Clinical Trials /

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

NCT02587650

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Capmatinib, Ceritinib, Regorafenib, or Entrectinib in Treating Patients With BRAF/NRAS Wild-Type Stage III-IV Melanoma
  • Official Title: A Phase II Trial of Targeted Kinase Fusion Inhibition in Unresectable Stage III/IV BRAF/NRAS Wild-Type Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 14859
  • SECONDARY ID: NCI-2017-01421
  • SECONDARY ID: 15-15712
  • SECONDARY ID: 14859
  • SECONDARY ID: P30CA082103
  • NCT ID: NCT02587650

Conditions

  • 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

Interventions

DrugSynonymsArms
CapmatinibINC-280, INC280, INCB 28060, INCB028060, INCB28060Arm A (capmatinib)
CeritinibLDK 378, LDK378, ZykadiaArm B (ceritinib)
EntrectinibRXDX-101Arm D (entrectinib)
RegorafenibBAY 73-4506, StivargaArm C (regorafenib)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (capmatinib)ExperimentalPatients 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.
  • Capmatinib
Arm B (ceritinib)ExperimentalPatients 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.
  • Ceritinib
Arm C (regorafenib)ExperimentalPatients 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.
  • Regorafenib
Arm D (entrectinib)ExperimentalPatients 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.
  • Entrectinib

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Analysis of study results will include ORR estimations of ALK, NTRK, ROS1, RET, MET, and BRAF rearrangement-positive patients.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Will be estimated for each arm along with a 95% confidence interval.
Measure:Incidence of adverse events according to Common Terminology Criteria for Adverse Events version 4.03
Time Frame:Up to 2 years
Safety Issue:
Description:Tabulated according to Common Terminology Criteria for Adverse Events version 4.03.
Measure:Overall survival
Time Frame:From treatment start to death, assessed up to 2 years
Safety Issue:
Description:Will be estimated using Kaplan-Meier methodology.
Measure: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
Safety Issue:
Description:Will be estimated using Kaplan-Meier methodology.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

Last Updated

December 20, 2017