermal growth factor receptor inhibitor (Cetuximab), which is enhanced by Hydroxychloroquine. This approach is chemotherapy-free and specifically designed for patients who have already received prior treatments, offering a targeted therapy option that can improve survival rates compared to standard therapies. ^{5 8 9 10 11}

Research Team

Devalingam Mahalingam, MBBChBAO

Principal Investigator

Northwestern University

Eligibility Criteria

Adults with stage IV colorectal cancer that has the BRAF V600E mutation, who have tried at least one other treatment but not BRAF inhibitors. They must be in good health otherwise, with no severe heart or eye conditions, and can't be pregnant or nursing. Participants need to have recovered from previous treatments and agree to use contraception.

Inclusion Criteria

I have another cancer that won't affect this treatment's safety or results.

Patients must have a QTc interval of ≤480 ms on the EKG

My organs and bone marrow are functioning well.

Exclusion Criteria

I have cancer that has spread to my brain or spinal cord.

Patients with severe eye disease, thromboembolic events, or certain neuromuscular disorders

I have a history of pancreatitis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive encorafenib, cetuximab or panitumumab, and hydroxychloroquine. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Variable, based on disease progression or toxicity

Weekly visits for IV cetuximab administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 3 months for 18 months.

18 months

Follow-up visits every 3 months

Treatment Details

Interventions

• Cetuximab
• Encorafenib
• Hydroxychloroquine

Trial Overview The trial is testing hydroxychloroquine combined with encorafenib and cetuximab (or panitumumab) on patients whose colorectal cancer has resisted prior treatments. The goal is to see if adding hydroxychloroquine helps overcome resistance to standard therapy.

Participant Groups

Group I: Treatment (Hydroxychloroquine) Experimental Treatment 1 Intervention

Cetuximab is already approved in United States, European Union for the following indications:

Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Cetuximab, a monoclonal antibody targeting the EGFR, has been approved for first-line treatment of KRAS mutation-negative metastatic colorectal cancer (mCRC) in combination with FOLFIRI, showing significant improvements in progression-free survival and overall survival.

The combination of cetuximab with FOLFIRI also resulted in higher objective response rates compared to FOLFIRI alone, making it a valuable treatment option for patients with EGFR-expressing, KRAS wild-type mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. Lyseng-Williamson, KA.[2021]

Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and show promise as therapies for colorectal cancer, particularly in cases where chemotherapy has failed.

The review discusses their effectiveness in both advanced and initial treatment settings, as well as factors that may predict patient response or resistance to these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of monoclonal antibodies to the epidermal growth factor receptor in colorectal cancer. Burtness, B.[2018]

In a phase II trial involving 82 patients with advanced colorectal cancer, the combination of cetuximab and FOLFOX6 showed an overall response rate of 44.8%, indicating its efficacy as a first-line treatment.

Patients who developed skin toxicity while on the treatment had significantly longer median survival times (21.7 months) compared to those who did not experience this side effect, suggesting a potential correlation between skin reactions and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. Boccia, RV., Cosgriff, TM., Headley, DL., et al.[2016]

In a post-marketing surveillance study involving 2126 patients with metastatic colorectal cancer, cetuximab was found to be well tolerated, with a median treatment duration of 15.3 weeks and a high incidence of adverse reactions at 89.6%.

The most common adverse reactions included skin disorders (83.7%) and infusion reactions (5.7%), primarily occurring during the first administration, indicating that while side effects are common, they align with previous reports and suggest that cetuximab is clinically useful in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Ishiguro, M., Watanabe, T., Yamaguchi, K., et al.[2022]

Encorafenib in combination with cetuximab significantly improves overall survival (9.3 months) and progression-free survival (4.27 months) in adult patients with metastatic colorectal carcinoma (mCRC) with the BRAFV600E mutation compared to standard treatments, showing a hazard ratio of 0.61 for overall survival and 0.44 for progression-free survival.

