Etrumadenant-Based Combinations for Colorectal Cancer

(ARC-9 Trial)

Recruiting at 102 trial locations

Overseen By Fadi Braiteh

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of different drug combinations for people with metastatic colorectal cancer (cancer that has spread to other parts of the body). The goal is to determine if these combinations can reduce tumors and ensure their safety for patients. Participants will receive treatments such as etrumadenant (also known as AB928) and other drugs through pills or infusions. Individuals with metastatic colorectal cancer, whose disease has worsened after at least one round of specific chemotherapy, might be suitable candidates. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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.

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

Previous studies have shown that the combination of AB680, etrumadenant, and zimberelimab has a manageable safety profile. Research indicates that AB680, which blocks a protein involved in tumor growth, is generally well-tolerated. Patients in earlier trials did not experience severe side effects.

For the combination of etrumadenant, zimberelimab, and mFOLFOX-6 (a chemotherapy treatment) with or without bevacizumab (a drug that stops blood vessels from feeding tumors), etrumadenant has demonstrated safety and effectiveness in treating solid tumors. The studies suggest that this treatment does not lead to major safety concerns.

Overall, these treatments have been tested in earlier trials, and results have shown they are generally safe for patients. However, like any treatment, side effects may occur, so discussing these options with a healthcare professional is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for colorectal cancer because they introduce innovative combinations and mechanisms of action that could enhance treatment effectiveness. Unlike standard chemotherapy regimens like mFOLFOX-6, these investigational treatments combine etrumadenant, an A2a receptor antagonist, with immune checkpoint inhibitors like zimberelimab, which may boost the body's immune response against cancer cells. Additionally, AB680, a CD73 inhibitor, is used in combination therapies to potentially enhance anti-tumor activity by disrupting cancer's protective environment. These novel approaches aim to offer more effective options by targeting cancer through multiple pathways, potentially improving outcomes for patients with colorectal cancer.

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

Research has shown that a combination of the drugs etrumadenant, zimberelimab, FOLFOX chemotherapy, and bevacizumab holds promise for treating advanced colorectal cancer. In this trial, participants may receive different combinations of these drugs. Studies indicate that this combination can reduce the risk of death by 63% and slow disease progression by 73%. Etrumadenant blocks pathways that help tumors grow, while zimberelimab boosts the immune system to attack cancer cells. Another drug under study, AB680, targets a protein that allows tumors to evade the immune system. Early findings suggest these treatments are safe and may improve outcomes for patients with this type of cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Medical Director

Principal Investigator

Arcus Biosciences

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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 + Etrumadenant + Zimberelimab Experimental Treatment 3 Interventions

Participants will receive oral etrumadenant 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

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.3_suppl.404

ARC-8: Phase I/Ib study to evaluate safety and tolerability ... AB680, the first clinical-stage small-molecule CD73 inhibitor, in combination with SOC chemotherapy + Zim has a manageable safety profile consistent with that ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9381133/

Targeting CD73 with AB680 (Quemliclustat), a Novel and ... In humans, initial data show that AB680 is well tolerated and exhibits a pharmacokinetic profile (long half-life) suitable for intravenous administration (36, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04660812

NCT04660812 | An Open Label Study Evaluating the ... The primary objective of this clinical study is to evaluate the safety of etrumadenant-based combination therapy in participants with metastatic colorectal ...

4. clinicaltrial.be clinicaltrial.be/en/details/49967?active_not_recruiting=1&completed=0&enrolling_by_invitation=1&not_yet_recruiting=0&only_active=0&only_eligible=0&only_recruiting=0&per_page=20

An Open Label Study Evaluating the Efficacy and Safety of... The primary objective of this clinical study is to evaluate the safety of etrumadenant-based combination therapy in participants with metastatic ...

5. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/Gilead-and-Arcus-Announce-Etrumadenant-Plus-Zimberelimab-Regimen-Significantly-Reduced-the-Risk-of-Death-in-Third-line-Metastatic-Colorectal-Cancer/default.aspx

Press Release Details Etrumadenant plus zimberelimab, FOLFOX chemotherapy and bevacizumab significantly reduced the risk of death by 63% and risk of disease progression by 73% ...

6. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2018/Arcus-Biosciences-Announces-Final-Safety-Results-From-Phase-1-Trial-for-AB928-in-Healthy-Volunteers/default.aspx

Press Release Details AB928 was safe and well tolerated at all doses evaluated -. - Safety and pharmacodynamic data from healthy volunteer trial support selection ...

7. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2021/Arcus-Biosciences-to-Present-Preliminary-Data-from-Phase-1-Portion-of-ARC-8-Study-for-AB680-in-Metastatic-Pancreatic-Cancer-at-ASCO-GI-Symposium/default.aspx

Press Release Details - Investors & Media - Arcus Biosciences AB680 was the first small-molecule CD73 inhibitor to enter the clinic and demonstrated a favorable safety profile with a long half-life in a ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10330720/

Inhibitors of the CD73-adenosinergic checkpoint as ... We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials ...