Trial Title:
Defactinib and Avutometinib, With or Without Encorafenib, for the Treatment of Patients With Brain Metastases From Cutaneous Melanoma
NCT ID:
NCT06194929
Condition:
Melanoma
Conditions: Official terms:
Melanoma
Brain Neoplasms
Melanoma, Cutaneous Malignant
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Cohort A will evaluate the hypothesis that avutometinib and defactinib will have clinical
benefit in terms of response rate and/or for prolonging organ specific PFS in patients
with cutaneous melanoma and at least one untreated brain metastases after at least one
line of immunotherapy (Cohort A), compared to historical controls.
Cohort B will evaluate the hypotheses that avutometinib, defactinib, and encorafenib will
have clinical benefit in terms of response rate and/or for prolonging organ specific PFS
in patients who have received at least one prior line of immunotherapy and also may have
received at least one line of prior BRAF/MEK therapy, compared to historical controls.
Cohort B will also include a limited dose escalation cohort using a BOIN design
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Defactinib
Description:
Defactinib will be administered at 200 mg twice daily orally per arm description.
Arm group label:
Phase II, Defactinib and Avutometinib (Cohort A)
Arm group label:
Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B)
Arm group label:
Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B)
Intervention type:
Drug
Intervention name:
Avutometinib
Description:
Avutometinib will be administered at 3.2 mg twice a week orally per arm description.
Arm group label:
Phase II, Defactinib and Avutometinib (Cohort A)
Arm group label:
Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B)
Arm group label:
Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B)
Intervention type:
Drug
Intervention name:
Encorafenib
Description:
Encorafinib administered orally per arm description.
Arm group label:
Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B)
Arm group label:
Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B)
Summary:
The goal of this interventional clinical trial is to provide proof-of-principle data for
the biologic activity of defactinib in combination with avutometinib in brain metastases
from melanoma, and to define the potential role of the combination with mutant BRAF
inhibitors or after BRAF/MEK inhibitors in BRAF V600E/K mutant tumors, in individuals
with advanced melanoma who experience the development or progression of brain metastases
after treatment with immune checkpoint inhibitors.
The main questions it aims to answer are:
- What is the preliminary response rate of defactinib and avutometinib in patients
with RAS mutant, BRAF mutant, NF1 mutant, triple RAS/BRAF/NF1 wild type (wt)
melanoma (including RAF fusions)?
- What is the safety and tolerability of the combination of defactinib, avutometinib,
and encorafenib in patients with BRAF V600E/K mutant melanoma with at least one
untreated brain metastases?
- What is the preliminary response rate of the three drug combination of defactinib,
avutometinib, and encorafenib in patients with BRAF V600E/K mutant melanoma.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age ≥ 18 years at the time of informed consent.
- Provide written informed consent and comply with the study protocol as judged by the
Investigator. Of note, If the subject has an impairment that prevents him/her from
providing written consent, the site may follow local institutional procedures for
obtaining consent.
- Histologically confirmed diagnosis of cutaneous melanoma with radiographically
confirmed metastases to the brain.
- Must have a tumor with known RAS, BRAF, and NF1 mutation status using a validated
testing method prior to enrollment.
- Cohort A: RAS, BRAF, NF1, or triple wildtype
- Cohort B: BRAF V600E or BRAF V600K
- Must have at least 1 untreated (no prior resection or radiation of the target
lesion) parenchymal brain metastasis with minimal dimensions of ≥ 0.5 cm diameter
and maximal dimensions ≤ 4 cm diameter, measured from a gadolinium enhanced MRI T1
sequence.
- Note: Subject may have received prior resection or radiation therapy for prior
brain metastases.
- Must have received at least 1 line of prior systemic immunotherapy.
- For Cohort B, may have received 1 line of prior BRAF or MEK inhibitor therapy.
