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.
One potential therapeutic option for pretreated patients with RAS-positive metastatic colorectal cancer (mCRC) could be hydroxychloroquine. The KRAS mutation drives uncontrolled proliferation and cell survival through pathways such as MAPK/ERK and PI3K/AKT. The pathways in KRAS-mutant tumor cells activate autophagy to recycle cellular components and sustain growth under stress conditions, such as hypoxia or nutrient deprivation. Autophagy serves as a pro-survival mechanism, enabling tumor cells to resist intrinsic stressors and treatment, such as chemotherapy or radiation therapy. Hydroxychloroquine inhibits autophagy by blocking the fusion of autophagosomes with lysosomes. This results in the accumulation of damaged organelles and toxic metabolites within the cell, ultimately triggering apoptosis. Suppressing autophagy may also disrupt tumor cell metabolism by increasing oxidative stress. In experimental models, KRAS-mutant tumors demonstrated enhanced sensitivity to autophagy inhibitors such as hydroxychloroquine. In murine studies, combining hydroxychloroquine with chemotherapy or MAPK pathway inhibitors, such as trametinib, augmented antitumor efficacy. Multiple studies have reported that hydroxychloroquine achieves rapid objective responses when combined with targeted therapy or chemotherapy. However, rapid development of acquired resistance remains a challenge. Methotrexate and capecitabine may be considered as options for overcoming acquired resistance to hydroxychloroquine. KRAS-mutant tumors frequently exhibit defects in DNA repair systems. Methotrexate inhibits thymidylate synthesis, causing accumulation of DNA damage, especially uracil misincorporation, which leads to "thymidylate-induced stress" and cell death. Cells with mutations in the KRAS gene may have increased expression of folate transporters, such as RFC or FPGS, making them more sensetive to antifolates such as methotrexate. This increases intracellular drug accumulation and cytotoxic effects. Preclinical studies have shown that exposure to methotrexate in tumor cells with KRAS mutations significantly decreases mRNA expression of the KRAS gene and total levels of KRAS protein. When combined with fluoropyrimidines like capecitabine, methotrexate may enhance suppression of DNA synthesis, which is a critical vulnerability in KRAS-mutant tumors. Capecitabine increases the sensitivity of KRAS-positive tumors to TRAIL-induced apoptosis, a process that may be amplified by hydroxychloroquine exposure. Bevacizumab can be used to improve the delivery of chemotherapy drugs to tumor cells by increasing drug concentration within the tumor through lowering vascular permeability.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
60
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.
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
First Pavlov State Medical University
Saint Petersburg, Sankt-Peterburg, Russia
RECRUITINGObjective 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).
Time frame: 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.
Time frame: From randomization until the first documentation of objective progression or death, whichever comes first (up to 24 months)
Overall Survival (OS)
Overall survival (OS) was measured as the duration (in months) from date of randomization to death resulting from any cause. Participants who had not experienced death by the time of data analysis were censored at their most recent confirmed date of survival.
Time frame: 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)
DCR defined as the proportion of participants with confirmed complete response (CR), partial response (PR), or stable disease (SD) as their best overall response, assessed using RECIST version 1.1 criteria for both target and non-target lesions. PR: A reduction of at least 30% in the total diameter of target lesions relative to the initial baseline measurements. CR: The complete resolution of all identified target lesions. Pathological lymph nodes (target or non-target) must also exhibit a short axis reduction to under 10 mm. SD: Lesions showing neither sufficient shrinkage to meet PR criteria nor sufficient growth to qualify as progressive disease (PD), using the smallest total lesion size recorded during the study as the reference point. PD: Defined as a minimum 20% increase in the total diameter of target lesions compared to the lowest recorded measurement (nadir), which must also include an absolute increase of ≥5 mm. The emergence of new lesions also constitutes PD.
Time frame: 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)
DOR was measured as the time (in months) from the initial documentation of a partial response (PR) or complete response (CR) according to RECIST version 1.1 criteria until the first confirmed instance of disease progression (PD) or death from any cause, whichever occurred earlier.
Time frame: 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
An adverse event (AE) refers to any unfavorable or unintended medical event experienced by a participant in a clinical trial involving a medicinal product, regardless of whether it is causally linked to the treatment. A treatment-emergent adverse event (TEAE) was defined as an AE that: began on or after the start of treatment, had an unspecified onset date, existed prior to treatment but worsened in severity after treatment initiation, continuing until 30 days after the final dose of the study drug or the start of subsequent anti-tumor therapy (whichever occurred first). Additionally, serious adverse events (SAEs) deemed treatment-related were classified as TEAEs even if they occurred after this 30-day period. AEs with missing or unreported onset dates were also categorized as TEAEs. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: From start of study drug administration up to approximately 38 months
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