Bevacizumab + Atezolizumab +/- Cobimetinib for Melanoma Brain Metastases

Overseen By Hussein Tawbi, MD, PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anticancer therapy, Immunosuppressants

Disqualifiers: Symptomatic brain metastases, Autoimmune disease, 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: Unknown

Duration: Up to 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two medications, bevacizumab (Avastin) and atezolizumab (Tecentriq), with or without a third drug, cobimetinib (Cotellic), in treating melanoma that has spread to the brain. Bevacizumab and atezolizumab aim to stop cancer cells from growing and spreading, while cobimetinib blocks certain enzymes that aid cancer cell growth. The goal is to determine if these drugs, when used together, can more effectively treat brain metastases from melanoma. Suitable participants have untreated melanoma that has spread to the brain but are not experiencing severe symptoms or requiring immediate surgery or radiation. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that certain treatments, like chemotherapy and hormonal therapy, should not be taken within 3 weeks before starting the study. It's best to discuss your specific medications with the trial team to ensure they don't interfere with the study.

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

A previous study found that the combination of atezolizumab and bevacizumab was safe for patients with certain liver cancers, with no major safety issues reported. This combination has been used before and is generally well-tolerated.

Research has shown that cobimetinib is safe when used with atezolizumab in patients with melanoma that has spread to the brain. While side effects can occur, they are usually manageable.

Since this trial is in Phase 2, some evidence suggests that the treatments are safe enough to continue testing. However, always discuss potential risks with your healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of atezolizumab and bevacizumab, with or without cobimetinib, for treating melanoma brain metastases because these treatments offer a unique approach compared to current options. Unlike traditional therapies that primarily rely on surgery and radiation, this combination includes atezolizumab, an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells more effectively. Bevacizumab, an anti-angiogenic drug, works by cutting off the blood supply tumors need to grow. The addition of cobimetinib, a MEK inhibitor, targets a specific pathway in cancer cells, potentially enhancing the treatment's effectiveness. This multi-faceted approach aims to provide a more comprehensive attack on the cancer, potentially leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for melanoma brain metastases?

Research has shown that using atezolizumab and bevacizumab together yields promising results for treating advanced cancers, including mucosal melanoma. This combination has been linked to better survival rates. In this trial, some participants will receive this combination, while another group will receive atezolizumab, bevacizumab, and cobimetinib. Studies have shown that adding cobimetinib significantly improves the time patients live without their cancer worsening for certain types of melanoma. Cobimetinib blocks enzymes that help cancer cells grow, potentially boosting the effects of the other drugs. Although the specific benefits for melanoma that has spread to the brain are still under investigation, current evidence for these drugs in other contexts is encouraging. ^{1 2 3 6 7}

Who Is on the Research Team?

Hussein A. Tawbi

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with untreated melanoma that has spread to the brain. Participants must be willing to use contraception, have an ECOG performance status of 0-2, and a life expectancy over 12 weeks. They should not have had certain prior treatments or suffer from conditions like autoimmune diseases, severe infections, or significant heart problems.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

Your blood clotting time is within normal limits.

You are expected to live for more than 12 weeks.

Exclusion Criteria

You are not expected to live for more than 12 weeks.

I have active tuberculosis.

I have not had severe infections in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive atezolizumab and bevacizumab with or without cobimetinib. Cycles repeat every 14 days for atezolizumab and bevacizumab, and every 28 days for cobimetinib.

Up to 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 90 days and then every 3 months.

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Bevacizumab
• Cobimetinib

Trial Overview The study is testing how well the combination of monoclonal antibodies (bevacizumab and atezolizumab) works with or without cobimetinib in treating melanoma brain metastases. It aims to see if adding cobimetinib improves treatment outcomes.

How Is the Trial Designed?

Group I: Arm II (atezolizumab, bevacizumab, cobimetinib) Experimental Treatment 4 Interventions

Patients receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Cycles with atezolizumab and bevacizumab repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients also receive cobimetinib PO TID on days 1-21. Cycles with cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (atezolizumab, bevacizumab) Experimental Treatment 3 Interventions

Participants receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 1b study involving 52 patients with advanced melanoma, first-line treatment with atezolizumab showed a confirmed objective response rate of 35%, indicating its effectiveness in this patient population.

Atezolizumab was found to be safe and tolerable, with common side effects including anemia and headache, and a median progression-free survival of 3.7 months, suggesting it can be a viable treatment option for advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line atezolizumab monotherapy in patients with advanced BRAFV600 wild-type melanoma. de Azevedo, SJ., de Melo, AC., Roberts, L., et al.[2022]

In a phase 2 study involving 65 patients with BRAFV600 mutation-positive melanoma, the combination of atezolizumab, vemurafenib, and cobimetinib showed a significant intracranial objective response rate of 42%, indicating its efficacy in treating CNS metastases.

