ATRA + Bevacizumab + Atezolizumab for Colorectal Cancer

Overseen By Carrie Manwaring

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Texas Southwestern Medical Center

Must be taking: Fluoropyrimidine, Irinotecan, Oxaliplatin

Must not be taking: Immunotherapy, Corticosteroids, Antibiotics, others

Disqualifiers: Autoimmune disease, Hypertension, Infection, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

22 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had chemotherapy, radiotherapy, or other cancer therapy within 3 weeks before starting the study treatment, and you must not be on any other investigational agents for the cancer under study within 28 days prior to starting the trial.

What data supports the effectiveness of the drug combination ATRA, Bevacizumab, and Atezolizumab for colorectal cancer?

Bevacizumab, when combined with chemotherapy, has shown promising results in improving survival rates and slowing disease progression in patients with metastatic colorectal cancer. It targets a protein that helps tumors grow new blood vessels, which is crucial for their growth and spread. ^{1 2 3 4 5}

Is the combination of ATRA, Bevacizumab, and Atezolizumab generally safe for humans?

Bevacizumab (Avastin) is generally safe for humans, with side effects like high blood pressure, protein in urine, and minor bleeding being mild to moderate and manageable. Serious side effects like wound healing issues, gastrointestinal perforations, and blood clots are uncommon. There is no specific safety data available for ATRA or Atezolizumab in the provided research. ^{1 2 3 6 7}

How is the drug combination of ATRA, Bevacizumab, and Atezolizumab unique for colorectal cancer?

This drug combination is unique because it combines ATRA, which is not typically used for colorectal cancer, with Bevacizumab and Atezolizumab, targeting both blood vessel growth and the immune system to potentially enhance treatment effectiveness. This approach is novel as it explores the synergy between these drugs to improve outcomes in colorectal cancer, especially in cases where standard treatments have failed. ^{2 3 5 8 9}

What is the purpose of this trial?

The main purpose of this clinical trial is to learn about the good and the bad effects of all trans retinoic acid (ATRA), atezolizumab and bevacizumab as a possible treatment for advanced colorectal patients. Participants will be treated with the following combination of these drugs: 1. ATRA will be given in a pill form to be taken twice a day at home for 7 days starting on day 1 of a cycle. 2. Atezolizumab will be given through a vein in arm or through mediport over 60-90 minutes every 2 weeks in the outpatient chemotherapy infusion centers at UTSW. 3. Bevacizumab will be given through a vein in arm or through mediport over 20-40 minutes every 2 weeks in the outpatient chemotherapy infusion centers at UTSW.

Research Team

Syed M. Kazmi

Principal Investigator

University of Texas Southwestern Medical Center

Eligibility Criteria

This trial is for adults over 18 with advanced stage IV colon adenocarcinoma. They must have tried at least two systemic chemotherapies and their tumors should be proficient in DNA mismatch repair or stable microsatellite status. Adequate organ function and certain blood levels are required.

Inclusion Criteria

My tumor is proficient in DNA repair, as shown by a specific test.

My tumor is stable and not prone to genetic changes, as confirmed by specific DNA tests.

I know my cancer's DNA repair or instability status.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of ATRA, atezolizumab, and bevacizumab. ATRA is taken orally twice a day for 7 days, while atezolizumab and bevacizumab are administered intravenously every 2 weeks.

24 months

Bi-weekly visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• all trans Retinoic Acid
• Atezolizumab
• Bevacizumab

Trial Overview The trial tests a combination of ATRA (pill form), Atezolizumab, and Bevacizumab (both via vein) on colorectal cancer patients to assess the benefits and side effects. Treatments occur every two weeks at UTSW outpatient centers.

Participant Groups

Group I: Treatment Arm Experimental Treatment 3 Interventions

* ATRA orally 45 mg/m2 daily in 2 divided doses days 1-7, repeat every 14 days * Atezolizumab IV D1, 840 mg every 14 days * Bevacizumab IV D1, 10 mg/kg every 14 days

all trans Retinoic Acid is already approved in United States, European Union for the following indications:

Approved in United States as Vesanoid for:

• Acute promyelocytic leukemia

Approved in European Union as Tretinoin for:

• Acute promyelocytic leukemia

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

Bevacizumab, a targeted therapy that inhibits vascular endothelial growth factor, significantly improves treatment outcomes in metastatic colorectal cancer when added to standard chemotherapy, showing a higher objective response rate (40% vs. 17%) and longer median survival (21.5 months vs. 13.8 months).

