Vemurafenib Plus Cobimetinib After Radiosurgery in Patients With BRAF-mutant Melanoma Brain Metastases

NCT03430947 | Terminated Phase 2 DMC

• 2 other identifiers: TUD-CoBRIM-672017-000768-13
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 3

Brief Summary

This is a phase II, open label, non-randomised study of vemurafenib and cobimetinib after radiosurgery in adult patients with BRAFV600-mutant melanoma brain metastases. All patients will receive vemurafenib 960 mg twice a day on days 1 - 28 combined with cobimetinib 60 mg once a day on days 1 - 21 of each 28-day treatment cycle until disease progression, drug toxicity or death. The primary objective of this study is to determine the best overall response rate (BORR) in the brain. The extracranial BORR, intra- and extracranial duration of response, progression-free survival and overall survival, adverse events, quality of life and radiomics features predicting long-term local control of brain metastases and treatment-related toxicity will also be examined.

Conditions

Malignant Melanoma Stage IV; BRAF V600 Mutation; Brain Metastases

Keywords

Stereotactic radiosurgery; BRAF inhibitor; MEK inhibitor; Vemurafenib; Cobimetinib

Outcome Measures

Primary Outcomes (1)

• Best overall response rate in the brain

  rate of patients with complete response or partial response (intracranial)

  2 years

Secondary Outcomes (9)

• Extracranial best overall response rate

  2 years

• Best overall response rate calculated for the whole body tumor sites

  2 years

• Intracranial duration of response

  2 years

• Extracranial duration of response

  2 years

• Progression-free survival

  2 years

Study Arms (1)

Treatment

EXPERIMENTAL

all patients will be treated with Vemurafenib + Cobimetinib

Drug: Vemurafenib; Drug: Cobimetinib

Interventions

Vemurafenib DRUG

Vemurafenib (960 mg twice a day) will be taken on days 1 - 28 of each 28-day treatment cycle.

Treatment

Cobimetinib DRUG

Cobimetinib (60 mg once a day) will be taken on days 1 - 21 of each 28-day treatment cycle.

Treatment

Eligibility Criteria

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

You may qualify if:

• Signed informed consent
• Female and male patients ≥ 18 years of age
• Histologically confirmed metastatic melanoma (stage IV, per AJCC staging), carrying BRAF V600-mutation
• Performed SRS 14 ±7 days before baseline using a harmonized protocol in patients with at least one measurable intracranial target lesion for which the following criteria are met:
• Previously untreated (Lesions in previously irradiated area should not be selected)
• Largest diameter of ≥ 0.5 but ≤ 4 cm as determined by contrast-enhanced MRI and
• ≤ 10 brain metastases
• ECOG performance status 0 - 2
• Life expectancy ≥ 12 weeks
• Adequate bone marrow function as indicated by the following:
• ANC ≥ 1500/µL,
• Platelets ≥ 100,000/µL and
• Hemoglobin ≥ 9 g/dL
• Adequate renal function, as indicated by creatinine ≤ 1.5 x ULN
• Adequate liver function, as indicated by bilirubin \< 1.5 x ULN and AST and ALT \< 3 x ULN (documented liver metastases: AST and ALT \< 5 x ULN)

You may not qualify if:

• Symptomatic brain metastases requiring immediate local interventions such as neurosurgery or radiosurgery
• Leptomeningeal disease (also synchronous with brain metastases)
• Prior therapy with BRAF or MEK inhibitors within 12 weeks prior to baseline visit (prior therapies for metastatic melanoma including chemo-, cytokine-, immuno-, biological and vaccine-therapy will be al-lowed) A period of at least 6 weeks must be observed between the last dose of ipilimumab and the first administration of the study treatments. Prior treatment with anti-programmed cell death (PD)-1 or anti-PD ligand 1 (PD-L1) is allowed.
• Prior whole brain irradiation (Patients with prior local therapy of brain metas-tases are eligible)
• Patients receiving therapeutic steroids are not stable on corticoster-oids 2 weeks before SRS
• Active and uncontrolled infection
• Known HIV infection or active HBV or HCV infection
• Active HBV infection (chronic and acute), defined as having a posi-tive hepatitis B surface antigen (HBsAg) test at screening (past or resolved HBV infection, defined as negative HBsAg test and a posi-tive total hepatitis B core antibody test at screening, are eligible)
• Active HCV infection, defined as positive HCV antibody test and positive HCV RNA test at screening
• Intracranial radiation therapy within 14 days prior to SRS
• Extracranial radiation therapy within the last 14 days prior to baseline visit
• Treatment with strong CYP3A4/5 inhibitors (e.g. ketoconazole) and inducers (e.g. phenytoin, carbamazepine). (anticonvulsant levetiracetam is allowed; patient should be stable on levetiracetam for 2 weeks)
• Unresolved toxicity of National Cancer Institute Common Terminology Crite-ria for Adverse Events, version 4.0 (NCI v4.0) \[NCI, 2009\] Grade 2 or higher from previous anti-cancer therapy, except alopecia.
• Conditions that will interfere significantly with the absorption of drugs (e.g. Colitis ulcerosa)
• Inability to undergo MRI secondary to:

Sponsors & Collaborators

• Technische Universität Dresden: lead

Study Sites (3)

Technische Universität Dresden

Dresden, 01307, Germany

Location

Ruprecht-Karls-University of Heidelberg, Faculty of Medicine

Heidelberg, 69120, Germany

Location

Eberhard Karls University of Tübingen, University Medical Center

Tübingen, 72076, Germany

Location

MeSH Terms

Conditions

Melanoma; Brain Neoplasms

Interventions

Vemurafenib; cobimetinib

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; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

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

Study Officials

• Friedegund Meier, MD

  Technische Universität Dresden

  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

Study Record Dates

• First Submitted: January 10, 2018
• First Posted: February 13, 2018
• Study Start: July 1, 2018
• Primary Completion: February 10, 2023
• Study Completion: February 10, 2023
• Last Updated: September 14, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• Time Frame: within 5 years

Locations

DE (3)