The treatment was associated with a high incidence of grade 3 or worse adverse events (68% in the BRAFV600 mutation-positive cohort), but no treatment-related deaths were reported, suggesting that while the therapy is effective, it carries a risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Dummer, R., Queirolo, P., Gerard Duhard, P., et al.[2023]

In a phase 1b study involving 103 patients with advanced BRAFV600 wild-type melanoma who had progressed on anti-PD-1 therapy, the combination of cobimetinib and atezolizumab showed an objective response rate of 14.6% and a disease control rate of 38.8%.

The treatment was associated with significant adverse events, including diarrhea (72.8%), dermatitis acneiform (55.3%), and nausea (50.5%), highlighting the need for careful monitoring of side effects despite the limited efficacy observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild-type melanoma progressing on prior anti-programmed death-1 therapy. Sandhu, S., Atkinson, V., Cao, MG., et al.[2023]

In a phase 2 study involving 65 patients with BRAFV600 mutation-positive melanoma and CNS metastases, the combination of atezolizumab with vemurafenib and cobimetinib showed a promising intracranial objective response rate of 42%.

The treatment was associated with significant adverse events, with 68% of patients experiencing grade 3 or worse side effects, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Dummer, R., Queirolo, P., Abajo Guijarro, AM., et al.[2023]

In a phase 2 trial involving 36 patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC), pembrolizumab demonstrated activity, achieving a brain metastasis response in 22% of melanoma patients and 33% of NSCLC patients, with responses being durable for most.

The treatment had an acceptable safety profile, with serious adverse events occurring in a small percentage of patients, indicating that systemic immunotherapy could be a viable option for those with untreated or progressive brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Goldberg, SB., Gettinger, SN., Mahajan, A., et al.[2022]

In the coBRIM trial, patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma who received cobimetinib in combination with vemurafenib experienced significantly longer progression-free survival compared to those treated with vemurafenib alone.

The combination treatment also resulted in a higher overall response rate and prolonged overall survival, while maintaining a manageable safety profile, making it a valuable treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cobimetinib Plus Vemurafenib: A Review in BRAF (V600) Mutation-Positive Unresectable or Metastatic Melanoma. Keating, GM.[2019]

In a study of 185 patients with advanced melanoma treated with cobimetinib and vemurafenib, the median overall survival was 16.1 months, indicating the effectiveness of this combination therapy in a real-world setting.

The safety profile was consistent with previous studies, with serious adverse events like increased CPK and retinal detachment occurring in 3% of patients, suggesting that while the treatment is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival in adult patients with BRAFV600 mutation-positive advanced melanoma: a noninterventional ambispective study of patients with cobimetinib combined with vemurafenib during the French early access program: MELANIS study. Meyer, N., Pérol, D., Duval-Modeste, AB., et al.[2023]

Citations

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Phase II Study of BEvacizumab (Avastin) in Combination ... It is not yet known if giving bevacizumab and atezolizumab with or without cobimetinib will work better in treating patients with melanoma brain metastases.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9623232/

Atezolizumab plus Bevacizumab in Patients with ... Atezolizumab in combination with bevacizumab showed promising efficacy and manageable safety in patients with advanced mucosal melanoma.

3. cancernetwork.com cancernetwork.com/view/atezolizumab-combo-results-shows-promising-option-in-egfr-mutated-nsclc

Atezolizumab Combo Results Shows Promising Option in ... “This study demonstrates the promising efficacy of combining atezolizumab, bevacizumab, pemetrexed, and cisplatin/carboplatin in [patients with] ...

4. onclive.com onclive.com/view/atezolizumab-bevacizumab-combo-maintains-survival-advantage-in-advanced-hcc

Atezolizumab/Bevacizumab Combo Maintains Survival ... The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) continued to display improved survival compared with sorafenib ...

5. gene.com gene.com/media/press-releases/14981/2023-01-18/genentechs-tecentriq-plus-avastin-is-the

Genentech: Press Releases | Wednesday, Jan 18, 2023 The study is evaluating Tecentriq® (atezolizumab) in combination with Avastin® (bevacizumab) as adjuvant treatment following surgery for ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11799967/

interim analysis results from the phase IIIb AMETHISTA trial This interim analysis shows the safety and effectiveness of first-line atezolizumab plus bevacizumab in an Italian population of patients with unresectable HCC ...

7. onclive.com onclive.com/view/casdozokitug-plus-atezolizumab-bevacizumab-yields-antitumor-activity-in-unresectable-advanced-hcc

Casdozokitug Plus Atezolizumab/Bevacizumab Yields ... We previously performed a phase 1 study of casdozokitug as a single agent, and it demonstrated favorable safety as well as antitumor activity.