Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Atezolizumab

Vemurafenib

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Protein Kinase Inhibitors

Enzyme Inhibitors

Arm A BRAF mutated patients. Over a period of 6 weeks (1) + (2):

1. Vemurafenib 960 mg bid p.o. from week 1 to week 6.
2. Cobimetinib 60 mg qd p.o. from week 1 to week 3 and week 5 to week 6. Week 4 off.

After surgery and a second screening period (up to six weeks): Atezolizumab 1200 mg IV for 52 weeks

Arm B BRAF mutated patients. Over a period of 6 weeks (1) + (2) + (3):

1. Vemurafenib 720 mg bid p.o. from week 1 to week 6.
2. Cobimetinib 60 mg qd p.o. from week 1 to week 3 and from week 5 to week 6. Week 4 off.
3. Atezolizumab 840 mg IV for 2 cycles (day 1 of week 4 and day 1 of week 7).

After surgery and a second screening period (up to six weeks): Atezolizumab 1200 mg IV for 52 weeks

Arm C BRAF WT patients. Over a period of six weeks (1) + (2):

1. Cobimetinib 60 mg qd p.o. from week 1 to week 3 and from week 5 to week 6,
2. Atezolizumab 840 mg IV for 2 cycles (day 1 of week 1 and day 1 of week 4).

After surgery and a second screening period (up to six weeks): Atezolizumab 1200 mg IV for 52 weeks

Cobimetinib 60 mg qd p.o. from week 1 to week 3 and week 5 to week 6. Week 4 off.

Cobimetinib 20 MG Oral Tablet

960 (arm A) /720 (arm B) mg bid p.o. from week 1 to week 6.

Vemurafenib 240 Mg Oral Capsule

840 mg IV for 2 cycles for Arm B and C. After surgery in all arms 1200 mg IV for 52 weeks

Atezolizumab 1200 MG in 20 ML Injection

Paolo Ascierto

Neoadjuvant plus adjuvant treatment with target therapy and immunotherapy given in combination or sequence may have an anti-tumour activity and may reduce the risk of relapse in patients with high-risk resectable melanoma (stage III B / C / D and oligometastatic stage IV).

Melanoma represents a considerable health burden and an ongoing area of unmet need in oncology. Despite melanoma accounts for only 1% of diagnosed skin cancers, it is the cause of most skin cancer-related deaths. Until recently, limited effective treatment options were available to patients with advanced melanoma. Historically, response rates to conventional chemotherapy and immunomodulation therapy (interleukin-2 or interferon-γ) have been reported at approximately 5-19%.

Adjuvant immune checkpoint blockade (ICB) and target therapy improve outcomes of patients with high-risk resectable melanoma. It has recently been demonstrated that treatment with neoadjuvant and adjuvant targeted therapy (dabrafenib and trametinib) is associated with a high pathologic complete response (pCR) rate and improved outcomes over surgery alone. However, treatment with ICB has not been well studied in the neoadjuvant setting, despite preclinical studies suggesting that neoadjuvant administration of ICB is associated with improved survival and enhanced anti-tumour immune responses compared to the same therapy administered in the adjuvant setting.

The advantage of neoadjuvant trials is the availability of blood and tumour tissue samples before and after systemic therapy for the conduct of novel mechanistic and biomarker studies in the circulation and the tumour microenvironment.

Prospective neoadjuvant clinical trials with targeted (dabrafenib/trametinib combo) or immunotherapeutic agents (nivolumab alone or nivolumab/ipilimumab combo) and combinations are now running in a subgroup of highrisk melanoma patients with pooled overall promising preliminary results of high rates of pathologic complete responses (pCRs, 30-50%) and early data of positive correlation between pCR and relapse-free survival. Based on the available results to date, we aim to conduct a randomized, noncomparative phase II trial to define the role of neoadjuvant plus adjuvant target and immunotherapy, given in combination or sequence, in patients with high risk surgically resectable melanoma.This approach has the potential to define whether neoadjuvant treatment has antitumour activity and whether it reduces the risk of relapse after surgery.

The study will be conducted according to an open-label, randomized, not comparative phase II design. Three arms for a total of 88 patients will be considered.

BRAF mutated patients will be randomized in two arms: Arm A and Arm B (27 patients per arm). BRAF WT patients will be included in Arm C (34 patients).

Combination or Sequence of Vemurafenib, Cobimetinib, and Atezolizumab in High-risk, Resectable Melanoma

"NEOadjuvant Plus Adjuvant Therapy With Combination or Sequence of Vemurafenib, cobImetinib, and atezolizuMab in Patients With High-risk, Surgically Resectable BRAF Mutated and Wild-type Melanoma"

Defined as the lack of all signs of cancer in tissue samples removed during surgery

Defined as the time from randomisation to recurrence event or last follow-up

Defined as the time from the date of randomisation to the date of death due to any cause

Defined as the sum of pathologic complete responses (pCRs), near pathologic complete responses near pCRs) and pathologic partial responses (pPRs).

All AEs, Grade 3 to 4 AEs, serious adverse events (SAEs), deaths, AEs of special interest (AESIs), and AEs leading to treatment discontinuation or withdrawal from the study

Immunoscore, Circulating cytokines and chemokines profiling, Metabolomic profiling,Tumour mutational burden, Myeloid-derived suppressors cells, immune cell subtypes expression and lymphocyte activation, Additional analysis of protein levels (i.e. CCR5), DNA mutations, and/or mRNA analysis

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Combination or Sequence of Vemurafenib, Cobimetinib, and Atezolizumab in High-risk, Resectable Melanoma	NCT04722575	Melanoma	Cobimetinib 20 ... Vemurafenib 240... Atezolizumab 12...	18 Years -	Fondazione Melanoma Onlus
Combination or Sequence of Vemurafenib, Cobimetinib, and Atezolizumab in High-risk, Resectable Melanoma	NCT04722575	Melanoma	Cobimetinib 20 ... Vemurafenib 240... Atezolizumab 12...	18 Years -	Fondazione Melanoma Onlus

Spots Global Cancer Trial Database for cobimetinib 20 mg oral tablet