Neoadjuvant Vemurafenib + Cobimetinib + Atezolizumab in Melanoma: NEO-VC

NCT02303951 | Terminated Phase 2

• 1 other identifier: EADO_VC_NEO_1
• Study Type: interventional
• Target: 47
• Locations: 2 countries
• Sites: 7

Brief Summary

Evaluation of the efficacy, safety and biologic effects of neo-adjuvant treatment with vemurafenib + cobimetinib + atezolizumab in patients with limited metastasis of melanoma in stage IIIC/IV melanoma.

Conditions

Malignant Melanoma

Outcome Measures

Primary Outcomes (1)

• Percent of patients who actually become resectable and are resected

  Percentage of patients becoming operable after the combined treatment within 18 weeks. The primary research question is the difference of this observed proportion with verum-treatment in the study which is compared to an assumed/known proportion without treatment based on an estimation of the scientific community

  Following 18 weeks of combined treatment

Secondary Outcomes (6)

• Progression free survival time after resection

  Following 18 weeks of combined treatment

• Progression free survival

  Following 6 and 12 months of combined treatment

• Objective response

  Up to 29 months

• Tolerability (Number of patients with adverse events and number of patients who prematurely discontinued treatment due to adverse events)

  Up to 29 months

• Overall survival

  Up to 29 months

Other Outcomes (4)

• Detection of biomarkers for response to vemurafenib + cobimetinib + atezolizumab in metastatic tumor tissue

  Screening (= pre-treatment) and following 18 weeks of combined treatment

• Detection of biomarkers for response to vemurafenib + cobimetinib in blood samples

  Screening (= pre-treatment)

• Detection of differences in gene expression in metastatic tumor tissue

  Screening (pre-treatment) and following 18 weeks of combined treatment

Study Arms (1)

vemurafenib + cobimetinib + atezolizumab

EXPERIMENTAL

Run-In (week 1-4): * Day 1-21: vemurafenib 960 mg bid orally + cobimetinib 60 mg od orally * Day 22-28: vemurafenib 720 mg bid orally Triple-Treatment (week 5 ongoing): atezolizumab 840 mg Q2W i.v. + vemurafenib 720 mg bid orally + cobimetinib 60 mg od 21/7 orally (vemurafenib: daily intake; cobimetinib: 3 weeks on drug, 1 week off)

Drug: Vemurafenib; Drug: Cobimetinib; Drug: Atezolizumab

Interventions

Vemurafenib DRUG

Run-In: Day 1-21 960 mg bid orally, Day 22-28 720 mg bid orally Triple-Treatment (week 5 ongoing): 720 mg bid orally

Also known as: Zelboraf

vemurafenib + cobimetinib + atezolizumab

Cobimetinib DRUG

Run-In: Day 1-21 60 mg od orally Triple-Treatment (week 5 ongoing): 60 mg od 21/7 orally (3 weeks on drug, 1 week off)

Also known as: Cotellic

vemurafenib + cobimetinib + atezolizumab

Atezolizumab DRUG

Triple-Treatment (week 5 ongoing): 840 mg Q2W i.v

Also known as: Tecentriq

vemurafenib + cobimetinib + atezolizumab

Eligibility Criteria

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

You may qualify if:

• Signed ICF
• Age ≥ 18 years
• Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIC (locally advanced) melanoma, as defined by the AJCC, 7th revised edition
• Naïve to prior systemic anti-cancer therapy for melanoma, with the following exceptions: Adjuvant treatment with IFN, IL-2, or vaccine therapies, if discontinued at least 28 days prior to initiation of study treatment
• Adjuvant treatment with herbal therapies, if discontinued at least 7 days prior to initiation of study treatment
• Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue (archival or newly obtained) through use of a clinical mutation test approved by the local health authority
• ECOG of 0 or 1
• Decision of eligibility for neoadjuvant combined vem+cobi+atezo treatment by in-terdisciplinary tumor board. Patient with limited numbers of metastases and few organ systems involved should be selected, making surgical resection after neo-adjuvant treatment probable.
• Measurable disease by RECIST V1.1 criteria (must be outside the CNS)
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment, with the exception of amylase, lipase, and LDH where up to 28 days is acceptable
• ANC ≥ 1.5 × 109/L without granulocyte colony-stimulating factor support
• WBC count ≥ 2.5 × 109/L
• Lymphocyte count ≥ 0.5 × 109/L
• Platelet count ≥ 100 × 109/L without transfusion
• Hemoglobin ≥ 9 g/dL without transfusion

