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.
PRIMARY OBJECTIVES: I. To estimate the percentage of patients with stage III BRAFV600 mutated (BRAFm) melanoma that achieves a pathologic complete response after 12 weeks of neoadjuvant vemurafenib/cobimetinib/atezolizumab (neoadjuvant phase). II. To estimate the percentage of patients with stage III BRAF-wild-type (BRAFwt) melanoma that achieves a pathologic complete response after 12 weeks of neoadjuvant cobimetinib/atezolizumab (neoadjuvant phase). III. To estimate the percentage of patients with stage III melanoma that achieves a pathologic complete response (pCR) after 12 weeks of neoadjuvant atezolizumab/tiragolumab (neoadjuvant phase). IV. To assess recurrence-free survival (RFS) in patients with stage III BRAFm melanoma after neoadjuvant vemurafenib/cobimetinib/ atezolizumab, surgery, and adjuvant atezolizumab (adjuvant phase). V. To assess RFS in patients with stage III BRAFwt melanoma after neoadjuvant cobimetinib/atezolizumab, surgery, and adjuvant atezolizumab (adjuvant phase). VI. To assess RFS in patients with stage III melanoma after neoadjuvant atezolizumab/tiragolumab, surgery, and adjuvant atezolizumab (adjuvant phase). SECONDARY OBJECTIVES: I. To determine the frequency of adverse events among patients with stage III BRAFm melanoma receiving neoadjuvant vemurafenib / cobimetinib / atezolizumab followed by surgery followed by adjuvant atezolizumab. II. To determine the frequency of adverse events among patients with stage III BRAFwt melanoma receiving neoadjuvant cobimetinib/atezolizumab followed by surgery followed by adjuvant atezolizumab. III. To determine the frequency of adverse events among patients with stage III melanoma receiving neoadjuvant atezolizumab/tiragolumab followed by surgery followed by adjuvant atezolizumab. TRANSLATIONAL OBJECTIVES: I. To determine the association between pretreatment, on treatment, post-neoadjuvant and post-adjuvant treatment soluble PD-L1 (sPD-L1) and RFS in patients with stage III melanoma receiving neoadjuvant vemurafenib / cobimetinib / atezolizumab or cobimetinib/atezolizumab, or atezolizumab/tiragolumab, followed by surgery and adjuvant atezolizumab. II. To determine the association between pretreatment, on treatment, post-neoadjuvant and post-adjuvant treatment intracellular bim in tumor-related T cells and RFS in patients with stage III melanoma after neoadjuvant vemurafenib/cobimetinib/atezolizumab or cobimetinib/atezolizumab, or atezolizumab/tiragolumab, followed by surgery and adjuvant atezolizumab. III. Evaluate associations between pre and post-neoadjuvant treatment molecular features of melanomas and the tumor immune microenvironment in responders versus non-responders with multiplex immunofluorescence (MxIF) (including T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains \[TIGIT\]) and ribonucleic acid-sequencing (RNA-Seq) in patients with stage III melanoma after neoadjuvant vemurafenib/cobimetinib/atezolizumab or cobimetinib/atezolizumab, or atezolizumab/tiragolumab, followed by surgery and adjuvant atezolizumab. IV. To determine the association between pretreatment tumor PD-L1, pCR, and RFS in patients with stage III melanoma receiving neoadjuvant vemurafenib/ cobimetinib/ atezolizumab or cobimetinib/atezolizumab, or atezolizumab/tiragolumab, followed by surgery and adjuvant atezolizumab. V. To evaluate changes in cell-free deoxyribonucleic acid (DNA) over time to determine whether these changes correlate with clinical outcomes, including pathologic complete response and cancer progression. VI. To compare T cell receptor diversity/clonality in pretreatment tumor, tumor and uninvolved lymph node from the time of surgery, as well as blood from before treatment, after neoadjuvant treatment, after surgery, and after adjuvant treatment. VII. To compare the frequency of neoantigen-specific T cells in pretreatment tumor, tumor and uninvolved lymph node from the time of surgery, as well as blood from before treatment, after neoadjuvant treatment, after surgery, and after adjuvant treatment. VIII. To compare peripheral blood mononuclear cell subsets from before treatment, after neoadjuvant treatment, after surgery, and after adjuvant treatment via multiparametric mass cytometry (CyTOF). IX. To assess whether treatment response to neoadjuvant systemic therapy in the index biopsy-proven metastatic node is indicative of the overall response in the nodal basin. X. To evaluate whether baseline or changes over time in microbiome samples correlate with clinical outcomes, including pathologic complete response and cancer progression. OUTLINE: Patients are assigned to Arm C. ARM A (BRAF mutant): Patients receive vemurafenib orally (PO) twice daily (BID) on days 1-28 and cobimetinib PO once daily (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. (CLOSED TO ACCRUAL) ARM B (BRAF wild-type): 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. (CLOSED TO ACCRUAL) ARM C: 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. 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. After completion of study treatment, patients are followed every 3 months for up to 3 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
59
Mayo Clinic in Florida
Jacksonville, Florida, United States
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, United States
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Pathologic complete response rate (pCR) in patients with stage III BRAFm (mutant) melanoma (neoadjuvant phase)
Pathologic complete response rate defined as the percentage of patients with no residual disease found in the surgical specimen among the patients who began neo-adjuvant protocol treatment. An interval estimate will be obtained using the formula for a 90% binomial confidence interval for one sample proportion.
Time frame: After 12 weeks of therapy
Pathologic complete response rate in patients with stage III BRAFwt (wild type) melanoma (neoadjuvant phase)
Pathologic complete response rate defined as the percentage of patients with no residual disease found in the surgical specimen among the patients who began neo-adjuvant protocol treatment. An interval estimate will be obtained using the formula for a 90% binomial confidence interval for one sample proportion.
Time frame: After 12 weeks of therapy
Median recurrence-free (RFS) rate (adjuvant phase)
Recurrence-free survival is defined as the time from surgery to radiographic or histologic evidence of local, regional, or distant recurrence of melanoma or death due to any cause. For each regimen, the distribution of recurrence-free survival times \[denoted as RFS(t)\] will be estimated using the Kaplan-Meier method. A 90% confidence interval for V(t) = log \[-log (RFS(t)\] will be constructed and then the inverse transformation exp\[-exp v(t)\] will be used to obtain a confidence for RFS(t).
Time frame: From surgery assessed up to 3 years
Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) (neoadjuvant phase)
For each cohort, the frequency and severity of toxicities will be documented using the CTCAE criteria and tabulated for the neo-adjuvant phase and post-operative visit separately.
Time frame: After 12 weeks of therapy
Change in the uptake on Positron emission tomography (PET)/computed tomography (CT) results
For each cohort, the percent change in the uptake on PET/CT scan taken at the completion of neo-adjuvant treatment from that on PET/CT scan taken prior to the start of neo-adjuvant treatment will be determined. Also, the appearance of new sites of uptake in the post neo-adjuvant treatment scan and lack of uptake in the areas where uptake was seen in the pre-treatment scan will be noted.
Time frame: Baseline to end of neo-adjuvant treatment
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