Hydroxychloroquine + FOLFIRI + Bevacizumab for Colorectal Cancer

Recruiting at 1 trial location

Overseen By Eric Chen, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Steroids, Anticonvulsants

Disqualifiers: Pregnancy, Nursing, Concurrent malignancy, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

Duration: Up to 48 months

155 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of medications to treat metastatic colorectal cancer (mCRC) that hasn't undergone systemic therapy. The researchers aim to determine the effectiveness of adding hydroxychloroquine (a drug often used for malaria and autoimmune diseases) to the standard FOLFIRI-bevacizumab treatment for individuals with a specific marker called "DTP-signature high." Bevacizumab, also known as Avastin, is part of this treatment. It suits those with confirmed colorectal cancer that can't be surgically removed and who haven't received chemotherapy or other systemic therapy for their metastatic disease. Participants will receive treatments every two weeks until disease progression occurs or they experience intolerable side effects. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received radiotherapy, chemotherapy, biological therapy, or investigational treatment less than four weeks before the first dose of the trial drugs.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you have had recent treatments like chemotherapy or radiotherapy, you must wait at least four weeks before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that hydroxychloroquine (HCQ) is usually well-tolerated by people with colorectal cancer. In studies, patients with advanced colorectal cancer took HCQ alongside other treatments, and it was considered safe. Some research even suggests that HCQ might help strengthen the immune system and slow tumor growth.

Past studies have shown that the FOLFIRI-bevacizumab combination is commonly used and well-understood for treating colorectal cancer. While these treatments can have side effects, doctors know what to expect and monitor them carefully.

This trial is in an early phase, meaning researchers are still closely studying the treatment's safety. Reaching this stage suggests there is enough evidence of its safety to test it further. Prospective participants should stay in close contact with the medical team and report any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatment for colorectal cancer, which typically involves chemotherapy combinations like FOLFIRI plus bevacizumab, the new approach incorporates hydroxychloroquine. Hydroxychloroquine is traditionally used for malaria and autoimmune conditions, but here it may enhance the effectiveness of the chemotherapy by interfering with cancer cells' survival mechanisms. Researchers are excited because this combination could potentially improve treatment outcomes by targeting cancer cells more effectively, offering a fresh angle on tackling this tough-to-treat cancer.

What evidence suggests that this trial's treatments could be effective for metastatic colorectal cancer?

In this trial, participants will divide into two groups to evaluate the effectiveness of adding hydroxychloroquine to standard treatments for advanced colorectal cancer. Research shows that hydroxychloroquine, when combined with cancer drugs like FOLFIRI and bevacizumab, may enhance the immune system's ability to fight colorectal cancer. Studies suggest this combination might also inhibit autophagy, a process some cancer cells use to survive. Although one study found limited success with hydroxychloroquine and other medications, other research indicates it can help prevent colon cancer growth in animals. Overall, these findings offer hope that adding hydroxychloroquine could enhance the effectiveness of standard treatments for advanced colorectal cancer. ^{1 3 4 5 6}

Who Is on the Research Team?

Eric Chen, MD

Principal Investigator

Princess Margaret Cancer Centre

Are You a Good Fit for This Trial?

This trial is for adults with metastatic colorectal cancer that can't be surgically removed, have a specific DTP-high signature, and haven't had treatment for their metastatic disease yet. They should be in good physical condition (ECOG 0-1), not pregnant or nursing, without certain blood disorders or eye diseases, and must not have had major surgery recently.

Inclusion Criteria

I have never had a retinal disorder.

My condition is identified as high DTP-signature for HCQ treatment.

I am not pregnant.

Exclusion Criteria

I haven't had cancer treatment in the last 4-6 weeks or still have side effects.

My brain metastases are stable, and I haven't taken steroids or anticonvulsants for 3 months.

I am not pregnant or nursing.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive FOLFIRI-beva and HCQ until disease progression, intolerable side effects, withdrawal of consent, or death

Up to 48 months

Every 2 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Fluorouracil
• Hydroxychloroquine
• Irinotecan
• Leucovorin

Trial Overview The study tests the combination of FOLFIRI-beva (5-FU, irinotecan, bevacizumab) with hydroxychloroquine on patients who haven't been treated before for their advanced colorectal cancer. It's a Phase II trial to see how well this combo works in those with high levels of a specific tumor marker called DTP-signature.

How Is the Trial Designed?