- An ECOG Performance Status of 0 or 1, or Karnofsky score >= 70
- Adequate bone marrow, organ function and laboratory parameters:
- ANC ≥ 1.5 × 109/L;
- Hemoglobin ≥ 9 g/dL with or without transfusions;
- Platelets ≥100,000/mm2;
- AST and ALT ≤ 2.5 × ULN; in patients with liver metastases ≤ 5 × ULN;
- 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
- Serum creatinine ≤ 1.5 × ULN; OR calculated creatinine clearance > 50 mL/min by
Cockcroft-Gault formula; OR estimated glomerular filtration rate > 50
mL/min/1.73m2.
- International normalized ratio (INR), prothrombin time (PT), or activated
partial thromboplastin time (aPTT) as follows:
- In the absence of therapeutic intent to anticoagulate the patient:
- INR < 1.5 × ULN.
- PT < 1.5 × ULN.
- aPTT < 1.5 × ULN.
- INR or PT and aPTT within therapeutic limits (according to the
medical standard in the institution).
- Adequate cardiac function with left ventricular ejection fraction ≥
55% by echocardiography (ECHO) or multiple-gated acquisition (MUGA)
scan.
- For women (any individual assigned female at birth) who are not postmenopausal (ie,
< 2 years after last menstruation) or surgically sterile (absence of ovaries and/or
uterus) and who are sexually active, must have a negative serum pregnancy test and
agree to use a highly effective method of contraception for the duration of the
study and for 30 days following the last dose of study drug.
- Male patients (any individual assigned male at birth) of reproductive potential must
avoid pregnancy in partners who are women of childbearing potential, and such
partners should not consider getting pregnant during the study and for at least 90
days after treatment is discontinued or longer if requested by local authorities.
Male patients are considered to be of reproductive potential unless permanently
sterile by bilateral orchidectomy or vasectomized with appropriate post-vasectomy
documentation of absence of sperm in ejaculate.
- Adequate recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any
prior treatments, unless AE(s) are clinically nonsignificant and/or stable on
supportive therapy per the treating investigator. Exceptions include alopecia and
peripheral neuropathy grade ≤ 2.
Exclusion Criteria:
- Receiving other investigational agents.
- Prior systemic anti-cancer therapy or any investigational therapy ≤ 28 days or
within five half-lives prior to starting study treatment, whichever is shorter.
- Patients with symptomatic brain metastasis, defined as neurologic symptoms with
localization attributable to an untreated brain metastases with severity >= Grade 2
by CTCAE criteria.
- History of allergy or hypersensitivity to any of the study treatments or any of
their excipients.
- Inability to swallow and retain study treatment.
- Uveal or mucosal melanoma.
- History of or current leptomeningeal metastases.
- QTcF > 450 msec if male and QTcF > 470 msec if female.
- Any hemorrhage or bleeding event that is ≥ Grade 3 based on the National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) or Grade 2
intracranial hemorrhage within 4 weeks prior to the start of study treatment.
- Uncontrolled or severe cardiac disease (eg, history of unstable angina, myocardial
infarction, coronary stenting, or bypass surgery within the last 6 months prior to
initiation of study treatment), symptomatic congestive heart failure, serious
uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation), requirement
for inotropic support or use of devices for cardiac conditions (eg,
pacemakers/defibrillators), or hypertension (patients with systolic blood pressure
[BP] of > 160 mm Hg or diastolic BP of > 100 mm Hg despite optimal medical
management are to be excluded).
- History of interstitial lung disease, history of slowly progressive dyspnea and
unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary
hypersensitivity pneumonitis, or symptomatic pleural effusion.
- Active, known, or suspected uncontrolled autoimmune disease, which required therapy
in the past 2 years, including but not limited to systemic lupus erythematosus,
Hashimotos thyroiditis, scleroderma, polyarteritis nodosa, or autoimmune hepatitis.
- Known HIV infection with a detectable viral load within 6 months of the anticipated
start of treatment. Note: Participants on effective antiretroviral therapy with an
undetectable viral load within 6 months of the anticipated start of treatment are
eligible for this trial.
