A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-Mutant Melanoma Brain Metastasis
- Conditions
- Mutant Melanoma Brain Metastasisskin cancer spread to the brain10040900
- Registration Number
- NL-OMON49456
- Lead Sponsor
- Array Biopharma Inc.
- Brief Summary
Trial never started
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 10
Patients must meet all the following criteria to be eligible for enrollment in
the study:
1. Able to provide written informed consent. Adult patients under guardianship
may participate if permitted by local regulations with the consent of their
legally authorized guardian. All local regulations concerning patients under
guardianship must be followed.
2. Age * 18 years at the time of informed consent.
3. Histologically confirmed diagnosis of cutaneous melanoma with metastases to
the brain.
4. Presence of BRAFV600 mutation in tumor tissue previously determined by a
local PCR or NGS-based assay at any time prior to Screening or by a central
laboratory during Screening.
5. Patients are required to submit archival or fresh tissue and a blood sample
prior to enrollment. Tissue samples will be used to determine BRAFV600-mutation
status by central laboratory.
6. Must have at least 1 parenchymal brain lesion * 0.5 cm and * 4 cm, defined
as an MRI contrast-enhancing lesion that may be accurately measured in at least
1 dimension.
Note: Measurable intracranial lesions that have been previously irradiated and
have not been shown to be progressing following irradiation should not be
considered as target lesions.
7.Patients may have received the following prior therapies:
a.Safety Lead-in, Phase 2 Randomized , Phase 2 Arm A Cohort 1: May have
received prior local therapy for brain metastases including but not restricted
to brain surgery, whole brain radiotherapy (WBRT), stereotactic radiotherapy or
stereotactic radiosurgery (e.g. gamma knife, linear-accelerated-based
radiosurgery, charged particles, and CyberKnife). Multiple local (brain)
therapies or combinations of local therapies are allowed. For patients
receiving local therapy to all brain lesions (including WBRT), progression of
pre-existing lesions based on RECIST 1.1 (> 20% increase in longest diameter on
baseline scan) or new measurable lesions are required. For patients receiving
local therapy for some but not all lesions, disease progression based on RECIST
1.1 is not required as long as there are remaining brain lesions that are
measurable and not previously treated.
b.Phase 2 Arm A Cohort 2: Received no prior local therapy (e.g., brain surgery,
craniotomy, SRS or SRT) for brain metastases.
c.All patients (Safety Lead-In and Phase 2): May have received prior
immunotherapy.
d.All patients (Safety Lead-In and Phase 2): If receiving concomitant
corticosteroids must be on a stable or decreasing dose (up to a total daily
dose of 4 mg of dexamethasone or equivalent) for at least 2 weeks prior to
first dose of study treatment.
8.An ECOG PS of 0 or 1 and Karnofsky score * 80
9. Adequate bone marrow, organ function and laboratory parameters:
a. ANC * 1.5 × 109/L;
b. Hemoglobin * 9 g/dL with or without transfusions;
c. Platelets * 100 × 109/L;
d. AST and ALT * 2.5 × ULN; in patients with liver metastases * 5 × ULN;
e. Total bilirubin * 1.5 × ULN; NOTE: Patients with documented Gilbert syndrome
or hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may
be enrolled following discussion and agreement with the SponsorMedical Monitor.
f. Serum creatinine * 1.5 × ULN; OR calculated creatinine clearance > 50 mL/min
by Cockcroft-Gault formula; OR estimated glomerular filtration rate > 50
mL/min
Patients meeting any of the following criteria are not eligible for enrollment
in the study.
1.Patients with symptomatic brain metastasis (e.g., have neurologic symptoms
related to brain metastases).
2.Prophylactic or preventive anti-epileptic therapy. Note: Anti-epileptic
therapy indicated in order to prevent neurologic symptoms caused by a
preexisting condition and not related to brain metastasis is allowed.
3.Known hypersensitivity or contraindication to any component of study
treatment or their excipients.
4. Inability to swallow and retain study treatment.
5. Uveal or mucosal melanoma.
6. History of or current leptomeningeal metastases.
7.Treatment with SRS or craniotomy within 14 days prior to start of study
treatment, or treatment with whole-brain radiation within 28 days prior to
study treatment. Patients who received local therapy should have complete
recovery with no neurological sequelae.
8. Either of the following:
a. Radiation therapy to non-brain visceral metastasis within 2 weeks prior to
start of study treatment;
b. Continuous or intermittent small-molecule therapeutics or investigational
agents within 5 half-lives of the agent (or within 4 weeks prior to start of
study treatment, when half-life is unknown).
9. Patients treated in the adjuvant setting with BRAF or MEK inhibitor(s) < 6
months prior to enrollment. Patients treated in the adjuvant setting with BRAF
or MEK inhibitors * 12 months prior to enrollment are eligible. Patients who
received BRAF or MEK inhibitors in the metastatic setting are excluded.
10. Is currently participating in a study and receiving an investigational
agent; has received an investigational agent or used an investigational device
within 14 days prior to start of study treatment.
11. Patients who have undergone major surgery (e.g. inpatient procedure with
regional or general anesthesia) * 6 weeks prior to start of study treatment.
For minor surgical procedures * 6 weeks prior to start of study treatment,
consult the Sponsor Medical Monitor.
12. Patient has not recovered to * Grade 1 from toxic effects of prior therapy
before starting study treatment. NOTE: Stable chronic conditions (* Grade 2)
that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior
therapy-related endocrinopathies) are exceptions and patients with these may
enroll.
13. Impaired cardiovascular function or clinically significant cardiovascular
disease including, but not limited to, the following:
a. History of acute coronary syndromes (including myocardial infarction,
unstable angina, coronary artery bypass grafting, coronary angioplasty or
stenting) < 6 months prior to Screening;
b. Congestive heart failure requiring treatment (New York Heart Association
Grade * 2);
c. An LVEF < 50% as determined by MUGA or ECHO;
d. Uncontrolled hypertension defined as persistent systolic blood pressure *
150 mmHg or diastolic blood pressure * 100 mmHg despite current therapy;
e. History or presence of clinically significant cardiac arrhythmias (including
resting bradycardia, uncontrolled atrial fibrillation or uncontrolled
paroxysmal supraventricular tachycardia);
f. Triplicate average baseline QTcF interval * 480 msec.
14. Impairment of gastrointestinal function or disease which may significantly
alter the absorption of study tre
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary Endpoint<br /><br><br /><br>Safety Lead-in<br /><br>* Incidence of DLTs<br /><br>* Incidence and severity of AEs graded according to the NCI CTCAE version 4.03<br /><br>and changes in clinical laboratory parameters, vital signs, ECGs<br /><br>* Incidence of dose interruptions, dose modifications and discontinuations due<br /><br>to AEs<br /><br><br /><br>Phase 2<br /><br>* BMRR per mRECIST v1.1</p><br>
- Secondary Outcome Measures
Name Time Method