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

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ClinicalTrials.gov Identifier: NCT02587650
Recruitment Status : Completed
First Posted : October 27, 2015
Last Update Posted : May 31, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Adil Daud, University of California, San Francisco

Brief Summary:
This phase II trial studies how well capmatinib, ceritinib, regorafenib, or entrectinib work in treating patients with BRAF/NRAS wild-type stage III-IV melanoma. Capmatinib, ceritinib, regorafenib, or entrectinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
ALK Fusion Protein Expression BRAF wt Allele Invasive Skin Melanoma MET Fusion Gene Positive NRAS wt Allele NTRK1 Fusion Positive NTRK2 Fusion Positive NTRK3 Fusion Positive RET Fusion Positive ROS1 Fusion Positive Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Drug: Capmatinib Drug: Ceritinib Drug: Entrectinib Other: Laboratory Biomarker Analysis Drug: Regorafenib Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the clinical activity of tyrosine kinase inhibitors matched to the tumor-specific fusion kinase in patients with metastatic melanoma.

SECONDARY OBJECTIVES:

I. To estimate tumor stability in melanoma patients treated with kinase inhibitors matched to the tumor-specific fusion kinase.

II. To estimate survival in melanoma patients treated with kinase inhibitors matched to the tumor-specific fusion kinase.

III. To examine the safety and tolerability of kinase inhibitors in patients with melanoma with a fusion kinase.

TERTIARY OBJECTIVES:

I. To explore molecular mechanisms of resistance for patients who progress on therapy.

OUTLINE: Patients are assigned to 1 of 4 arms.

ARM A: Patients with MET fusion receive capmatinib orally (PO) twice daily (BID) on day 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM B: Patients with ALK fusion receive ceritinib PO once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM C: Patients with RET or BRAF fusion receive regorafenib PO QD on day 1-21. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM D: Patients with NTRK1, NTRK2, NTRK3, or ROS1 fusion receive entrectinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, patients are followed up within 30 days and then periodically.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Targeted Kinase Fusion Inhibition in Unresectable Stage III/IV BRAF/NRAS Wild-Type Melanoma
Actual Study Start Date : March 26, 2015
Actual Primary Completion Date : January 15, 2018
Actual Study Completion Date : March 21, 2018


Arm Intervention/treatment
Experimental: Arm A (capmatinib)
Patients with MET fusion receive capmatinib PO BID on day 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Drug: Capmatinib
Given PO
Other Names:
  • INC-280
  • INC280
  • INCB 28060
  • INCB028060
  • INCB28060

Other: Laboratory Biomarker Analysis
Correlative studies

Experimental: Arm B (ceritinib)
Patients with ALK fusion receive ceritinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Drug: Ceritinib
Given PO
Other Names:
  • LDK 378
  • LDK378
  • Zykadia

Other: Laboratory Biomarker Analysis
Correlative studies

Experimental: Arm C (regorafenib)
Patients with RET or BRAF fusion receive regorafenib PO QD on day 1-21. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Regorafenib
Given PO
Other Names:
  • BAY 73-4506
  • Stivarga

Experimental: Arm D (entrectinib)
Patients with NTRK1, NTRK2, NTRK3, OR ROS1 fusion receive entrectinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Drug: Entrectinib
Given PO
Other Name: RXDX-101

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Overall response rate (ORR) defined as a complete or partial response as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria [ Time Frame: 24 weeks ]
    Analysis of study results will include ORR estimations of ALK, NTRK, ROS1, RET, MET, and BRAF rearrangement-positive patients.


Secondary Outcome Measures :
  1. Clinical benefit rate defined as the proportion of patients achieving a complete response or partial response or stable disease [ Time Frame: Up to 2 years ]
    Will be estimated for each arm along with a 95% confidence interval.

  2. Incidence of adverse events according to Common Terminology Criteria for Adverse Events version 4.03 [ Time Frame: Up to 2 years ]
    Tabulated according to Common Terminology Criteria for Adverse Events version 4.03.

  3. Overall survival [ Time Frame: From treatment start to death, assessed up to 2 years ]
    Will be estimated using Kaplan-Meier methodology.

  4. Progression free survival [ Time Frame: From treatment start to the progression or death and overall survival defined as the time from treatment start to death, assessed up to 2 years ]
    Will be estimated using Kaplan-Meier methodology.


Other Outcome Measures:
  1. Expression levels of the fusion kinase protein assessed by immunohistochemistry [ Time Frame: Up to 2 years ]
    Measures taken at baseline as well as after four weeks of therapy will be summarized. Changes in expression level will be assessed between baskets using a paired t-test if data permit. For patients who progress on therapy, an additional biopsy may be obtained and will be compared with baseline expression levels if data permit. This will inform on molecular mechanisms of resistance for patients who progress while on therapy.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 re

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02587650


Locations
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United States, California
UCSF Medical Center-Mount Zion
San Francisco, California, United States, 94115
Sponsors and Collaborators
University of California, San Francisco
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Adil Daud UCSF Medical Center-Mount Zion

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Responsible Party: Adil Daud, Principal Investigator, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02587650     History of Changes
Other Study ID Numbers: 14859
NCI-2017-01421 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
15-15712
14859 ( Other Identifier: UCSF Medical Center-Mount Zion )
First Posted: October 27, 2015    Key Record Dates
Last Update Posted: May 31, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Melanoma
Skin Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Skin Diseases
Ceritinib
Entrectinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action