MC# 17-33 - A Sequential 2-arm, Open-label Phase I Study to Evaluate the Effects of Encorafenib in Combination with Binimetinib on the Pharmacokinetics of Losartan, Midazolam, Caffeine, Omeprazole, and Dextromethorphan Administered in a Cocktail Approach and on the Pharmacokinetics of Rosuvastatin in Patients with BRAF V600-mutant Unresectable or Metastatic Melanoma or Other Advanced Solid Tumors

  • Agent(s): Encorafenib, Binimetinib
  • Disease Type(s): Bladder, Breast, Cervical, Colorectal, Endometrial, Esophageal, Gastric, Head and Neck, Hepatocellular, Lung-NSCLC, Lung-SCLC, Melanoma, Mesothelioma, Neuroendocrine, Ovarian, Pancreatic, Prostate, Renal, Sarcoma, Solid Tumor, Squamous Cell, Thyroid, Cholangiocarcinoma
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): BRAF

Mechanism of Action

The study uses the combination of Encorafenib, an inhibitor of V600E mutated BRAF and Binimetinib, an inhibitor of MEK. Both BRAF and MEK are components of the same signaling pathway. It has been found in treatment of melanomas with V600E BRAF mutation that tumors readily overcome inhibition in one of several ways that involve alternative signaling in the same pathway. Inhibition of two points in the signaling sequence has been shown to be significantly more effective in treatment of melanoma. This study uses such a combination for patients with BRAF-mutated tumors and is a drug-drug interaction study using substrates of cytochrome metabolic enzymes.

Purpose

In this study, the sponsor and investigators want to learn:

  • The safety and tolerability of the study drugs when given with the drug cocktail or Rosuvastatin and bupropion, or modafinil
  • How much of the study drugs are absorbed into the blood and how fast it is removed when given with the drug cocktail or Rosuvastatin and bupropion, or modafinil
  • How much of the drug cocktail, Rosuvastatin, bupropion, or modafinil is absorbed into the blood and how fast it is removed when given with the study drugs
  • If research tests can be used in the future to predict who will benefit from the study drugs
  • The effects of the study drugs on the electrical activity of the heart
Inclusion Criteria
  • Signed written informed consent,
  • Male or female patient, age ≥ 18 years;
  • Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV, or other BRAF V600-mutant advanced solid tumors;
  • Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined locally using an approved test;
  • Evidence of measurable or non-measurable lesions as detected by radiological or photographic methods according to guidelines based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1;
  • Subject with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy Note: Prior therapy with a BRAF inhibitor (e.g., vemurafenib, dabrafenib, encorafenib and XL281/BMS-908662) and/or a MEK inhibitor (e.g., trametinib, binimetinib, selumetinib, cobimetinib and refametinib) is permitted except in the regimen immediately prior to study entry. Progression during prior BRAF/MEK inhibitor treatment is not required;
  • Subject with other (non-melanoma) BRAF V600-mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry. Progression during prior BRAF/MEK inhibitor treatment is not required; if it occurred, the patient’s circumstances (e.g., ≥ 1 year since prior BRAF and/or MEK inhibitor, equivocal progression, refractory to available therapies) must be discussed with the Sponsor prior to enrollment;
  • Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose (Arm 1 only)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1;
  • Adequate bone marrow, organ function and laboratory parameters:
    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L,
    • Hemoglobin (Hgb) ≥ 9 g/dL without transfusions,
    • Platelets (PLT) ≥ 100 x 109/L without transfusions,
    • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN); patient with liver metastases ≤ 5 ×ULN,
    • Total bilirubin ≤ 2 × ULN,
    • Creatinine ≤ 1.5 mg/dL, or calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 50mL/min;
  • Able to take oral medications;
  • Patient is deemed by the Investigator to have the initiative and means to be compliant with the protocol (treatment and follow-up);
  • Negative serum beta-human chorionic gonadotropin (β-HCG) test (female patient of childbearing potential only) performed within 72 hours prior to first dose and consent to ongoing urine pregnancy testing during the course of the study;
  • Male patients and female patients of childbearing potential must agree to use an acceptable method of contraception as defined in the study protocol.
Exclusion Criteria
  • Symptomatic brain metastasis. Patients previously treated or untreated for these conditions who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT] demonstrating no current evidence of progressive brain metastases at screening);
  • History of reaction to any of the study medications in the arm the patient is enrolled in this trial;
  • Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on Day 1 and through DDI phase (Day 28), of any herbal medications/supplements or any medications or foods that are moderate or strong inhibitors or inducers of CYP3A4/5
  • Consumption of grapefruit, pomegranates, star fruits, Seville oranges or products containing the juice of each starting from Day -14 and through the DDI phase (Day 28), due to potential CYP3A4 interaction with the study drugs. Orange juice is allowed;
  • Symptomatic or untreated leptomeningeal disease;
  • History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes);
  • Clinically significant cardiac disease including any of the following:
    • Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2)
    • Left ventricular ejection fraction (LVEF) < 50% as determined by MUGA or ECHO
    • Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy
    • History or presence of clinically significant ventricular arrhythmias or atrial fibrillation
    • Clinically significant resting bradycardia
    • Unstable angina pectoris ≤ 3 months prior to start of study drug
    • Acute myocardial infarction ≤ 3 months prior to start of study drug
    • QT interval corrected for heart rate using the Fridericia formula (QTcF) > 480 msec at screening;
  • Impaired hepatic function as defined by Child-Pugh class B or C;
  • Impaired gastrointestinal function or disease which may significantly alter the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
  • Known hyper-coagulability risks other than malignancy
  • Thromboembolic event, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis, or pulmonary emboli, except catheter-related venous thrombosis ≤ 12 weeks prior to starting study treatment.
  • Any of the following:
    • Nitrosourea or mitomycin-C within 6 weeks prior to start of study drug
    • Other chemotherapy, radiation therapy that included > 30% of the bone marrow reserve, or biological therapy (e.g., antibodies) within 4 weeks prior to start of study drug
    • 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 drug, when half-life is unknown)
    • Residual Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 side effects of any such therapy (residual Grade 2 alopecia is permitted);
  • Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion
  • Known positive serology for human immunodeficiency virus (HIV) infection, active hepatitis B and/or active hepatitis C infection;
  • Positive urine cotinine test at screening (Arm 1 only);
  • Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on Day 1 and through DDI phase (Day 28), of any substrates, inhibitors or inducers of CYP3A4, CYP2C9, CYP1A2 or CYP2C19 and any substrates or inhibitors of CYP2D6 (Arm 1 only)
  • History of Gilbert’s syndrome;
  • Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgement of the Investigator, would make the patient inappropriate for the study;
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until termination of gestation, confirmed by a positive β-hCG laboratory test (> 5 mIU/mL).
  • Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on Day 1 and through DDI phase (Day 28), of any substrates, inhibitors or inducers of CYP2B6 or any substrates or inhibitors of BCRP, OATP1B1 or OATP1B3 (Arm 2 only);
  • History of psychosis, depression, or mania (Arm 3 only);
  • History of angioedema (Arm 3 only);
  • History of mitral valve prolapse (Arm 3 only);
  • History of left ventricular hypertrophy (Arm 3 only);
  • Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on Day 1 and through DDI phase (Day 28), of any substrates, inhibitors or inducers of CYP3A4 (Arm 3 only).

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City

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Re: MC# 17-33