While bevacizumab is associated with manageable safety concerns such as hypertension and thrombosis, its efficacy in extending time to disease progression (9.0 months vs. 5.2 months) highlights its potential as a valuable addition to colorectal cancer treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapy of colorectal cancer: clinical experience with bevacizumab. Fernando, NH., Hurwitz, HI.[2019]

In a phase 2 clinical trial involving 133 patients with refractory metastatic colorectal cancer, the addition of atezolizumab to capecitabine and bevacizumab therapy resulted in a median progression-free survival (PFS) of 4.4 months compared to 3.6 months for the placebo group, indicating a potential benefit, although not clinically meaningful.

Patients with microsatellite-stable disease and those without liver metastasis showed greater benefits from the combination therapy, suggesting that specific patient characteristics may influence the efficacy of atezolizumab in this treatment context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial. Mettu, NB., Ou, FS., Zemla, TJ., et al.[2022]

In a phase II trial involving 44 patients with refractory metastatic colorectal cancer, the combination of bevacizumab, S-1, and raltitrexed demonstrated a 15.9% objective response rate and a disease control rate of 54.5%, indicating potential effectiveness in this challenging patient population.

The treatment was well tolerated, with a median progression-free survival of 110 days and overall survival of 367 days, suggesting that this combination therapy could be a viable option for patients who have not responded to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab Combined with S-1 and Raltitrexed for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies: A Phase II Study. Chen, Y., Zhou, YW., Cheng, K., et al.[2021]

Bevacizumab (Avastin) is an FDA-approved VEGF inhibitor that significantly improves overall and progression-free survival in patients with metastatic colorectal cancer when used alongside fluorouracil-based chemotherapy.

The review highlights the unique side effects of bevacizumab and discusses ongoing trials exploring its potential for additional cancer indications and the development of new angiogenesis inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The horizon of antiangiogenic therapy for colorectal cancer. Olszewski, AJ., Grossbard, ML., Kozuch, PS.[2015]

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]

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]

Bevacizumab is an effective first-line treatment for metastatic colorectal cancer (mCRC) when used in combination with various chemotherapy regimens, as supported by multiple phase II and phase III clinical trials.

The review highlights the need for careful selection and optimization of bevacizumab-based regimens, considering patient populations and potential adverse events associated with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer. Strickler, JH., Hurwitz, HI.[2023]

In a phase 2 study involving 218 patients with previously untreated metastatic colorectal cancer, the addition of atezolizumab to the standard chemotherapy regimen (FOLFOXIRI plus bevacizumab) significantly improved median progression-free survival to 13.1 months compared to 11.5 months in the control group.

The treatment was found to be safe, with the most common serious side effects being neutropenia and diarrhoea, although there were two treatment-related deaths in the atezolizumab group, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial. Antoniotti, C., Rossini, D., Pietrantonio, F., et al.[2022]

Atezolizumab, a monoclonal antibody targeting PD-L1, shows promising efficacy in treating metastatic colorectal cancer (mCRC), particularly in patients with deficient mismatch repair (dMMR), indicating a potential new treatment avenue for this subgroup.

Ongoing clinical trials suggest that atezolizumab may be even more effective when combined with chemotherapy or targeted therapies, such as the MEK inhibitor cobimetinib, paving the way for its inclusion in future treatment protocols for mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab for the treatment of colorectal cancer: the latest evidence and clinical potential. Tapia Rico, G., Price, TJ.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Targeted therapy of colorectal cancer: clinical experience with bevacizumab. [2019]

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

Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Bevacizumab Combined with S-1 and Raltitrexed for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies: A Phase II Study. [2021]

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

The horizon of antiangiogenic therapy for colorectal cancer. [2015]

5. 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]

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

Managing patients treated with bevacizumab combination therapy. [2015]

7. England pubmed.ncbi.nlm.nih.gov

Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Atezolizumab for the treatment of colorectal cancer: the latest evidence and clinical potential. [2022]