Clinical trial NCT02230306: Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastases
Official title: Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastases
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Active Melanoma Brain Metastases
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2014-09-03
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the effectiveness of the combination of vemurafenib with cobimetinib in patients with active melanoma brain metastases.


Eligibility criteria: Inclusion Criteria:

* Signed informed consent
* Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600-mutation
* Melanoma must be documented to contain a BRAFV600 mutation by a CLIA approved laboratory
* At least one measurable intracranial target lesion for which all of the following criteria are met:

  1. previously untreated or progressive according to RECIST 1.1 (equal to or greater than 20% increase in longest diameter on baseline scan) after previous local therapy (SRS and/or craniotomy)
  2. immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy (SRS and/or craniotomy)
  3. largest diameter of ≥ 0.5cm but ≤ 4 cm as determined by contrast-enhanced MRI
* Prior therapies for extracranial metastatic melanoma including chemo-, cytokine-, immuno-, biological- and vaccine-therapy will be allowed but prior BRAF or MEK not allowed
* ECOG PS 0-2
* Life expectancy \>12 weeks
* Age 18 years or older
* Adequate bone marrow function as indicated by the following:

  1. ANC \> 1500/µL
  2. Platelets ≥ 100,000/µL
  3. Hemoglobin \> 9 g/dL
* Adequate renal function, as indicated by creatinine =/\< 1.5 x the upper limit of normal (ULN)
* Adequate liver function, as indicated by bilirubin =/\< 1.5 x ULN
* AST or ALT \< 3 x ULN (patients with documented liver metastases: AST and/or ALT =/\< 5 x ULN)
* Able to swallow pills
* Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year
* Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the Investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.)

Exclusion Criteria:

* Active infection
* Prior therapy with BRAFi and/or MEKi
* Leptomeningeal disease
* Symptomatic brain metastases requiring immediate local interventions such as craniotomy or SRS
* Increasing corticosteroid dose in 7 days prior to administration of first dose of study drug. Symptomatic patients that have stable or decreasing corticosteroid use in the past 7 days will be allowed
* Current use of therapeutic warfarin
* Unresolved toxicity of National Cancer Institute Common Terminology Criteria 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
* Inability to undergo MRI secondary to metal, claustrophobia, Gadolinium Contrast allergy
* Pregnant, lactating, or breast feeding women
* Prior radiation therapy within the last 14 days
* Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
* Unwillingness or inability to comply with study and follow-up procedures
* The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:

  1. St. John's wort or hyperforin
  2. Grapefruit juice
* History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, Retinal Vein Occlusion (RVO), or neovascular macular degeneration
* Uncontrolled glaucoma with intra-ocular pressures \> 21mmHg
* Serum cholesterol ≥ Grade 2
* Hypertriglyceridemia ≥ Grade 2
* Hyperglycemia (fasting) ≥ Grade 2
* History of clinically significant cardiac dysfunction, including the following:

  1. Current unstable angina
  2. Current symptomatic congestive heart failure of NYHA class 2 or higher
  3. History of congenital long QT syndrome or mean QTcF \> 450 msec at baseline or uncorrectable electrolyte abnormalities
  4. Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible)
  5. Left ventricular ejection fraction (LVEF) below 50%
  6. Uncontrolled Arrhythmias
  7. Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within the previous 6 months

Primary outcomes:
measure: Objective Intracranial Response (OIRR)
timeFrame: Until disease progression, less than or equal to 5 years.
Secondary outcomes:
measure: Overall Response
timeFrame: Until disease progression, less than or equal to 5 years.
measure: Progression-free Survival (PFS)
timeFrame: Up to 5 years
measure: Overall Survival (OS)
timeFrame: Up to 5 years
measure: Duration of Response
timeFrame: Until disease progression, less than or equal to 5 years.
measure: Immune Modulation in Peripheral Blood
timeFrame: Up to 5 years
measure: Early Markers of Progression in Peripheral Blood
timeFrame: Up to 5 years
measure: Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br)
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Harriet Kluger
state: Connecticut
city: Iowa City
country: United States
facility: Mohammed Milhem, MD
state: Iowa
city: New York
country: United States
facility: Anna Pavlick, MD
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: Ravi Amaravadi, MD
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Melissa Burgess, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Memorial Sloan Kettering Cancer Center
name: Richard Carvajal, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NYU Clinical Cancer Center
name: Anna Pavlick, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Univ of Iowa
name: Mohammed Milhem, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Univ of Pennsylvania
name: Ravi Amaravadi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale New Haven Hospital
name: Harriet Kluger, MD
role: PRINCIPAL_INVESTIGATOR
References: