Capmatinib, Ceritinib, Regorafenib, or Entrectinib in Treating Patients with BRAF/NRAS Wild-Type Stage III-IV Melanoma

Inclusion Criteria

• CAPMATINIB INCLUSION CRITERIA: Ability to understand a written informed consent document, and the willingness to sign it
• CAPMATINIB INCLUSION CRITERIA: Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• CAPMATINIB INCLUSION CRITERIA: Life expectancy >= 12 weeks
• CAPMATINIB INCLUSION CRITERIA: Histologically or cytologically confirmed invasive melanoma
• CAPMATINIB INCLUSION CRITERIA: Unresectable stage III or stage IV melanoma by clinical or radiographic criteria
• CAPMATINIB INCLUSION CRITERIA: Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• CAPMATINIB INCLUSION CRITERIA: Documentation of absence of activating and targetable BRAF or NRAS point mutations
• CAPMATINIB INCLUSION CRITERIA: Presence of an oncogenic kinase fusion involving MET, confirmed by assay by a Clinical Laboratory Improvement Act (CLIA)-approved laboratory
• CAPMATINIB INCLUSION CRITERIA: Prior treatment with at least one Food and Drug Administration (FDA)-approved drug for unresectable/metastatic melanoma; patients who are treatment-naive but who refuse available standard options and prefer to enroll on this study as their first line of treatment after a thorough informed consent process will be eligible at the discretion of the treating physician
• CAPMATINIB INCLUSION CRITERIA: Resolution of all acute toxic effects (excluding alopecia) of prior radiotherapy, chemotherapy or surgical procedures to Common Terminology Criteria for Adverse Events (CTCAE) v4.03 grade =< 1
• CAPMATINIB INCLUSION CRITERIA: Absolute neutrophil count >= 1,500/mm^3
• CAPMATINIB INCLUSION CRITERIA: Platelets >= 75,000/mcL
• CAPMATINIB INCLUSION CRITERIA: Hemoglobin >= 9 g/dL (transfusions are allowed)
• CAPMATINIB INCLUSION CRITERIA: 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
• CAPMATINIB INCLUSION CRITERIA: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN if no liver metastases are present; =< 5 x ULN if liver metastases are present
• CAPMATINIB INCLUSION CRITERIA: Alkaline phosphatase (ALP) =< 5 x ULN
• CAPMATINIB INCLUSION CRITERIA: 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.)
• CAPMATINIB INCLUSION CRITERIA: Serum lipase =< ULN
• CAPMATINIB INCLUSION CRITERIA: Creatinine OR creatinine clearance within normal limits > 40 mL/min (calculated by Cockgraft-Gault) for patients with creatinine levels above ULN
• CAPMATINIB INCLUSION CRITERIA: Serum potassium, calcium (corrected for serum albumin), magnesium, phosphorus within normal limits with or without supplementation
• CERITINIB INCLUSION CRITERIA: Ability to understand a written informed consent document, and the willingness to sign it
• CERITINIB INCLUSION CRITERIA: ECOG performance status 0-1
• CERITINIB INCLUSION CRITERIA: Life expectancy >= 12 weeks
• CERITINIB INCLUSION CRITERIA: Histologically or cytologically confirmed invasive melanoma
• CERITINIB INCLUSION CRITERIA: Unresectable stage III or stage IV melanoma by clinical or radiographic criteria
• CERITINIB INCLUSION CRITERIA: Measurable disease by RECIST v1.1
• CERITINIB INCLUSION CRITERIA: Documentation of absence of activating and targetable BRAF or NRAS point mutations
• CERITINIB INCLUSION CRITERIA: Presence of an oncogenic kinase fusion involving ALK, confirmed by assay by a CLIA-approved laboratory
• CERITINIB INCLUSION CRITERIA: Prior treatment with at least one FDA-approved drug for unresectable/metastatic melanoma; patients who are treatment-naive but who refuse available standard options and prefer to enroll on this study as their first line of treatment after a thorough informed consent process will be eligible at the discretion of the treating physician
• CERITINIB INCLUSION CRITERIA: Resolution of all acute toxic effects (excluding alopecia) of prior radiotherapy, chemotherapy or surgical procedures to CTCAE v4.03 grade =< 1
• CERITINIB INCLUSION CRITERIA: Absolute neutrophil count >= 1.5 x 10^9/L
• CERITINIB INCLUSION CRITERIA: Platelets >= 75 x 10^9/L
• CERITINIB INCLUSION CRITERIA: Hemoglobin >= 8 g/dL (transfusions are allowed)