Group I: High DTP-signature Experimental Treatment 5 Interventions

Take HCQ, 400 mg by mouth, twice daily. Receive FOLFIRI+bevacizumab (irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46 - 48 hours, bevacizumab 5 mg/kg), intravenously, every 2 weeks

Group II: Low DTP-signature Active Control 4 Interventions

Receive FOLFIRI+bevacizumab (irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46 - 48 hours, bevacizumab 5 mg/kg), intravenously, every 2 weeks

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

In a study of 1,401 patients with metastatic colorectal cancer, adding bevacizumab to first-line oxaliplatin-based chemotherapy significantly improved progression-free survival (PFS) from 8.0 months to 9.4 months compared to placebo.

While overall survival was longer in the bevacizumab group (21.3 months vs. 19.9 months), this difference was not statistically significant, indicating that while bevacizumab helps delay disease progression, it may not necessarily extend overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study. Saltz, LB., Clarke, S., Díaz-Rubio, E., et al.[2023]

In a phase IV trial involving 209 treatment-naïve patients with metastatic colorectal cancer, the combination of bevacizumab and FOLFIRI resulted in a median progression-free survival (PFS) of 11.1 months and a median overall survival (OS) of 22.2 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with most adverse events being mild (grade 1/2), while serious side effects like neutropenia and venous thromboembolic events occurred in over 10% of patients, indicating manageable safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Sobrero, A., Ackland, S., Clarke, S., et al.[2022]

In a study of 107 patients with metastatic colorectal cancer, the combination of irinotecan plus bevacizumab showed similar efficacy to FOLFIRI plus bevacizumab, with median progression-free survival of 6.4 months versus 5.8 months, and overall survival of 16.6 months versus 16.5 months, respectively.

Omitting fluorouracil from the FOLFIRI regimen resulted in fewer adverse events, such as nausea and neutropenia, suggesting that irinotecan plus bevacizumab may be a safer second-line treatment option for patients who are refractory to fluoropyrimidines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of omitting fluorouracil from FOLFIRI plus bevacizumab as second-line chemotherapy for patients with metastatic colorectal cancer. Matsubara, Y., Masuishi, T., Ogata, T., et al.[2023]

The FOLFOXIRI-Bev chemotherapy regimen shows a high overall response rate of 69% in patients with initially unresectable metastatic colorectal cancer, based on a systematic review of 11 studies involving 889 patients.

This treatment leads to significant surgical conversion rates, with approximately 39.1% of patients becoming eligible for surgery and 28.1% achieving R0 resection, indicating its potential to improve outcomes for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFOXIRI Plus Bevacizumab as Conversion Therapy for Patients With Initially Unresectable Metastatic Colorectal Cancer: A Systematic Review and Pooled Analysis. Tomasello, G., Petrelli, F., Ghidini, M., et al.[2022]

In a study involving 1,401 patients with metastatic colorectal cancer, adding bevacizumab to oxaliplatin-based chemotherapy significantly improved progression-free survival (PFS) from 8.0 months to 9.4 months compared to placebo.

While overall survival was slightly better in the bevacizumab group (21.3 months vs. 19.9 months), this difference was not statistically significant, and the response rates were similar between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. Saltz, LB., Clarke, S., Díaz-Rubio, E., et al.[2023]

In a study of 49 metastatic colorectal cancer patients treated with bevacizumab and FOLFIRI-3, 22.4% achieved a partial response and 53.1% had stable disease, indicating that this combination can be effective after previous chemotherapy failures.

The treatment resulted in a median progression-free survival of 7 months and overall survival of 13 months, with manageable adverse events, suggesting that while there are risks, the therapy can be a viable option for patients who have exhausted other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab plus FOLFIRI-3 in chemotherapy-refractory patients with metastatic colorectal cancer in the era of biotherapies. Ghiringhelli, F., Vincent, J., Guiu, B., et al.[2021]

In a meta-analysis of 11 randomized controlled trials involving 3178 patients, the combination of bevacizumab (BEV) with the FOLFOX regimen significantly improved the objective response rate and cancer control rate compared to FOLFOX alone.

However, this combination treatment was associated with a higher incidence of gastrointestinal adverse reactions, indicating a trade-off between increased efficacy and potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of bevacizumab combined with FOLFOX regimen in the treatment of advanced colorectal cancer: A systematic review and meta-analysis. Zhang, H., You, J., Liu, W., et al.[2023]

Bevacizumab (Avastin) effectively targets VEGF to inhibit tumor angiogenesis, showing a safety profile that includes mostly mild to moderate side effects such as hypertension and proteinuria, which are manageable in clinical settings.

