Etrumadenant-Based Combinations for Colorectal Cancer

(ARC-9 Trial)

Recruiting at 86 trial locations

Overseen By MIchael Cecchini, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Arcus Biosciences, Inc.

Must not be taking: Antibiotics, Antivirals, Immunostimulants, Vaccines

Disqualifiers: CNS metastases, Cardiovascular disease, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 10 months

227 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase 1b/2 open-label study will evaluate the antitumour activity and safety of etrumadenant (AB928) treatment combinations in participants with metastatic colorectal cancer.

Will I have to stop taking my current medications?

The trial requires that you stop any previous anticancer treatment and systemic immunostimulatory agents at least 4 weeks before starting the study treatment. Additionally, you should not have taken therapeutic antibiotics within 2 weeks before starting the trial. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination for colorectal cancer?

Regorafenib, a component of the treatment, has been shown to improve survival in patients with metastatic colorectal cancer who have already tried other treatments. It is FDA-approved for this use and has demonstrated benefits in extending progression-free survival in various cancers. ^{1 2 3 4 5}

What safety data exists for regorafenib in colorectal cancer treatment?

Regorafenib, used for metastatic colorectal cancer, has a safety profile similar to other similar drugs, with common side effects including hand-foot skin reaction, high blood pressure, fatigue, diarrhea, and liver issues. These side effects often occur early in treatment and can be managed with dose adjustments and temporary treatment breaks. ^{2 6 7 8 9}

What makes the Etrumadenant-based drug combination unique for colorectal cancer?

The Etrumadenant-based drug combination is unique because it includes a novel CD73 inhibitor (Etrumadenant) that targets the tumor microenvironment, potentially enhancing the immune response against cancer cells, which is different from standard treatments that primarily focus on directly attacking cancer cells. ^{1 10 11 12 13}

Research Team

Medical Director

Principal Investigator

Arcus Biosciences

Eligibility Criteria

Adults with metastatic colorectal cancer who've had no more than two prior treatments can join this trial. They must have a measurable tumor, be HIV and hepatitis negative, have good organ function and performance status (able to carry out daily activities), and agree to contraception. Exclusions include certain heart conditions, active infections, recent vaccines or surgeries, other cancers within 2 years (except some skin cancers), CNS metastases, autoimmune diseases, or previous treatment with similar drugs.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

My blood and organs are functioning well.

My cancer is a type of colorectal cancer that has spread.

Exclusion Criteria

I haven't taken any immune-boosting drugs in the last 4 weeks.

I have active tuberculosis.

I have a bleeding disorder that increases my risk of bleeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive etrumadenant-based treatment combinations, including mFOLFOX-6 +/- bevacizumab, regorafenib, or chemotherapy-free combinations

10 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3-7 years

Treatment Details

Interventions

• AB680
• Bevacizumab
• Etrumadenant
• mFOLFOX-6 regimen
• Regorafenib
• Zimberelimab

Trial Overview The study is testing combinations of Etrumadenant with other cancer drugs like Zimberelimab and Bevacizumab in patients whose disease has progressed after treatment. It's an open-label trial where everyone knows what treatment they're getting; it aims to see how well these drug combos work against advanced colorectal cancer.

Participant Groups

Group I: Etrumadenant + Zimberelimab + mFOLFOX-6 +/- Bevacizumab Experimental Treatment 4 Interventions

Participants will receive oral etrumadenant in combination with zimberelimab +mFOLFOX-6 +/-bevacizumab by IV infusion.

Group II: AB680 + Etrumadent+ Zimberelimab Experimental Treatment 3 Interventions

Participants will receive oral etrmadenant in combination with AB680 + zimberelimab by IV infusion.

Group III: mFOLFOX-6 +/- Bevacizumab Active Control 2 Interventions

Participants will receive mFOLFOX-6 +/- bevacizumab by IV infusion.

Group IV: Regorafenib Active Control 1 Intervention

Participants will receive oral regorafenib

Who Is Running the Clinical Trial?

Arcus Biosciences, Inc.

Lead Sponsor

Trials

44

Recruited

7,500+

Gilead Sciences

Industry Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Findings from Research

Regorafenib is an oral multi-kinase inhibitor that has shown significant survival benefits in metastatic colorectal cancer and has been FDA approved for this use since 2012.

The drug also improves progression-free survival in patients with metastatic gastrointestinal stromal tumors and advanced hepatocellular carcinoma, leading to its FDA approval for these conditions as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib. Ettrich, TJ., Seufferlein, T.[2018]

Regorafenib significantly improves median overall survival and progression-free survival in patients with previously treated metastatic colorectal cancer (mCRC), as shown in the CORRECT trial with a regimen of 160 mg daily for 3 weeks of each 4-week cycle.

The drug has a generally acceptable tolerability profile and does not compromise health-related quality of life, making it a valuable addition to treatment options for patients with progressive mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. Carter, NJ.[2021]

Regorafenib is an effective oral multikinase inhibitor used in treating colorectal cancer, targeting multiple pathways involved in tumor growth.