• CERITINIB INCLUSION CRITERIA: Total bilirubin =< 1.5 x upper limit of normal (ULN); patients with Gilbert’s syndrome may be included if total bilirubin =< 3 x ULN and direct bilirubin =< 1.5 x ULN
• CERITINIB INCLUSION CRITERIA: AST (SGOT) and ALT (SGPT) =< 3 x ULN if no liver metastases are present; =< 5 x ULN if liver metastases are present
• CERITINIB INCLUSION CRITERIA: Alkaline phosphatase (ALP) =< 5 x ULN
• CERITINIB INCLUSION CRITERIA: Serum amylase =< 2 x ULN
• CERITINIB INCLUSION CRITERIA: Serum lipase =< ULN
• CERITINIB INCLUSION CRITERIA: Fasting plasma glucose =< 175 mg/dL (=< 9.8 mmol/L)
• CERITINIB INCLUSION CRITERIA: Creatinine OR creatinine clearance < 1.5 mg/dL >= 30 mL/min (calculated by Cockgraft-Gault) for patients with creatinine levels above ULN
• CERITINIB INCLUSION CRITERIA: Serum potassium, calcium (corrected for serum albumin), magnesium, phosphorus within normal limits with or without supplementation
• REGORAFENIB INCLUSION CRITERIA: Ability to understand a written informed consent document, and the willingness to sign it
• REGORAFENIB INCLUSION CRITERIA: ECOG performance status 0-1
• REGORAFENIB INCLUSION CRITERIA: Life expectancy >= 12 weeks
• REGORAFENIB INCLUSION CRITERIA: Histologically or cytologically confirmed invasive melanoma
• REGORAFENIB INCLUSION CRITERIA: Unresectable stage III or stage IV melanoma by clinical or radiographic criteria
• REGORAFENIB INCLUSION CRITERIA: Measurable disease by RECIST v1.1
• REGORAFENIB INCLUSION CRITERIA: Documentation of absence of activating and targetable BRAF or NRAS point mutations
• REGORAFENIB INCLUSION CRITERIA: Presence of an oncogenic kinase fusion involving BRAF or RET, confirmed by assay by a CLIA-approved laboratory
• REGORAFENIB INCLUSION CRITERIA: Prior treatment with at least one FDA-approved drug for unresectable/metastatic melanoma; patients who are treatment-naive but who refuse available standard options and prefer to enroll on this study as their first line of treatment after a thorough informed consent process will be eligible at the discretion of the treating physician
• REGORAFENIB INCLUSION CRITERIA: Resolution of all acute toxic effects (excluding alopecia) of prior radiotherapy, chemotherapy or surgical procedures to CTCAE v4.03 grade =< 1
• REGORAFENIB INCLUSION CRITERIA: Absolute neutrophil count >= 1,500/mm^3
• REGORAFENIB INCLUSION CRITERIA: Platelets >= 100,000/mm^3
• REGORAFENIB INCLUSION CRITERIA: Hemoglobin >= 9 g/dL
• REGORAFENIB INCLUSION CRITERIA: 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
• REGORAFENIB INCLUSION CRITERIA: AST (SGOT) and ALT (SGPT) =< 2.5 x ULN if no liver metastases are present; =< 5 x ULN if liver metastases are present
• REGORAFENIB INCLUSION CRITERIA: Alkaline phosphatase (ALP) =< 2.5 x ULN if no liver metastases are present; =< 5 x ULN if bone or liver metastases are present
• REGORAFENIB INCLUSION CRITERIA: Creatinine OR creatinine clearance =< 1.5 x ULN; > 40 mL/min (calculated by Cockgraft-Gault) for patients with creatinine levels above ULN
• REGORAFENIB INCLUSION CRITERIA: Serum potassium, calcium (corrected for serum albumin), magnesium, phosphorus within normal limits with or without supplementation
• REGORAFENIB INCLUSION CRITERIA: International normalized ratio (INR) and partial thromboplastin time (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 predose as defined by the local standard of care)
• ENTRECTINIB INCLUSION CRITERIA: Ability to understand a written informed consent document, and the willingness to sign it
• ENTRECTINIB INCLUSION CRITERIA: ECOG performance status 0-2
• ENTRECTINIB INCLUSION CRITERIA: Histologically or cytologically confirmed invasive melanoma
• ENTRECTINIB INCLUSION CRITERIA: Unresectable stage III or stage IV melanoma by clinical or radiographic criteria
• ENTRECTINIB INCLUSION CRITERIA: Measurable disease by RECIST v1.1
