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

29 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well bevacizumab and atezolizumab with or without cobimetinib work in treating patients with untreated melanoma that has spread to the brain (brain metastases). Monoclonal antibodies, such as bevacizumab and atezolizumab, may interfere with the ability of tumor cells to grow and spread. Cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if giving bevacizumab and atezolizumab with or without cobimetinib will work better in treating patients with melanoma brain metastases.

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.

What data supports the effectiveness of the drug combination Bevacizumab, Atezolizumab, and Cobimetinib for treating melanoma brain metastases?

Research shows that Atezolizumab, when used with Cobimetinib, has shown activity in treating advanced melanoma, including cases with brain metastases. Additionally, Atezolizumab alone has demonstrated antitumor activity in advanced melanoma, suggesting potential effectiveness in combination therapies. ^{1 2 3 4 5}

What safety data exists for the combination of Bevacizumab, Atezolizumab, and Cobimetinib?

Studies have evaluated the safety of Atezolizumab and Cobimetinib in patients with advanced melanoma, showing that these drugs can be used together, although they may cause side effects like skin rash and diarrhea. Atezolizumab has also been studied in patients with lung cancer and brain metastases, indicating it is generally safe but can cause immune-related side effects. ^{1 2 3 4 6}

How is the drug combination of Bevacizumab, Atezolizumab, and Cobimetinib unique for treating melanoma brain metastases?

This drug combination is unique because it combines targeted therapy and immunotherapy, which have shown activity in the brain, addressing an unmet need for patients with melanoma that has spread to the brain. The combination of Bevacizumab (which inhibits blood vessel growth), Atezolizumab (an immunotherapy drug), and Cobimetinib (a targeted therapy) offers a novel approach by potentially enhancing the immune response and targeting cancer cell pathways. ^{1 2 3 7 8}

Research Team

Hussein A. Tawbi

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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 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 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]

References

1. England 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. [2023]

2. England 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. [2023]

3. England 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. [2023]

4. England 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. [2022]

5. England pubmed.ncbi.nlm.nih.gov

First-line atezolizumab monotherapy in patients with advanced BRAFV600 wild-type melanoma. [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study. [2019]

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

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

8. England 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. [2023]