- Systemic active infection including tuberculosis (clinical evaluation that includes
clinical history, physical examination, radiographic findings, and TB testing in
line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg)
result), or hepatitis C. Note: Participants with a past or resolved HBV infection
(defined as the presence of hepatitis B core antibody [anti-HBc] and absence of
HBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody are
eligible only if polymerase chain reaction is negative for HCV RNA.
- History of bleeding diathesis (irrespective of severity) in the absence of
therapeutic anticoagulation.
- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection.
- Any condition that could make the patient noncompliant with the study procedures
and/or study requirements, as judged by the Investigator.
- Active skin disorder that has required systemic therapy within the past 1 year.
- History of rhabdomyolysis.
- Concurrent ocular disorders:
- Patients with history of glaucoma, history of retinal vein occlusion (RVO),
predisposing factors for RVO, including uncontrolled hypertension, uncontrolled
diabetes.
- Patients with history of retinal pathology or evidence of visible retinal
pathology that is considered a risk factor for RVO, intraocular pressure > 21
mm Hg as measured by tonometry, or other significant ocular pathology, such as
anatomical abnormalities that increase the risk for RVO.
- Patients with active or chronic, visually significant corneal disorders, other
active ocular conditions requiring ongoing therapy or clinically significant
corneal disease that prevents adequate monitoring of drug-induced keratopathy.
Examples of visually significant corneal disorders include corneal
degeneration, active or recurrent keratitis, and other forms of serious ocular
surface inflammatory conditions. Visually significant corneal disorders do NOT
include dry eyes, blepharitis, and uncomplicated corneal erosions.
- Patients with a history of hypersensitivity to any of the active (avutometinib,
defactinib, encorafenib) or inactive ingredients of the investigational products.
- Exposure to medications (with or without prescriptions), supplements, herbal
remedies, or foods with potential for drug-drug interactions with study
interventions within 14 days prior to the first dose of study intervention and
during the course of therapy, including:
- Strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactions
with both avutometinib and defactinib.
- Strong CYP2C9 inhibitors or inducers, due to potential drug-drug interactions
with defactinib.
- Strong P-glycoprotein (P-gp) inhibitors or inducers, due to potential drug-drug
interactions with both avutometinib and defactinib.
- Strong breast cancer resistance protein (BCRP) inhibitors or inducers, due to
potential drug-drug interactions with avutometinib.
- Concomitant treatment with warfarin. Patients who require anticoagulation but cannot
discontinue warfarin must be excluded from the study.
- Participants taking other prohibited medications in protocol, including anticancer
therapy or investigational agents and colony-stimulating factors (CSFs). A washout
period of prohibited medications for a period of at least five half-lives or as
clinically indicated should occur before the start of treatment.
- The diagnosis of another malignancy within ≤ 2 years before study enrollment, except
for those considered to be adequately treated with no evidence of disease or
symptoms and/or will not require therapy during the study duration (i.e., basal cell
or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the
cervix, or low-grade prostate cancer with Gleason Score ≤ 6)
- Any other condition that would, in the Investigator's judgment, contraindicate the
subject's participation in the clinical study due to safety concerns or compliance
with clinical study procedures (e.g., infection/inflammation, intestinal
obstruction, unable to swallow medication, [subjects may not receive the drug
through a feeding tube], social/ psychological issues, etc.)
- Medical, psychiatric, cognitive, or other conditions that may compromise the
subject's ability to understand the subject information, give informed consent,
comply with the study protocol or complete the study.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Huntsman Cancer Institute
Address:
City:
Salt Lake City
Zip:
84112
Country:
United States
Status:
Recruiting
Contact:
Last name:
Rachel Kingsford
Phone:
801-585-0115
Email:
rachel.kingsford@hci.utah.edu
Investigator:
Last name:
Howard Colman, MD, PhD
Email:
Principal Investigator
Start date:
February 8, 2024
Completion date:
January 15, 2030
Lead sponsor:
Agency:
University of Utah
Agency class:
Other
Collaborator:
Agency:
Verastem, Inc.
Agency class:
Industry
Source:
University of Utah
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06194929