• ENTRECTINIB INCLUSION CRITERIA: Patients with central nervous system (CNS) involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previously-treated and controlled, are allowed; the use of seizure prophylaxis is allowed as long as patients are taking non enzyme-inducing anti-epileptic drugs (non-EIAEDs); if patients were previously on EIAEDs and these have been discontinued, they must have been discontinued for at least 2 weeks prior to the start of entrectinib treatment; if patients require an anti-epileptic medication, a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate, or lacosamide; moderate inducers of CYP450, such as dexamethasone or other glucocorticoids, may be used at the discretion of the investigator; patients requiring steroids must be at a stable or decreasing doses for at least 2 weeks prior to the start of entrectinib treatment
• ENTRECTINIB INCLUSION CRITERIA: Documentation of absence of activating and targetable BRAF or NRAS point mutations
• ENTRECTINIB INCLUSION CRITERIA: Presence of an oncogenic kinase fusion involving ROS1 or NTRK1/2/3, confirmed by assay by a CLIA-approved laboratory
• ENTRECTINIB INCLUSION CRITERIA: Prior treatment with at least one FDA-approved drug for unresectable/metastatic melanoma; patients who are treatment-naive but who refuse available standard options and prefer to enroll on this study as their first line of treatment after a thorough informed consent process will be eligible at the discretion of the treating physician
• ENTRECTINIB INCLUSION CRITERIA: Resolution of all acute toxic effects (excluding alopecia) of prior radiotherapy, chemotherapy or surgical procedures to CTCAE v4.03 grade =< 1
• ENTRECTINIB INCLUSION CRITERIA: Absolute neutrophil count >= 1,000/mm^3
• ENTRECTINIB INCLUSION CRITERIA: Platelets >= 75,000/mcL
• ENTRECTINIB INCLUSION CRITERIA: Hemoglobin >= 8 g/dL (transfusions are allowed)
• ENTRECTINIB INCLUSION CRITERIA: 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
• ENTRECTINIB INCLUSION CRITERIA: AST (SGOT) and ALT (SGPT) =< 3.0 x ULN if no liver metastases are present; =< 5 x ULN if liver metastases are present
• ENTRECTINIB INCLUSION CRITERIA: Creatinine OR creatinine clearance within normal limits; > 40 mL/min (calculated by Cockgraft-Gault) for patients with creatinine levels above ULN

Exclusion Criteria

• CAPMATINIB EXCLUSION CRITERIA: Uveal melanoma
• CAPMATINIB EXCLUSION CRITERIA: Current participation in another therapeutic clinical trial
• CAPMATINIB EXCLUSION CRITERIA: Inability to swallow intact tablets or capsules
• CAPMATINIB EXCLUSION CRITERIA: Previously identified allergy or hypersensitivity to components of capmatinib formulation (crospovidone, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide, and various coating premixes)
• CAPMATINIB EXCLUSION CRITERIA: 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)
• CAPMATINIB EXCLUSION CRITERIA: Prior treatment with the following antineoplastic therapies within the following time frame: * Any prior treatment with capmatinib, crizotinib, or any other cMET or HGF inhibitor * Thoracic radiotherapy to lung fields =< 4 weeks prior to starting capmatinib; for all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy =< 2 weeks prior to starting capmatinib; palliative radiotherapy for bone lesions =< 2 weeks prior to starting capmatinib is allowed * Receipt of any anticancer or investigational agent within 4 weeks or =< 5 half-lives of the agent (whichever is longer) prior to the first dose of capmatinib; if previous treatment is a monoclonal antibody, then the treatment must be discontinued at least 4 weeks before the first dose of capmatinib
• CAPMATINIB EXCLUSION CRITERIA: Major surgery (e.g., intrathoracic, intraabdominal or intrapelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting capmatinib; 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
• CAPMATINIB EXCLUSION CRITERIA: 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 capmatinib treatment and for the duration of the study: * Strong and moderate inhibitors of CYP3A4 * Strong inducers of CYP3A4 * Proton pump inhibitors (PPI)
• CAPMATINIB EXCLUSION CRITERIA: 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 capmatinib
• CAPMATINIB EXCLUSION CRITERIA: Presence or history of carcinomatous meningitis
• CAPMATINIB EXCLUSION CRITERIA: 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 capmatinib administration; if patients require an antiepileptic medication, then a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate or lacosamide