The side effects associated with bevacizumab, including rare but serious events like gastrointestinal perforation and arterial thrombosis, do not typically exacerbate the toxicity of standard chemotherapy, making it a suitable adjunct treatment for metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. Gordon, MS., Cunningham, D.[2015]

The treatment of metastatic colorectal cancer (mCRC) in Serbia has improved significantly over the past decade, with combination therapies like 5-FU/LV with oxaliplatin or irinotecan showing better efficacy than 5-FU/LV alone.

Sequential therapy using FOLFIRI and FOLFOX has been identified as the most effective treatment strategy, outperforming other two-drug combinations and demonstrating comparable effectiveness to existing therapies in terms of time to progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic treatment of colorectal cancer in Serbia: what have we done and what can we offer in the new century? Popov, I.[2019]

In a study of 14 patients with advanced colorectal cancer who had previously undergone chemotherapy, the combination of bevacizumab with FOLFIRI showed a response rate of 28.5%, with one complete response and three partial responses, indicating its potential efficacy in this heavily treated population.

The treatment was generally well tolerated, with manageable side effects; serious complications like hypertension, bowel perforation, or thromboembolic events were not observed, suggesting a favorable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab plus infusional 5-fluorouracil, leucovorin and irinotecan for advanced colorectal cancer that progressed after oxaliplatin and irinotecan chemotherapy: a pilot study. Kwon, HC., Oh, SY., Lee, S., et al.[2022]

The combination of FOLFOXIRI and bevacizumab demonstrated a promising progression-free survival (PFS) rate of 74% at 10 months in patients with unresectable metastatic colorectal cancer, based on a phase 2 study involving 57 patients.

The treatment was found to be safe, with no unexpected adverse events reported, although common serious side effects included neutropenia and hypertension, indicating that while effective, careful monitoring for these side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Masi, G., Loupakis, F., Salvatore, L., et al.[2022]

Bevacizumab, a monoclonal antibody that targets VEGF, significantly improves response rates, time to tumor progression, and overall survival in patients with advanced colorectal cancer when added to fluorouracil-based chemotherapy regimens, based on two clinical trials.

While bevacizumab shows efficacy in treating advanced colorectal cancer, it is associated with serious safety concerns, including thromboembolic events, hypertension, hemorrhage, and gastrointestinal perforation, highlighting the need for careful monitoring and further studies comparing its effectiveness with other chemotherapy options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab for advanced colorectal cancer. Hadj Tahar, A.[2013]

In a study of six patients with unresectable colorectal cancer treated with bevacizumab, the combination chemotherapy was well-tolerated, with most adverse drug reactions being grade 2 or less.

Only one patient experienced grade 3 neutropenia, and there were no specific adverse effects directly related to bevacizumab, suggesting it can be safely used in combination with chemotherapy for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A clinical experience in treatment with bevacizumab for unresectable colorectal cancer]. Fujimoto, T., Yoshimatsu, K., Yokomizo, H., et al.[2016]

In patients with unresectable RAS wild-type metastatic colorectal cancer, first-line bevacizumab-based chemotherapy significantly reduces the risk of dermatological and renal adverse events, but increases the risk of cardiovascular issues like hypertension and arrhythmia.

Conversely, cetuximab-based chemotherapy is associated with a higher incidence of dermatological and renal adverse events, particularly rashes and electrolyte disorders, highlighting the need for careful selection of targeted therapies based on safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability on Serious Adverse Events of First-Line Bevacizumab and Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. Han, YN., Choi, YJ., Rhie, SJ.[2022]

Citations

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Vorinostat and hydroxychloroquine improve immunity and ... VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.3545

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3. clinicaltrials.gov clinicaltrials.gov/study/NCT06949982

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4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006295216301307

Therapeutic effect of hydroxychloroquine on colorectal ... We found that HCQ treatment dramatically protected against colitis, colon carcinogenesis and tumor growth in a murine AOM/DSS model. These effects were ...

5. academic.oup.com academic.oup.com/oncolo/article/27/9/716/6585299

Phase I Trial of Regorafenib, Hydroxychloroquine, and ... There was no evident anti-cancer activity, with a median progression-free survival of 1.8 months and a median overall survival of 5.2 months. No ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27288548/

Therapeutic effect of hydroxychloroquine on colorectal ... Our data presented herein may help guide the clinical use of HCQ as a prevention and treatment strategy for CAC. Keywords: Colitis-associated ...