Patient case: 55-year-old male with Melanoma. Genetic variant: NRAS (Q61K). Other conditions: Hypertension.

Clinical trial: Trial of TKF Inhibition in Unresectable Stage III/IV BRAF/NRAS WT Melanoma

Summary: This is a phase II multi-center prospective basket trial designed to test the hypothesis that targeting specific kinase fusions in metastatic melanoma with pre-specified kinase inhibitors will result in objective tumor shrinkage and durable response. The study design is a 2 stage optimal design with a sample size of N=35, with n1=11 during stage I and n2=24 during stage II. If 1 or fewer responses are observed during stage I, the trial will be stopped. If 6 or fewer responses are observed by the end of stage II, the trial will be stopped.

Detailed description: This is a phase II prospective multi-center basket trial designed to test the hypothesis that targeting specific kinase fusions in metastatic melanoma with kinase inhibitors matched to the activated kinase fusion will result in tumor response. The study design is a 2-stage optimal design. Patients will be screened for one of the eligible fusion proteins using various assays developed in a CLIA-approved laboratory (targeted next-generation sequencing of tumor tissue, fluorescence in situ hybridization and immunohistochemistry) under a separate protocol. If identified, patients will be offered enrollment in this protocol and will be treated in one of five baskets.
  The dose of INC280 at 600 mg PO BID is based on the recommended phase II dose (RP2D) by Novartis. The dose of ceritinib at 750 mg PO daily is the FDA-approved dose for ALK-rearranged NSCLC resistant to intolerant to crizotinib. For regorafenib we will dose at 160 mg PO daily (first 21 days of each 28 day cycle) which is the FDA-approved dose for both colon cancer and GIST. The dose of entrectinib at 600 mg PO QD is the RP2D based on two Phase 1 studies conducted by Ignyta.