Aflibercept and ramucirumab are both angiogenesis inhibitors that help treat metastatic colorectal cancer by blocking blood vessel formation, with aflibercept being the second FDA-approved anti-angiogenic agent for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New molecular targeting drugs for metastatic colorectal cancer]. Komatsu, Y., Harada, K., Fukushima, H., et al.[2023]

In a study of 43 patients aged 70 and older with metastatic colorectal cancer, regorafenib showed a disease control rate of 31.4% after 2 months, indicating it can be an effective treatment option for older patients who have failed previous therapies.

However, the treatment was associated with significant toxicities, with 35 out of 42 patients experiencing grade 3-4 adverse events, particularly fatigue, hypertension, and hand-foot skin reactions, suggesting that careful monitoring is needed, especially for patients over 80 or with impaired autonomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 - REGOLD. Aparicio, T., Darut-Jouve, A., Khemissa Akouz, F., et al.[2021]

Regorafenib is the first approved tyrosine kinase inhibitor for metastatic colorectal cancer, showing significant improvements in progression-free and overall survival in patients who had previously undergone multiple lines of chemotherapy and targeted therapies, based on results from two phase III trials.

While regorafenib has a safety profile similar to other tyrosine kinase inhibitors, it is associated with specific adverse events like hand-foot skin reaction and hypertension, which can be managed effectively through patient education and timely dose adjustments, allowing patients to continue benefiting from the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. Hofheinz, RD., Arnold, D., Kubicka, S., et al.[2015]

Regorafenib is an effective treatment for patients with metastatic colorectal cancer who have previously undergone multiple chemotherapy regimens, showing a significant improvement in overall survival compared to placebo (6.4 months vs 4 months).

The treatment is associated with manageable side effects, with the most common severe adverse events being hand-foot syndrome (17%) and asthenia (10%), indicating that while it is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Regorafenib approved in Metastatic Colorectal cancer]. André, T., Dumont, SN.[2022]

Regorafenib significantly improves overall survival by up to 2.5 months and progression-free survival by up to 1.5 months in patients with metastatic colorectal cancer (mCRC) who have not responded to standard therapies, based on phase 3 studies.

The treatment is generally well-tolerated, with most side effects being mild to moderate, and it does not negatively impact health-related quality of life compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. Dhillon, S.[2019]

Adverse events (AEs) related to regorafenib are significantly more common in patients under 65 years old and are strongly correlated with the higher starting dose of 160 mg, suggesting that younger patients may be at greater risk.

Lowering the regorafenib dose to 120 mg may reduce the incidence of AEs while maintaining efficacy, as 57% of patients recovered from AEs after dose adjustments, indicating the importance of monitoring and managing side effects for continued treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-Analysis of Regorafenib-Associated Adverse Events and Their Management in Colorectal and Gastrointestinal Stromal Cancers. Xie, G., Gong, Y., Wu, S., et al.[2020]

In a study of 49 patients with refractory metastatic colorectal cancer, the sequence of treatment with regorafenib (REG) followed by trifluridine/tipiracil (FTD/TPI) resulted in a median overall survival of 27 months, compared to 20 months for the reverse sequence.

The REG-to-FTD/TPI treatment sequence also demonstrated a higher disease control rate of 45.0%, indicating that this order may be more effective in stabilizing cancer growth compared to the FTD/TPI-to-REG sequence, which had a rate of 24.1%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib-to-trifluridine/tipiracil Versus the Reverse Sequence for Refractory Metastatic Colorectal Cancer Patients: A Multicenter Retrospective Real-life Experience. Signorelli, C., Gemma, D., Grande, R., et al.[2021]

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]

References

1. Japan pubmed.ncbi.nlm.nih.gov

[Regorafenib versus S-1 plus Bevacizumab for Metastatic Colorectal Cancer as Salvage Line-A Phase Ⅱ Study (OGSG1301)]. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Regorafenib. [2018]

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

Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. [2021]

4. Japan pubmed.ncbi.nlm.nih.gov

[New molecular targeting drugs for metastatic colorectal cancer]. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 - REGOLD. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. [2015]

7. France pubmed.ncbi.nlm.nih.gov

[Regorafenib approved in Metastatic Colorectal cancer]. [2022]

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

Regorafenib: A Review in Metastatic Colorectal Cancer. [2019]

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

Meta-Analysis of Regorafenib-Associated Adverse Events and Their Management in Colorectal and Gastrointestinal Stromal Cancers. [2020]

10. Greece pubmed.ncbi.nlm.nih.gov

Regorafenib-to-trifluridine/tipiracil Versus the Reverse Sequence for Refractory Metastatic Colorectal Cancer Patients: A Multicenter Retrospective Real-life Experience. [2021]

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

Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. [2021]

12. Switzerland 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. [2022]

13. China pubmed.ncbi.nlm.nih.gov

[Efficacy of Avastin in combination with irinotecan for metastatic colorectal cancer]. [2018]