• CAPMATINIB EXCLUSION CRITERIA: 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 human chorionic gonadotropin [hCG] laboratory test); pregnant women are excluded from this study; nursing women are excluded unless they discontinue breastfeeding during the study
• CAPMATINIB EXCLUSION CRITERIA: Women of childbearing 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 capmatinib; 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: ** 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 childbearing 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
• CAPMATINIB EXCLUSION CRITERIA: 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 postvasectomy 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
• CAPMATINIB EXCLUSION CRITERIA: 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
• CAPMATINIB EXCLUSION CRITERIA: 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 > 480 msec using Fridericia correction on screening electrocardiography (ECG) * Uncontrolled hypertension (systolic pressure >= 160 mmHg or diastolic pressure >= 100 mmHg on repeated measurement) despite optimal medical management; initiation or adjustment of anti-hypertensive medications are allowed prior to screening
• CAPMATINIB EXCLUSION CRITERIA: Gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption
• CAPMATINIB EXCLUSION CRITERIA: Other severe, acute, or chronic medical or psychiatric conditions or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation, or that may interfere with the interpretation of study results
• CAPMATINIB EXCLUSION CRITERIA: Any other condition that would, in the Investigator’s judgment, contraindicate patient’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, social/psychological issues, etc
• CERITINIB EXCLUSION CRITERIA: Uveal melanoma
• CERITINIB EXCLUSION CRITERIA: Current participation in another therapeutic clinical trial
• CERITINIB EXCLUSION CRITERIA: Inability to swallow intact tablets or capsules
• CERITINIB EXCLUSION CRITERIA: Previously identified allergy or hypersensitivity to components of ceritinib formulation
• CERITINIB EXCLUSION CRITERIA: Diagnosis of concurrent malignancy or previous malignancy within 3 years before study administration (exceptions are superficial skin cancers, or any in situ cancers deemed surgically resected, cured and not requiring systemic therapy)
• CERITINIB EXCLUSION CRITERIA: Prior treatment with the following antineoplastic therapies within the following time frame: * Any prior treatment with ceritinib * Radiotherapy to lung fields =< 4 weeks prior to starting ceritinib; for all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy =< 2 weeks prior to starting ceritinib; palliative radiotherapy for bone lesions =< 2 weeks prior to starting ceritinib is allowed * 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)
• CERITINIB EXCLUSION CRITERIA: 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 * Strong inhibitors or strong inducers of CYP3A4/5 * Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5, and/or CYP2C9 * Therapeutic doses of warfarin sodium (coumadin) or any other coumadin-derived anticoagulant; anticoagulants not derived from warfarin are allowed (e.g., dabigatran, rivaroxaban, apixaban) * Unstable or increasing doses of corticosteroids * Enzyme-inducing anticonvulsive agents * Herbal supplements
• CERITINIB EXCLUSION CRITERIA: History of carcinomatous meningitis
• CERITINIB EXCLUSION CRITERIA: Known symptomatic brain metastases or on unstable/increasing doses of steroid * Patients with asymptomatic brain metastases may be enrolled at the discretion of the sponsor as long as the patient is stable or has received treatment by a focal approach for brain metastases (e.g., radiation at least 2 weeks prior to starting ceritinib, or fully healed from neurosurgery) * 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 capmatinib administration; if patients require an antiepileptic medication, then a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate or lacosamide * Moderate inducers of CYP3A, CYP3A4, or CYP3A4/5 such as dexamethasone or other glucocorticoids may be used at the discretion of the Investigator; patients requiring steroid must be at a stable or decreasing for at least 5 days prior to study drug administration