Eligibility: General: Inclusion Criteria
  -  Ability to understand a written informed consent document, and the willingness to sign it.
  -  Age ≥ 18 years ECOG performance status 0-1 or 2 pending on the treatment arm
  -  Life expectancy ≥ 12 weeks
  -  Histologically or cytologically confirmed invasive melanoma.
  -  Unresectable Stage III or Stage IV melanoma by clinical or radiographic criteria.
  -  Measureable disease by RECIST v1.1.
  -  Documentation of absence of activating and targetable BRAF or NRAS point mutations.
  -  Presence of an oncogenic kinase fusion involving MET, ROS1, NTRK1, NTRK2, or NTRK3, confirmed by assay by a CLIA-approved laboratory.
  -  Resolution of all acute toxic effects (excluding alopecia) of prior radiotherapy, chemotherapy or surgical procedures to CTCAE v4.03 grade ≤ 1.
  -  Adequate bone marrow and organ function as defined by the following parameters:
  -  Adequate bone marrow function:
  -  Absolute neutrophil count ≥ 1,500/mm3
  -  Platelets ≥ 75,000/mcL
  -  Hemoglobin ≥ 9 g/dL (transfusions are allowed)
  -  Adequate hepatic and pancreatic function:
  -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN). Patients with Gilbert's syndrome may be included if total bilirubin ≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN
  -  AST (SGOT) and ALT (SGPT) ≤ 3 x ULN if no liver metastases are present; ≤ 5 x ULN if liver metastases are present
  -  Alkaline phosphatase (ALP) ≤ 5 x ULN
  -  Serum amylase ≤ grade 2 and asymptomatic. Patients with grade 1 or 2 serum amylase at the beginning of the study must be confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
  -  Serum lipase ≤ ULN
  -  Adequate renal function:
  -  Creatinine within normal limits or creatinine clearance > 40 mL/min (calculated by Cockgraft-Gault) for patients with creatinine levels above ULN
  -  Serum potassium, calcium (corrected for serum albumin), magnesium, phosphorous within normal limits with or without supplementation
  -  Normal coagulation parameters:
  -  INR and PTT ≤ 1.5 x ULN (Patients who are prophylactically treated with an agent such as warfarin or heparin will be allowed to participate, provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.)
  General: Exclusion Criteria
  -  Uveal melanoma.
  -  Current participation in another therapeutic clinical trial.
  -  Inability to swallow intact tablets or capsules.
  -  Previously identified allergy or hypersensitivity to components of INC280 formulation (crospovidone, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide, and various coating premixes), ceritinib formulation, regorafenib
  -  Diagnosis of concurrent malignancy or previous malignancy within 3 years before study drug administration (exceptions are superficial skin cancers, or any in situ cancers deemed surgically resected, cured and not requiring systemic therapy, and indolent malignancies that currently do not require treatment).
  -  Prior treatment with the following anti-neoplastic therapies within the following time frame:
  -  Any prior treatment with INC280, ceritinib, regorafenib, or entrectinib or any other cMET or HGF, TRK, ROS1, or ALK inhibitors.
  -  Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting INC280. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to starting INC280. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting INC280 is allowed.
  -  Receipt of any anti-cancer or investigational agent within 4 weeks or ≤ 5 half-lives of the agent (whichever is longer) prior to the first dose of INC280. If previous treatment is a monoclonal antibody, then the treatment must be discontinued at least 4 weeks before the first dose of INC280.
  -  Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting INC280. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and patients can be enrolled in the study ≥ 1 week after the procedure.
  -  Patients receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of INC280 treatment and for the duration of the study:
  -  Strong and moderate inhibitors of CYP3A4
  -  Strong inducers of CYP3A4
  -  Proton pump inhibitors (PPI)
  -  Patients on unstable or increasing doses of corticosteroids. If patients are on corticosteroids for endocrine deficiencies or tumor-associated symptoms other than CNS related, dose must have been stabilized or decreasing for at least 5 days before first dose of INC280.
  -  Presence or history of carcinomatous meningitis.
  -  Known symptomatic brain metastases requiring increasing doses of steroid to manage CNS symptoms within 2 weeks prior to study entry.
  -  Patients with asymptomatic brain metastases may be enrolled at the discretion of the Sponsor as long as the patient is stable and has not required increasing dose of steroids to manage CNS symptoms for at least 2 weeks prior to study enrollment.
  -  Patients requiring seizure prophylaxis must be taking non-enzyme-inducing anti- epileptic drugs (non-EIAED). If patients were previously on EIAEDs and these have been discontinued, they must be discontinued for at least 1 weeks prior to INC280 administration. If patients require an anti-epileptic medication, then a CYP3A4 non- EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate or lacosamide.
  -  Pregnant or nursing women, or women intending to become pregnant during the study (where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum hCG laboratory test). Pregnant women are excluded from this study because the study drugs are either teratogenic or have unknown teratogenicity. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, nursing women are excluded unless they discontinue breastfeeding during the study.
  -  Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 7 days after the last dose of INC280. Highly effective contraception methods include:
  -  Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal are not acceptable methods of contraception.
  -  Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
  -  Combination of any two of the following (i+ii or i+iii or ii+iii):
  -  Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.
  -  Placement of an intrauterine device (IUD) or intrauterine system (IUS).
  -  Barrier methods of contraception: Condom or occlusive cap (diaphragm or cervical/ vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
  -  Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
  -  Sexually active males unless:
  -  A condom is used during intercourse while taking drug and 7 days after the last dose of entrectinib. Male patients should not father a child in the 7 days after the last dose of the study treatment.
  -  Male sterilization has taken place, with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. Condom use is also required in vasectomized men in order to prevent delivery of the drug via seminal fluid.
  -  Any of the following in the past 6 months prior to screening:
  -  Myocardial infarction
  -  Severe/unstable angina
  -  Clinically significant cardiac arrhythmias
  -  Cerebrovascular accident or transient ischemic attack
  -  Coronary/peripheral artery bypass graft
  -  Cardiovascular disorders including:
  -  Symptomatic congestive heart failure (New York Heart Association class III or IV)
  -  Personal or family history of congenital long QT syndrome
  -  Corrected QTc >470 msec using Fridericia correction on screening ECG
  -  Uncontrolled hypertension (systolic pressure ≥160 mmHg or diastolic pressure
  ≥100 mmHg on repeated measurement) despite optimal medical management. Initiation or adjustment of antihypertensive medications are allowed prior to screening.
  -  Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
  -  Receipt of any cytotoxic chemotherapy, biologic agent, or investigational agent within 4 weeks prior to the first dose of study drug (within 6 weeks for nitrosoureas, mitomycin C or liposomal doxorubicin).
  -  Receiving medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of treatment with study drug and for the duration of participation:
  -  Medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (please refer to http://www.azcert.org/medical-pros/drug-lists/drug- lists.cfm)
  -  Therapeutic doses of warfarin sodium (coumadin) or any other coumadin- derived anticoagulant. Anticoagulants not derived from warfarin are allowed (e.g., dabigatran, rivaroxaban, apixaban).
  -  Enzyme-inducing anticonvulsive agents
  -  Herbal supplements
  -  Any of the following in the past 6 months prior to study drug administration:
  -  Ventricular arrythmias
  -  Supraventricular, nodal, or other cardiac arrhythmias not controlled with medication
  -  Cerebrovascular accident or transient ischemic attack
  -  Coronary/peripheral artery bypass graft
  -  Known active infection (bacterial, fungal, viral including HIV positivity).
  -  Known history of extensive disseminated bilateral interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and clinically significant radiation pneumonitis.
  -  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 may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromised protocol objectives in the opinion of the Investigator and/or the Sponsor.
  -  Peripheral neuropathy ≥ Grade 2.
  -  Presence of a non-healing wound, non-healing ulcer, or bone fracture.
  -  History of organ allograft (including corneal transplant).
  -  Pleural effusion or ascites causing respiratory compromise (dyspnea Grade 2 or higher).
  -  Persistent proteinuria ≥ Grade 3 (> 3.5 g/24 hrs, measured by urine protein: creatinine ratio on a random urine sample).
  -  Patients with pheochromocytoma.

Relevance to patient case: possibly relevant