Combination Therapy for Melanoma

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of treatments to determine their effectiveness against high-risk stage III melanoma, a serious form of skin cancer. The treatments include drugs like vemurafenib and cobimetinib, which block cancer cell growth, and immunotherapy drugs like atezolizumab (Tecentriq) and tiragolumab, which help the immune system attack cancer. Patients diagnosed with high-risk stage III melanoma, particularly those with nodal metastasis (cancer spread to lymph nodes), might be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in melanoma treatment.

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.

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

Research has shown that the combination of atezolizumab and tiragolumab is generally safe for patients with high-risk stage III melanoma. In one study, only 5.9% of patients experienced serious side effects related to the treatment, indicating it is usually well-tolerated.

For the combination of vemurafenib, cobimetinib, and atezolizumab, studies have found that a rash is a common side effect, affecting 75% of patients. Other common side effects include joint pain and changes in liver enzymes, occurring in at least 20% of patients. While these side effects are frequent, they can usually be managed.

Research on the combination of cobimetinib and atezolizumab has shown it to be moderately effective and safe for certain types of melanoma. This suggests the treatment might be safe for many, though individual experiences can differ.

Overall, these treatments have been studied for safety and are generally well-tolerated, but side effects can occur. It's important to discuss any concerns with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for melanoma because they offer promising new combinations and mechanisms of action. Atezolizumab and tiragolumab, used in Arm C, are both immunotherapies that work by blocking proteins that inhibit the immune system, potentially boosting the body's natural ability to fight cancer. This combination targets both PD-L1 and TIGIT pathways, which is different from many standard treatments that typically focus on the BRAF mutation. While traditional therapies for melanoma often rely on targeted drugs like vemurafenib, which directly inhibits the BRAF protein in tumors, this new approach aims to harness and amplify the immune system's response, offering a potentially powerful alternative for both BRAF wild-type and mutant melanoma cases.

What evidence suggests that this trial's treatments could be effective for high-risk stage III melanoma?

Research has shown that using vemurafenib, cobimetinib, and atezolizumab together can significantly delay the progression of certain types of melanoma. In this trial, participants in Arm A, now closed, received this combination, which extended the time before disease worsening by an average of 4.5 months for patients with BRAF V600+ melanoma compared to standard treatments.

In Arm B, also closed, participants received cobimetinib and atezolizumab together, resulting in a 45% overall response rate, with nearly half of the patients experiencing tumor shrinkage, and a 75% disease control rate, indicating the disease was kept in check.

Currently, Arm C is open, where participants receive the combination of atezolizumab and tiragolumab. This combination has shown promising results in high-risk stage III melanoma, with nearly half of the patients experiencing significant tumor shrinkage. Overall, these combinations have demonstrated potential in controlling and reducing the progression of melanoma. ^{1 3 4 6 7}

Who Is on the Research Team?

Matthew S. Block, MD, PhD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

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

Various blood and urine test results within specified ranges

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

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 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]

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]

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 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 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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40795522/

Phase II trial of neoadjuvant atezolizumab and tiragolumab ... Thirty patients had per protocol TLND. Major pathologic responses (MPR, ≤10 % viable tumor) were observed in 16/34 patients (47.1 %). With 19.9 ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0959804925004708

Phase II trial of neoadjuvant atezolizumab and tiragolumab ... Neoadjuvant immunotherapy has recently been shown to have improved efficacy compared with adjuvant therapy alone for melanoma patients with ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05060003?intr=Signatera&rank=9&tab=results

Study Results | Tiragolumab Plus Atezolizumab Versus ... These trials gather additional information about a drug's safety, efficacy, or optimal use. ... Melanoma Patients Who Are ctDNA-positive Following ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.9503

NeoACTIVATE arm C: Phase II trial of neoadjuvant ... Conclusions: Among patients with high-risk resectable stage III melanoma, neoadjuvant atezo/tira was a promising regimen with a favorable safety ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05060003

NCT05060003 | Tiragolumab Plus Atezolizumab Versus ... This study's hypothesis is that patients with stage II melanoma who test positive for circulating tumor DNA are at a higher risk for recurrence and ...

6. ejcancer.com ejcancer.com/article/S0959-8049(25)00470-8/fulltext

Phase II trial of neoadjuvant atezolizumab and tiragolumab ... In this phase II trial, we observed a major pathologic response rate to neoadjuvant treatment with the combination of atezolizumab and ...

7. targetedonc.com targetedonc.com/view/tiragolumab-plus-atezolizumab-fails-to-improve-outcomes-as-consolidation-in-nsclc

Tiragolumab Plus Atezolizumab Fails to Improve ... The 24-month PFS event-free rates were 39.0% and 38.5%, respectively. The median overall survival (OS) was 45.6 months (95% CI, 37.1–not ...