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

This trial tests whether blocking a cellular recycling process called autophagy can help a standard two-drug cancer regimen work better in patients with a specific type of aggressive colorectal cancer. The cancer in question carries a BRAF V600E mutation, which makes tumors particularly hard to treat and prone to developing resistance to targeted therapies. The standard treatment — encorafenib (a BRAF inhibitor) plus cetuximab (an antibody targeting EGFR) — often stops working because cancer cells activate autophagy as a survival escape route, essentially digesting and recycling damaged components to stay alive under drug pressure. Hydroxychloroquine, a decades-old antimalarial drug, blocks the final step of autophagy and has been repurposed in oncology trials as a resistance-breaking strategy. By adding hydroxychloroquine to the standard doublet, researchers at Northwestern University hypothesize they can shut down this escape mechanism and restore drug sensitivity. The trial is a Phase II, open-label, single-arm study enrolling patients whose metastatic BRAF V600E colorectal cancer has progressed on at least one prior line of therapy. If the hypothesis holds, this triplet combination could offer a meaningful new option for a patient population with very limited alternatives.

• Trial is currently recruiting (as of 2026-05-26); no efficacy or safety results have been reported yet — findings listed here reflect the study's design rationale and scientific hypothesis, not outcome data.
• The central hypothesis is that autophagy induction represents a dominant resistance mechanism to BRAF inhibition in stage IV BRAF V600E colorectal cancer, based on preclinical and mechanistic evidence cited in the protocol.
• The study tests whether pharmacological autophagy inhibition via hydroxychloroquine, added to encorafenib plus cetuximab (or panitumumab), can overcome this resistance in a clinically refractory population with prior treatment progression.

This is a Phase II, open-label, single-arm clinical trial conducted at Northwestern University (NCT05576896). Eligible patients have metastatic BRAF V600E-mutated colorectal cancer with progression on at least one prior line of systemic therapy. The intervention is the addition of hydroxychloroquine to standard-of-care encorafenib combined with either cetuximab or panitumumab (anti-EGFR antibodies). Specific sample size targets, dosing schedules, primary endpoints (e.g., overall response rate, progression-free survival), and follow-up duration are not detailed in the available abstract but are registered in the full ClinicalTrials.gov protocol.

Because this is an actively recruiting trial with no published results, no conclusions about efficacy, safety, or the validity of the autophagy-resistance hypothesis can yet be drawn — all key findings above are best-effort extrapolations from the protocol rationale, and confidence in outcome-level interpretation is low. The single-arm design without a randomized comparator will make it difficult to attribute any clinical benefit definitively to the addition of hydroxychloroquine versus patient selection or natural disease variation. Hydroxychloroquine achieves only partial autophagy inhibition and may not fully suppress the pathway at tolerable doses, leaving open the question of whether incomplete blockade is sufficient for meaningful clinical impact. A future randomized Phase II or III trial comparing encorafenib/cetuximab with and without hydroxychloroquine, ideally with paired tumor biopsies measuring autophagy flux as a pharmacodynamic biomarker, would be needed to confirm the mechanism and establish clinical utility.

This trial directly extends the autophagy-in-cancer-therapy theme explored in [§63], which examines mechanistic crosstalk between autophagy modulation and colorectal cancer treatment, by moving from mechanistic characterization to an interventional clinical test in the same tumor type. The combination-resistance-reversal logic parallels [§39], which investigates metformin-phytochemical combinations to overcome single-agent resistance through metabolic and autophagy pathway modulation, underscoring a broader pattern of using autophagy or mitochondrial pathway inhibitors as resistance-breaking adjuncts across different cancer contexts. The study also parallels [§91], another Phase II trial (eRapa in familial adenomatous polyposis) testing an mTOR-autophagy axis modulator in a gastrointestinal malignancy, highlighting a convergent clinical strategy of targeting autophagic flux regulation in colorectal neoplasia. Together, these articles reflect an emerging clinical consensus — supported by preliminary mechanistic work such as [§62] on PI3K/AKT/mTOR pathway regulation in renal cell carcinoma — that autophagy inhibition or modulation is a tractable therapeutic target across multiple cancer types, though the optimal agent, timing, and combination partner remain actively investigated.

• The Mechanistic Crosstalk between Probiotics, ncRNAs, and Autophagy: Implications for Colorectal Cancer Precision Medicine
  Directly addresses autophagy mechanisms in colorectal cancer treatment, providing the mechanistic and ncRNA-level context that underpins the resistance hypothesis this trial is testing.
• Metformin-phytochemical combination therapy in metabolic dysfunction-associated steatotic liver disease: mechanistic insights and therapeutic potential
  Tests a parallel strategy of combining an autophagy/metabolic modulator (metformin) with other agents to overcome single-agent resistance, offering a comparison point for how this approach performs in a different disease setting.
• Phase 3 Trial of eRapa in Patients With Familial Adenomatous Polyposis
  Another Phase II clinical trial targeting the mTOR-autophagy axis in a gastrointestinal cancer (familial adenomatous polyposis), enabling direct comparison of trial design, endpoints, and tolerability in a related GI oncology context.
• Mechanism of Inonotus hispidus in suppressing renal cell carcinoma proliferation via regulation of the PI3K/AKT/mTOR pathway
  Examines PI3K/AKT/mTOR pathway regulation — the upstream signaling network that controls autophagy flux — in a refractory solid tumor, providing mechanistic context for why autophagy blockade may sensitize BRAF-mutated tumors to targeted therapy.