• CERITINIB EXCLUSION CRITERIA: 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; nursing women are excluded unless they discontinue breastfeeding during the study
• CERITINIB EXCLUSION CRITERIA: Women of childbearing 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 capmatinib; 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 * In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment
• CERITINIB EXCLUSION CRITERIA: Male sterilization (at least 6 months prior to screening); the vasectomized male partner should be the sole partner for that subject; use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception
• CERITINIB EXCLUSION CRITERIA: 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 postvasectomy 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
• CERITINIB EXCLUSION CRITERIA: 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
• CERITINIB EXCLUSION CRITERIA: 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 > 480 msec using Fridericia correction on screening electrocardiography (ECG) * Uncontrolled hypertension (systolic pressure > 140 mmHg or diastolic pressure > 90 mmHg on repeated measurement) despite optimal medical management
• CERITINIB EXCLUSION CRITERIA: Gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption
• CERITINIB EXCLUSION CRITERIA: History of pancreatitis, or history of increased amylase or lipase that was due to pancreatic disease
• CERITINIB EXCLUSION CRITERIA: Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting capmatinib; 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
• CERITINIB EXCLUSION CRITERIA: Known active infection (bacterial, fungal, viral including human immunodeficiency virus [HIV] positivity)
• CERITINIB EXCLUSION CRITERIA: 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
• CERITINIB EXCLUSION CRITERIA: 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
• REGORAFENIB EXCLUSION CRITERIA: Uveal melanoma
• REGORAFENIB EXCLUSION CRITERIA: Current participation in another therapeutic clinical trial
• REGORAFENIB EXCLUSION CRITERIA: Previous assignment to treatment during this study; patients permanently withdrawn from study participation will not be allowed to reenter
• REGORAFENIB EXCLUSION CRITERIA: Inability to swallow intact tablets or capsules
• REGORAFENIB EXCLUSION CRITERIA: Previously identified allergy or hypersensitivity to components of regorafenib formulation
• REGORAFENIB EXCLUSION CRITERIA: 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 curatively treated and without evidence of disease for more than 3 years before regorafenib treatment)
• REGORAFENIB EXCLUSION CRITERIA: Prior treatment with the following anti-neoplastic therapies within the following time frame: * Any prior treatment with regorafenib * Radiotherapy within 2 weeks prior to enrollment * 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)
• REGORAFENIB EXCLUSION CRITERIA: Known symptomatic brain metastases leptomeningeal involvement on unstable/increasing doses of steroid * Patients with asymptomatic brain metastases or leptomeningeal carcinomatosis may be enrolled at the discretion of the Sponsor as long as the patient is in clinically stable condition and, if requiring steroid, must be on a stable or decreasing dose for at least 5 days prior to regorafenib administration
• REGORAFENIB EXCLUSION CRITERIA: Patients with seizure disorder requiring medication
• REGORAFENIB EXCLUSION CRITERIA: 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; nursing women are excluded unless they discontinue breastfeeding during the study
• REGORAFENIB EXCLUSION CRITERIA: Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 months after the last dose of entrectinib; 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: ** 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
• REGORAFENIB EXCLUSION CRITERIA: Sexually active males unless: * A condom is used during intercourse while taking drug and for 3 months after the last dose of entrectinib; male patients should not father a child in the 3 months 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