You may not qualify if:

• Candidates for direct surgery: patients with single site easily resectable metasta-sis
• Major surgical procedure or significant traumatic injury within 2 weeks prior to first dose of study drug treatment
• Palliative radiotherapy within 14 days prior to initiation of study treatment
• Active malignancy (other than BRAFV600 mutation-positive melanoma) or malig-nancy within 3 years prior to screening are excluded, with the exception of resected melanoma, resected BCC, resected cuSCC, resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or any other curatively treated malignancies from which the patient has been disease-free for at least 3 years
• a. Patients with a history of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer are eligible for the study.
• A history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, CSCR, RVO, or ne-ovascular macular degeneration
• a. Patients will be excluded from study participation if they currently are known to have any of the following risk factors for RVO: i. History of serous retinopathy ii. History of RVO iii. Evidence of ongoing serous retinopathy or RVO at baseline
• History of clinically significant cardiac dysfunction, including the following:
• Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline hypertension consistently above 159/99mmHg despite opti-mal medical management
• Unstable angina, or new-onset angina within 3 months prior to initiation of study treatment
• Symptomatic congestive heart failure, defined as NYHA Class II or higher
• Myocardial infarction within 3 months prior to initiation of study treatment
• Unstable arrhythmia
• History of congenital long QT syndrome
• QTcF ≥480 ms at screening, or uncorrectable abnormalities in serum electro-lytes

Sponsors & Collaborators

• University Hospital Tuebingen: lead

Study Sites (7)

Department of Dermatology & Skin Cancer University Hospital La Timone, Aix-Marseille University

Marseille, 13385, France

Location

Department of Dermatology, University Hospital of Nantes

Nantes, 44093, France

Location

Hopital Saint-Louis Hopitaux Universitaires Saint-Louis Laboisiere Fernand-Widal

Paris, 75010, France

Location

Department of Dermatology, Elbe Hospital

Buxtehude, 21614, Germany

Location

Universitätsklinikum Carl Gustav Carus

Dresden, 01307, Germany

Location

Department of Dermatology, University Hospital

Kiel, 24105, Germany

Location

University hospital Tübingen

Tübingen, 72076, Germany

Location

Related Publications (1)

• Gorry C, McCullagh L, O'Donnell H, Barrett S, Schmitz S, Barry M, Curtin K, Beausang E, Barry R, Coyne I. Neoadjuvant treatment for stage III and IV cutaneous melanoma. Cochrane Database Syst Rev. 2023 Jan 17;1(1):CD012974. doi: 10.1002/14651858.CD012974.pub2.

  PMID: 36648215 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Vemurafenib; cobimetinib; atezolizumab

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)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Claus Garbe, Prof.

  University Hospital Tübingen

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: Single armed, two-cohort Cohort I: Treatment with cobimetinib + vemurafenib; 45 patients enrolled; recruitment closed Cohort II: Treatment with cobimetinib + vemurafenib + atezolizumab; 45 patients planned; recruitment open

Study Record Dates

• First Submitted: November 13, 2014
• First Posted: December 1, 2014
• Study Start: January 22, 2015
• Primary Completion: May 14, 2020
• Study Completion: May 14, 2020
• Last Updated: February 3, 2021

Record last verified: 2020-05

Locations

DE (4); FR (3)