The most common side effects reported with this treatment combination include fatigue, nausea, and skin-related issues, indicating that while the treatment is effective, it does come with a range of manageable adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The EMA assessment of encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal carcinoma harbouring the BRAFV600E mutation who have received prior therapy. Trullas, A., Delgado, J., Koenig, J., et al.[2021]

In a study of 31 patients with advanced colorectal cancer treated with cetuximab, 61.3% developed skin rashes, with no significant differences in rash severity or duration between young and elderly patients (≥ 65 years).

The analysis indicated that age does not significantly influence the occurrence, duration, or severity of skin toxicity from cetuximab, suggesting that other factors may play a more critical role in skin reactions during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Skin rash during cetuximab treatment in advanced colorectal cancer: is age a clinical predictor? Giuliani, J., Marzola, M.[2021]

In a study of 8 patients with recurrent/advanced colorectal cancer, 6 patients showed a positive response to cetuximab, a targeted therapy that binds to epidermal growth factor receptors (EGFR), indicating its efficacy even in later lines of treatment.

Patients receiving cetuximab in combination with CPT-11 had significantly better progression-free survival (7.3 months) and time to treatment failure (9.3 months) compared to those on cetuximab monotherapy (3.0 months and 4.5 months, respectively), highlighting the potential benefits of combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy of cetuximab for metastatic colorectal cancer]. Katsumoto, Y., Aritake, N., Endoh, A.[2018]

The combination of cytotoxic chemotherapy (FOLFOX or FOLFIRI) with the targeted therapy encorafenib + cetuximab (E+C) shows improved antitumor activity as a first-line treatment for BRAFV600E metastatic colorectal cancer (mCRC) compared to using either treatment alone.

Using FOLFOX with E+C as initial therapy, followed by E+C with or without 5-FU for maintenance, is the most effective strategy for long-term disease control, highlighting the importance of combining these treatment modalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer. Napolitano, S., Woods, M., Lee, HM., et al.[2023]

In the BEACON CRC clinical trial, the combination of encorafenib and cetuximab significantly improved median overall survival and progression-free survival in adults with metastatic colorectal cancer harboring a BRAF V600E mutation, compared to standard therapies.

The treatment was found to have a manageable safety profile, making it a promising targeted option for patients who have already undergone previous systemic therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. Al-Salama, ZT.[2021]

The combination of the BRAF inhibitor encorafenib and the EGFR inhibitor cetuximab is the only approved targeted therapy for previously treated patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC), which is crucial given the poor prognosis associated with this mutation.

The BEACON CRC study highlights that this combination therapy has a distinct safety profile, with specific adverse events that differ from those seen with other treatments, emphasizing the need for tailored management strategies for these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events from the treatment of encorafenib plus cetuximab for patients with BRAF V600E-mutant metastatic colorectal cancer: insights from the BEACON CRC study. Tabernero, J., Velez, L., Trevino, TL., et al.[2022]

In a study involving approximately 550 Japanese patients with BRAF V600E-mutated metastatic colorectal cancer, the triplet and doublet regimens of encorafenib plus cetuximab showed a safety profile consistent with previous studies, with no deaths reported due to adverse drug reactions (ADRs).

The most common ADRs included nausea, retinal detachment, and decreased appetite, while serious ADRs were reported in 42 patients, with 20 out of 22 patients with serious eye disorders recovering during the study period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer: an early post-marketing phase vigilance study. Sakata, H., Murase, M., Kato, T., et al.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Clinical use of monoclonal antibodies to the epidermal growth factor receptor in colorectal cancer. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. [2016]

4. England pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. [2022]

5. England pubmed.ncbi.nlm.nih.gov

The EMA assessment of encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal carcinoma harbouring the BRAFV600E mutation who have received prior therapy. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Skin rash during cetuximab treatment in advanced colorectal cancer: is age a clinical predictor? [2021]

7. Japan pubmed.ncbi.nlm.nih.gov

[The efficacy of cetuximab for metastatic colorectal cancer]. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer. [2023]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Management of adverse events from the treatment of encorafenib plus cetuximab for patients with BRAF V600E-mutant metastatic colorectal cancer: insights from the BEACON CRC study. [2022]

11. Japan pubmed.ncbi.nlm.nih.gov

Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer: an early post-marketing phase vigilance study. [2023]