Combination Therapy for Melanoma

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Antidepressants, Immunosuppressants

Disqualifiers: Prior melanoma therapy, Active malignancy, CNS metastasis, 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: 4

59 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take any anticancer treatments or investigational agents during the pre-registration period, and certain medications that cause QT prolongation are not allowed for some participants. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination therapy for melanoma?

Research shows that combining atezolizumab with cobimetinib and vemurafenib in patients with BRAF-mutated melanoma resulted in a high response rate, with 71.8% of patients showing a positive response. Additionally, the combination of cobimetinib and vemurafenib significantly improved survival rates in patients with BRAF mutation-positive melanoma. ^{1 2 3 4 5}

What safety data exists for the combination therapy involving Atezolizumab, Cobimetinib, and Vemurafenib in melanoma treatment?

The combination of Atezolizumab, Cobimetinib, and Vemurafenib has been studied for safety in patients with melanoma, showing that Atezolizumab monotherapy is generally safe and tolerable. Common side effects include anemia (low red blood cell count), headache, high blood pressure, constipation, diarrhea, low thyroid function, weakness, and pain in the limbs. ^{3 4 5 6 7}

What makes the combination therapy for melanoma unique?

This combination therapy for melanoma is unique because it combines targeted therapy with immunotherapy, using drugs like atezolizumab (an immunotherapy drug) and vemurafenib (a targeted therapy drug), which may enhance the treatment's effectiveness, especially in patients with brain metastases. ^{2 3 4 8 9}

What is the purpose of this trial?

This trial studies how well vemurafenib, cobimetinib, and atezolizumab work in treating patients with high-risk stage III melanoma. Vemurafenib and cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as atezolizumab and tiragolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving vemurafenib, cobimetinib, and atezolizumab may work better in treating high-risk stage III melanoma. Giving atezolizumab and tiragolumab together may also work better in treating high-risk stage III melanoma.

Research Team

Matthew S. Block, MD, PhD

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for adults over 18 with high-risk stage III melanoma that can be surgically removed. Participants must have a specific BRAFV600 mutation, agree to provide tissue samples, and not use other cancer treatments during the study. They should not have certain health conditions like active psoriasis or uncontrolled diabetes, nor should they be pregnant or unwilling to use contraception.

Inclusion Criteria

Negative serology for acute Epstein-Barr virus (EBV) infection (Arm C only)

Agreement to remain abstinent or use contraceptive methods

My melanoma has spread to more than one lymph node area.

Exclusion Criteria

I do not have any uncontrolled illnesses or active infections.

I have received cancer treatments or been part of a study before registering.

History of severe allergic, anaphylactic or other hypersensitivity reactions to specific agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Patients receive neoadjuvant therapy with vemurafenib, cobimetinib, atezolizumab, and tiragolumab depending on their BRAF mutation status

12 weeks

Multiple visits for drug administration

Surgery

Patients undergo surgery to remove residual tumor after neoadjuvant treatment

1 week

1 surgical visit

Adjuvant Treatment

Patients receive adjuvant atezolizumab therapy post-surgery

Up to 8 cycles, every 21 days

Regular visits for drug administration

Follow-up

Participants are monitored for recurrence-free survival and adverse events

Up to 3 years

Every 3 months

Treatment Details

Interventions

• Atezolizumab
• Cobimetinib
• Tiragolumab
• Vemurafenib

Trial Overview The trial tests how well vemurafenib and cobimetinib (which block enzymes for cell growth) work with atezolizumab and tiragolumab (monoclonal antibodies boosting immune response against cancer). It aims to see if this combination is more effective in treating patients than current methods.

Participant Groups

Group I: Arm C (atezolizumab, tiragolumab) Experimental Treatment 2 Interventions

Patients with BRAF wild-type or BRAF mutant melanoma receive atezolizumab IV over 30-60 minutes and tiragolumab IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm B - CLOSED (cobimetinib, atezolizumab) Experimental Treatment 2 Interventions

Patients receive cobimetinib as in Arm A and atezolizumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after treatment, patients undergo surgery then receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

Group III: Arm A - CLOSED (vemurafenib, cobimetinib, atezolizumab) Experimental Treatment 3 Interventions

Patients receive vemurafenib PO BID on days 1-28 and cobimetinib PO QD on days 1-21. Patients also receive atezolizumab intravenously (IV) over 30-60 minutes on days 1 and 15 of cycles 2 and 3. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after treatment, patients undergo surgery then receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeat every 21 days for up to 8 cycles 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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

SU2C (StandUp 2 Cancer)

Collaborator

Trials

1

Recruited

60+

Findings from Research

The combination of atezolizumab (anti-PD-L1) with BRAF and MEK inhibitors showed a high confirmed objective response rate of 71.8% in patients with BRAFV600-mutated metastatic melanoma, indicating strong anti-tumor activity.

This phase Ib study demonstrated that the triple therapy had manageable toxicity and resulted in a median duration of response of 17.4 months, with 39.3% of patients still responding after nearly 30 months, suggesting long-lasting effects of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Sullivan, RJ., Hamid, O., Gonzalez, R., 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 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]

Atezolizumab, an anti-PD-L1 therapy, was well tolerated in a study of 45 patients with advanced melanoma, showing that most side effects were mild (grade 1/2) and no treatment-related deaths occurred.

The treatment resulted in a 30% overall response rate and a median overall survival of 23 months, with certain biomarkers like PD-L1 expression and tumor mutational burden linked to better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Clinical Activity, and Biological Correlates of Response in Patients with Metastatic Melanoma: Results from a Phase I Trial of Atezolizumab. Hamid, O., Molinero, L., Bolen, CR., et al.[2020]

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 retrospective analysis of 40 advanced melanoma patients, a treatment regimen combining short-term CTLA-4 blockade (ipilimumab) followed by PD-1 blockade (nivolumab or pembrolizumab) achieved a best overall response rate of 55% and a disease control rate of 75%, indicating promising efficacy.

The combination therapy resulted in grade 3 and 4 adverse events in 38% of patients, suggesting that this approach may offer similar effectiveness to concurrent therapies but with potentially lower toxicity, warranting further investigation in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience. Meerveld-Eggink, A., Rozeman, EA., Lalezari, F., et al.[2020]

References

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

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. [2022]

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

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

3. 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]

4. 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]

5. 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]

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

Safety, Clinical Activity, and Biological Correlates of Response in Patients with Metastatic Melanoma: Results from a Phase I Trial of Atezolizumab. [2020]

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

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

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

The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations. [2021]

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

Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience. [2020]