• REGORAFENIB EXCLUSION CRITERIA: 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
• REGORAFENIB EXCLUSION CRITERIA: 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 > 480 msec using Fridericia correction on screening electrocardiography (ECG) * Uncontrolled hypertension (systolic pressure > 140 mmHg or diastolic pressure > 90 mmHg on repeated measurement) despite optimal medical management
• REGORAFENIB EXCLUSION CRITERIA: Gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption
• REGORAFENIB EXCLUSION CRITERIA: Evidence or history of bleeding diathesis or coagulopathy
• REGORAFENIB EXCLUSION CRITERIA: Any hemorrhage or bleeding event >= grade 3 within 4 weeks prior to start of regorafenib
• REGORAFENIB EXCLUSION CRITERIA: Major surgical procedure or significant traumatic injury within 28 days before start of regorafenib
• REGORAFENIB EXCLUSION CRITERIA: Presence of a non-healing wound, non-healing ulcer, or bone fracture
• REGORAFENIB EXCLUSION CRITERIA: Known active infection (bacterial, fungal, viral); viral infection includes known HIV positivity, or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy
• REGORAFENIB EXCLUSION CRITERIA: History of organ allograft (including corneal transplant)
• REGORAFENIB EXCLUSION CRITERIA: 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
• REGORAFENIB EXCLUSION CRITERIA: Pleural effusion or ascites causing respiratory compromise (dyspnea grade 2 or higher)
• REGORAFENIB EXCLUSION CRITERIA: Renal failure requiring hemodialysis or peritoneal dialysis
• REGORAFENIB EXCLUSION CRITERIA: Persistent proteinuria >= grade 3 (> 3.5 g/24 hours [hrs], measured by urine protein:creatinine ratio on a random urine sample)
• REGORAFENIB EXCLUSION CRITERIA: Patients with pheochromocytoma
• REGORAFENIB EXCLUSION CRITERIA: 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
• ENTRECTINIB EXCLUSION CRITERIA: Uveal melanoma
• ENTRECTINIB EXCLUSION CRITERIA: Current participation in another therapeutic clinical trial
• ENTRECTINIB EXCLUSION CRITERIA: Inability to swallow intact tablets or capsules
• ENTRECTINIB EXCLUSION CRITERIA: Previously identified allergy or hypersensitivity to components of entrectinib formulation
• ENTRECTINIB EXCLUSION CRITERIA: History of other previous cancer that would interfere with the determination of safety or efficacy of entrectinib in melanoma
• ENTRECTINIB EXCLUSION CRITERIA: Prior treatment with the following anti-neoplastic therapies within the following time frame: * Any prior treatment with entrectinib * Any prior treatment with TRK, ROS1, or ALK inhibitors * Radiotherapy within 2 weeks prior to enrollment * Whole brain radiotherapy within 2 weeks prior to enrollment, or stereotactic radiation to the brain within 1 week prior to enrollment * Receipt of any cytotoxic chemotherapy, biologic agent, or investigational agent within 2 weeks prior to the first dose of study drug
• ENTRECTINIB EXCLUSION CRITERIA: Females of childbearing potential must have a negative serum pregnancy test during screening and must not be breastfeeding or intending to become pregnant during the study
• ENTRECTINIB EXCLUSION CRITERIA: 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
• ENTRECTINIB EXCLUSION CRITERIA: 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 > 480 msec using Fridericia correction on screening electrocardiography (ECG) * Uncontrolled hypertension (systolic pressure > 140 mmHg or diastolic pressure > 90 mmHg on repeated measurement) despite optimal medical management
• ENTRECTINIB EXCLUSION CRITERIA: Gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption
• ENTRECTINIB EXCLUSION CRITERIA: Incomplete recovery from any surgery prior to treatment
• ENTRECTINIB EXCLUSION CRITERIA: Known active infection (bacterial, fungal, viral including HIV positivity)
• ENTRECTINIB EXCLUSION CRITERIA: 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
• ENTRECTINIB EXCLUSION CRITERIA: Pulmonary embolism in the 3 months prior to study drug administration
• ENTRECTINIB EXCLUSION CRITERIA: Peripheral neuropathy >= grade 2
• ENTRECTINIB EXCLUSION CRITERIA: 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