Hydroxychloroquine + Encorafenib/Cetuximab for Colorectal Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
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
Prior Safety Data
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.
12345What 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).
14567What 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.
5891011Eligibility 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.
+14 more
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.
+9 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (Hydroxychloroquine)Experimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Northwestern UniversityChicago, IL
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Who Is Running the Clinical Trial?
Northwestern UniversityLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. [2021]Cetuximab (Erbitux(®)) is a monoclonal antibody that targets the epidermal growth factor receptor (EGFR). In the USA, the approval of cetuximab has been recently expanded to include the first-line treatment of patients with KRAS mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer (mCRC) when used in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin [folinic acid]). The addition of cetuximab to first-line treatment with FOLFIRI improved progression-free survival, overall survival, and objective response rates relative to treatment with FOLFIRI alone in patients with EGFR-expressing mCRC with KRAS wild-type tumors. Therefore, cetuximab plus FOLFIRI is a useful biomarker-directed option in the first-line treatment of this patient population.
Clinical use of monoclonal antibodies to the epidermal growth factor receptor in colorectal cancer. [2018]Monoclonal antibodies to the epidermal growth factor receptor (EGFR) are among the promising novel targeted therapies being explored in colorectal cancer. Two such agents that inhibit EGFR signaling by interfering with ligand-binding are cetuximab (Erbitux) and panitumumab (Vectibix). This review will address the use of cetuximab and panitumumab in chemotherapy-refractory colorectal cancer as well as in front-line therapy for the disease, consider predictors of response and resistance, and outline comparisons between these agents.
A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. [2016]This phase II trial evaluated the efficacy and safety of cetuximab combined with FOLFOX6 (leucovorin [LV] 5-fluorouracil [5-FU]/oxaliplatin) in the first-line treatment of patients with advanced or metastatic colorectal cancer.
A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. [2022]Cetuximab (Erbitux(®)) was approved for the treatment of metastatic colorectal cancer in Japan in 2008. To verify information on the safety in practical use of cetuximab, we conducted post-marketing surveillance in accordance with the conditions for approval.
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]On 2 June 2020, a marketing authorisation valid through the European Union (EU) was issued for encorafenib in combination with cetuximab in adult patients with metastatic colorectal carcinoma (mCRC) with the BRAFV600E mutation who had received prior systemic therapy. Encorafenib plus cetuximab was evaluated in a randomised phase III trial of encorafenib plus binimetinib plus cetuximab versus encorafenib plus cetuximab versus cetuximab plus irinotecan or FOLFIRI (control arm) to adult patients with BRAFV600E mCRC who had received prior therapy for metastatic disease. The median overall survival was 9.3 months [95% confidence interval (CI): 8.05-11.30] versus 5.88 months (95% CI: 5.09-7.10) for encorafenib plus cetuximab (doublet) versus the control arm, respectively [hazard ratio (HR) 0.61, 95% CI: 0.48-0.77]. Progression-free survival (PFS) was 4.27 months (95% CI: 4.07-5.45) versus 1.54 months (95% CI: 1.48-1.91) (HR 0.44; 95% CI: 0.35-0.55). The most frequent adverse events in patients receiving encorafenib plus cetuximab were fatigue, nausea, diarrhoea, acneiform dermatitis, abdominal pain, arthralgia, decreased appetite, vomiting and rash. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the EU.
Skin rash during cetuximab treatment in advanced colorectal cancer: is age a clinical predictor? [2021]The aim of this study is to evaluate the intensity and the duration of skin rash in young and elderly patients treated with cetuximab for advanced colorectal cancer, in order to define a possible relationship between age and skin toxicity.
[The efficacy of cetuximab for metastatic colorectal cancer]. [2018]Cetuximab (Erbitux) is a targeted therapy that used to treat metastatic colorectal cancer. It is classified as a "monoclonal antibody" and "signal transduction inhibitor" by binding to epidermal growth factor receptors (EGFR). We report 6 patients who responded well to cetuximab out of 8 patients with recurrent/advanced colorectal cancer who have received the drug at our hospital since November 2008. Four patients were men and 2 were women, with their ages ranging from 48 to 77 years. The primary cancers were located in the rectum (n=1), sigmoid colon (n=4), and ascending colon (n=1). Performance status (PS) was 0-1. These patients were treated with cetuximab as second-line (n=1), third-line (n=3), fifth-line (n=1), or seventh-line (n=1) therapy. Three patients received cetuximab monotherapy, while the other 3 were given CPT-11 (150 mg/m2, every 2 weeks) as concomitant therapy. Among the 3 patients receiving combination therapy, 2 patients had already received treatment with FOLFIRI. Even in the cetuximab monotherapy group, a partial response (PR) was observed in 2 patients, demonstrating a strong cytoreductive effect. Tumor markers also showed large decreases, with the percent decrease at 1 month being 31.7% and 60.8% in the monotherapy and combination therapy groups, respectively, while it was respectively 14.1% and 29.5% at 2 months. The mean progression-free survival (PFS) time and the time to treatment failure (TTF) were respectively 3.0 months and 4.5 months in the monotherapy group versus 7.3 months and 9.3 months in the combination therapy group. Acneiform rash and paronychia occurred in all 6 patients.
Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer. [2023]Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC.
Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. [2021]Encorafenib (Braftovi®) is an oral small molecule BRAF inhibitor used in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, who have received prior systemic therapy. In a clinical trial in adults with BRAF V600E-mutated mCRC who had disease progression after one or two previous regimens (BEACON CRC), encorafenib plus cetuximab was associated with a significantly longer median overall survival (OS), a higher objective response rate (ORR) and longer median progression-free survival (PFS), compared with standard therapy. Encorafenib plus cetuximab had a manageable tolerability profile in BEACON CRC. Current evidence suggests that encorafenib plus cetuximab combination therapy is an important targeted regimen for patients with mCRC and a BRAF V600E mutation who have received prior therapy.
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]Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC. As a class, BRAF inhibitors are associated with dermatologic, gastrointestinal, and renal events, as well as pyrexia and secondary skin malignancies. Adverse event (AE) profiles of specific BRAF inhibitors vary, however, and are affected by the specific agents given in combination. In patients with mCRC, commonly reported AEs of cetuximab monotherapy include infusion reactions and dermatologic toxicities. Data from the phase III BEACON CRC study indicate that the combination of encorafenib with cetuximab has a distinct safety profile. Here we review the most frequently reported AEs that occurred with this combination in BEACON CRC and best practices for managing and mitigating AEs that require more than standard supportive care.
Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer: an early post-marketing phase vigilance study. [2023]Triplet and doublet regimens of encorafenib plus cetuximab with and without binimetinib, respectively, were approved in Japan for unresectable, metastatic, BRAF V600E-mutated colorectal cancer (mCRC) that had progressed after 1-2 prior chemotherapies. This early post-marketing phase vigilance (EPPV) study collected adverse drug reactions (ADRs) from Japanese patients to ensure safety measures as appropriate.