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

NCT04722575 | Active Not Recruiting Phase 2

• 1 other identifier: NEO-TIM
• Study Type: interventional
• Target: 95
• Locations: 1 country
• Sites: 6

Brief Summary

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).

Conditions

Melanoma

Keywords

resectable melanoma; BRAF mutated; high risk melanoma; wild type

Outcome Measures

Primary Outcomes (1)

• Pathologic Complete Response (pCR) rate (Centrally/Independently determined)

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

  At surgery (from week 8 to week 9)

Secondary Outcomes (5)

• Recurrence-free survival (RFS)

  At 2-years, 3-years and at the end of the study

• Overall survival (OS)

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years

• pORR

  At surgery (from week 8 to week 9) after neoadjuvant treatment and at disease relapse up to 5 years

• Safety - adverse events

  Continuosly during the trial while on treatment or within 30 days after the last study treatment

• Molecular and immunophenotypic changes

  At baseline, prior to surgery, every 12 weeks during adjuvant treatment and at the disease relapse up to 5 years

Study Arms (3)

ARM A

EXPERIMENTAL

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

Drug: Cobimetinib 20 MG Oral Tablet; Drug: Vemurafenib 240 Mg Oral Capsule; Drug: Atezolizumab 1200 MG in 20 ML Injection

ARM B

EXPERIMENTAL

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

Drug: Cobimetinib 20 MG Oral Tablet; Drug: Vemurafenib 240 Mg Oral Capsule; Drug: Atezolizumab 1200 MG in 20 ML Injection

ARM C

EXPERIMENTAL

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

Drug: Cobimetinib 20 MG Oral Tablet; Drug: Atezolizumab 1200 MG in 20 ML Injection

Interventions

Cobimetinib 20 MG Oral Tablet DRUG

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

Also known as: Cotellic

ARM A; ARM B; ARM C

Vemurafenib 240 Mg Oral Capsule DRUG

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

Also known as: Zelboraf

ARM A; ARM B

Atezolizumab 1200 MG in 20 ML Injection DRUG

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

Also known as: Tecentriq

ARM A; ARM B; ARM C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients of either sex aged ≥18 years;
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form;
• Patients must have histologically or cytologically confirmed Stage IIIB/C/D or oligometastatic stage IV1 resectable melanoma. The definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumour Conference attended by melanoma medical and surgical oncology staff. Resectable tumours are defined as having no significant vascular, neural or bony involvement. Only cases where a complete surgical resection with tumour-free margins can safely be achieved are defined as resectable;
• All patients must have a BRAF V600E/K mutation status known;
• Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team;
• Patients must have measurable disease, defined by RECIST 1.1;
• ECOG performance status 0-1; \*
• Patients must have organ and marrow function
• Absence of any psychological, familiar or social condition that may affect compliance with study protocol and schedule follow-up;
• Female subjects of childbearing potential must have a negative pregnancy test result at baseline and must practice a reliable method of contraception for the total study duration plus 23 weeks (i.e. 30 days plus the time required for experimental drugs to undergo five half-lives) after the last dose of experimental drugs; \*
• Men who are sexually active with women of childbearing potential must practice a reliable method of contraception for the total study duration plus 31 weeks (i.e. 80 days plus the time required for experimental drugs to undergo five half-lives) after the last dose of experimental drugs.

You may not qualify if:

• Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug; \*
• Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, thyroid cancer (except anaplastic) or any cancer from which the patient has been disease-free for 2 years;
• Any major surgery within the last 3 weeks;
• Pregnancy and/or breast feeding or of childbearing potential and not practicing a reliable method of birth control;\*
• Unwillingness or inability to follow the procedures required in the protocol; \*
• Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity;\*
• Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at therapeutic levels\*
• Patients with a history of uncontrolled cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy;
• Subjects with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment; \*
• Prior BRAF or MEK directed therapy; patients who have received prior interferon are eligible;
• History of retinopathy or any finding at ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular de generation;
• Presence of any of the following risk factors for RVO: a) Uncontrolled glaucoma with intraocular pressures ≥ 21mmHg; b) Serum cholesterol ≥Grade 2; c) Hypertriglyceridemia ≥ Grade 2; d) Hyperglycaemia (fasting) ≥Grade 2;
• Correct QT interval \> 450msec to baseline, history of congenital long QT syndrome;
• Uncontrolled medical condition among which endocrine disorders (such as hypothyroidism, hyperthyroidism and diabetes mellitus);
• Other severe medical or psychiatric conditions (like depression) or abnormalities of laboratory tests that may increase the risk associated with study participation or the assumption of Vemurafenib, Atezolizumab and Cobimetinib or that may interfere with the interpretation of study results, which in the judgment of the Investigator can make the patient not eligible for the study;

Sponsors & Collaborators

• Fondazione Melanoma Onlus: lead
• Clinical Research Technology S.r.l.: collaborator

Study Sites (6)

Ospedale S.M. Annunziata - Azienda USL Toscana Centro

Bagno a Ripoli, Firenze, 50012, Italy

Location

IRCCS - Istituto Scientifico Romagnolo per la Cura e lo Studio dei Tumori (I.R.S.T) S.r.l.

Meldola, Forlì-Cesena, 47014, Italy

Location

Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori

Milan, Milano, 20133, Italy

Location

Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"

Naples, Naples, 80131, Italy

Location

Istituto Oncologico Veneto

Padua, Padova, 35128, Italy

Location

IRCCS San Martino - IST

Genova, 16132, Italy

Location

MeSH Terms

Conditions

Melanoma

Interventions

cobimetinib; Tablets; Vemurafenib; atezolizumab; Injections

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations; Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Paolo Ascierto

  Fondazione Melanoma Onlus

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: January 18, 2021
• First Posted: January 25, 2021
• Study Start: October 12, 2020
• Primary Completion: December 15, 2023
• Study Completion (Estimated): June 1, 2027
• Last Updated: March 13, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (6)