ATRA + Bevacizumab + Atezolizumab for Colorectal Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Syed M. Kazmi

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Breakthrough Therapy

Trial Summary

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.

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}

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.

Trial 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 (Other)
• Atezolizumab (Monoclonal Antibodies)
• Bevacizumab (Monoclonal Antibodies)

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Texas Southwestern Medical Center Dallas, TX

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center Lead Sponsor

Genentech, Inc. Industry Sponsor

References

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

Targeted therapy of colorectal cancer: clinical experience with bevacizumab. [2019] Advanced colorectal cancer remains an urgent health concern, despite improvements in systemic chemotherapy. Targeted therapeutics promise effective tumor therapy with minimal side effects. Angiogenesis (the formation of new blood vessels) is essential for tumor growth and metastasis and may be an ideal target in the search for new antineoplastic agents. Vascular endothelial growth factor is one of the best characterized of the proangiogenic growth factors that regulate angiogenesis and is a logical target in colorectal cancer therapy. Bevacizumab (Avastin; Genentech Inc.; South San Francisco, CA), a humanized murine monoclonal antibody directed at vascular endothelial growth factor, is being evaluated in the treatment of various types of cancer. It has shown promising efficacy in phase II clinical trials in patients with metastatic colorectal cancer. Addition of bevacizumab at a dose of 5 mg/kg to chemotherapy (5-fluorouracil plus leucovorin) resulted in a higher objective response rate (40% versus 17%), longer time to disease progression (9.0 versus 5.2 months), and longer median survival time (21.5 versus 13.8 months). Hypertension and thrombosis were the principal safety concerns, but were manageable. Further phase II/III studies of bevacizumab, administered with 5-fluorouracil plus leucovorin, with or without irinotecan and/or oxaliplatin, in colorectal cancer, are under way.

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] Cotargeting vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 may produce anticancer activity in refractory metastatic colorectal cancer (mCRC). The clinical benefit of atezolizumab combined with chemotherapy and bevacizumab remains unclear for the treatment of mCRC.

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] Bevacizumab combined with S-1 and raltitrexed demonstrated positive antitumor efficacy and acceptable toxicity. This combination might represent a treatment option for refractory metastatic colorectal cancer.

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

The horizon of antiangiogenic therapy for colorectal cancer. [2015] Vascular endothelial growth factor (VEGF) plays a crucial role in the growth and metastatic spread of cancer. Bevacizumab (Avastin) is the first commercially available VEGF inhibitor, earning U.S. Food and Drug Administration (FDA) approval in February 2004. In combination with fluorouracil (5-FU)-based chemotherapy, this agent significantly prolongs overall and progression-free survival of patients with metastatic colorectal cancer. This review details the emerging role of the drug, its unique side effects, and other practical considerations related to bevacizumab therapy. Ongoing trials attempting to define additional indications for bevacizumab as well as the development of other promising angiogenesis inhibitors are also reviewed.

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] Bevacizumab (Avastin) significantly improves overall survival (OS) and progression-free survival (PFS) when combined with first-line irinotecan (IFL) plus bolus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic colorectal cancer (CRC). This open-label, phase IV trial evaluated the efficacy and safety of first-line bevacizumab in combination with IFL and infusional 5-FU/LV (FOLFIRI).

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

Managing patients treated with bevacizumab combination therapy. [2015] The anti-angiogenic agent bevacizumab (Avastin) has been rationally designed to target vascular endothelial growth factor (VEGF), a key mediator of tumor angiogenesis. Based on its limited roles in adults, VEGF inhibition using bevacizumab would be expected to have limited side effects. Furthermore, because its mechanism of action is different to that of standard chemotherapeutic agents, bevacizumab would not be expected to cause typical cytotoxic agent-related toxicity or to exacerbate the toxicity of concomitant chemotherapy. We have reviewed clinical trials published to date, primarily in metastatic colorectal cancer, and describe the safety profile of bevacizumab. The review focuses on hypertension, proteinuria, arterial thrombosis, effects on wound healing, bleeding and gastrointestinal (GI) perforation, which are the principal bevacizumab-related events seen in clinical trials. These events are for the most part mild to moderate in severity and clinically manageable (hypertension, proteinuria, minor bleeding) or occur uncommonly (wound healing complications, GI perforations and arterial thrombosis). The side-effect profile of bevacizumab makes it a suitable adjunct to standard chemotherapy in settings where efficacy has been demonstrated, and it is now approved for use in the USA, the European Union and other markets worldwide.

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

Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer. [2023] Since its approval for the first-line treatment of metastatic colorectal cancer (mCRC), bevacizumab has become a standard treatment option in combination with chemotherapy for patients with mCRC. Bevacizumab has demonstrated efficacy in combination with a number of different backbone chemotherapy regimens, and its widespread use has introduced several important questions regarding the selection and optimization of bevacizumab-based treatment regimens, its use in various patient populations, and the identification of associated adverse events. This review discusses the results of several phase II and phase III clinical trials, as well as large observational studies, to address the use of bevacizumab in the treatment of patients with mCRC in the first-line setting.

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] Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy (FOLFOXIRI; fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours. We aimed to provide preliminary evidence of benefit from the addition of the anti-PD-L1 agent atezolizumab to first-line FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer.

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

Atezolizumab for the treatment of colorectal cancer: the latest evidence and clinical potential. [2022] Atezolizumab is a fully humanized, engineered monoclonal antibody that specifically targets PD-L1, key molecule in the cancer-immunity pathway. Atezolizumab is currently approved for the treatment of metastatic non-small-cell lung cancer and advanced urothelial carcinomas. Areas covered: In this review, we will present the available data supporting the efficacy of atezolizumab for the treatment of metastatic colorectal cancer (mCRC). We will also provide an update on the ongoing/future clinical trials evaluating the role of atezolizumab for the treatment of CRC in different settings (alone or in combination with other checkpoint inhibitors and/or targeted therapies). So far, a small subgroup of mCRC (those with deficiency in mismatch repair - dMMR) appears to benefit significantly from checkpoint inhibitors. As expected, further research is needed to develop biomarkers, effective therapeutic strategies and novel combinations to overcome immune escape resistance and achieve better responses with minimal toxicities. Expert opinion: Interim analyses from ongoing early-phase studies in mCRC have shown encouraging activity of atezolizumab in combination with chemotherapy and/or targeted therapies, especially with MEK inhibitor cobimetinib. Within the next few years, this PD-L1 checkpoint inhibitor will likely be included as one of the treatment options for CRC, at least for patients with dMMR.