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 IIIA Cutaneous Melanoma, Stage IIIB Cutaneous Melanoma, Stage IIIC Cutaneous Melanoma, Stage III Cutaneous Melanoma, Stage IV Cutaneous Melanoma
Conditions
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.
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.
Interventions
DRUGCapmatinib
Given PO
DRUGCeritinib
Given PO
DRUGEntrectinib
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGRegorafenib
Given PO
Sponsors
University of California, San Francisco
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* CAPMATINIB INCLUSION CRITERIA: * Ability to understand a written informed consent document, and the willingness to sign it * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Life expectancy \>= 12 weeks * Histologically or cytologically confirmed invasive melanoma * Unresectable stage III or stage IV melanoma by clinical or radiographic criteria * Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 * Documentation of absence of activating and targetable BRAF or NRAS point mutations * Presence of an oncogenic kinase fusion involving MET, confirmed by assay by a Clinical Laboratory Improvement Act (CLIA)-approved laboratory * 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 * 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 * Absolute neutrophil count \>= 1,500/mm\^3 * Platelets \>= 75,000/ microliters (mcL) * Hemoglobin \>= 9 g/dL (transfusions are allowed) * 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 * 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 * 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 * Creatinine OR creatinine clearance within normal limits \> 40 mL/min (calculated by Cockgraft-Gault) for patients with creatinine levels above ULN * 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 * ECOG performance status 0-1 * Life expectancy \>= 12 weeks * Histologically or cytologically confirmed invasive melanoma * Unresectable stage III or stage IV melanoma by clinical or radiographic criteria * Measurable disease by RECIST v1.1 * Documentation of absence of activating and targetable BRAF or NRAS point mutations * Presence of an oncogenic kinase fusion involving ALK, confirmed by assay by a CLIA-approved laboratory * 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 * Resolution of all acute toxic effects (excluding alopecia) of prior radiotherapy, chemotherapy or surgical procedures to CTCAE v4.03 grade =\< 1 * Absolute neutrophil count \>= 1.5 x 10\^9/L * Platelets \>= 75 x 10\^9/L * Hemoglobin \>= 8 g/dL (transfusions are allowed) * 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 * 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 =\< 2 x ULN * Serum lipase =\< ULN * Fasting plasma glucose =\< 175 mg/dL (=\< 9.8 mmol/L) * Creatinine OR creatinine clearance \< 1.5 mg/dL \>= 30 mL/min (calculated by Cockgraft-Gault) for patients with creatinine levels above ULN * 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 * ECOG performance status 0-1 * Life expectancy \>= 12 weeks * Histologically or cytologically confirmed invasive melanoma * Unresectable stage III or stage IV melanoma by clinical or radiographic criteria * Measurable disease by RECIST v1.1 * Documentation of absence of activating and targetable BRAF or NRAS point mutations * Presence of an oncogenic kinase fusion involving BRAF or RET, confirmed by assay by a CLIA-approved laboratory * 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 * Resolution of all acute toxic effects (excluding alopecia) of prior radiotherapy, chemotherapy or surgical procedures to CTCAE v4.03 grade =\< 1 * Absolute neutrophil count \>= 1,500/mm\^3 * Platelets \>= 100,000/mm\^3 * Hemoglobin \>= 9 g/dL * 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) =\< 2.5 x ULN if no liver metastases are present? =\< 5 x ULN if liver metastases are present * Alkaline phosphatase (ALP) =\< 2.5 x ULN if no liver metastases are present; =\< 5 x ULN if bone or liver metastases are present * Creatinine OR creatinine clearance =\< 1.5 x ULN; \> 40 mL/min (calculated by Cockgraft-Gault) for patients with creatinine levels above ULN * Serum potassium, calcium (corrected for serum albumin), magnesium, phosphorus within normal limits with or without supplementation * 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 * ECOG performance status 0-2 * Histologically or cytologically confirmed invasive melanoma * Unresectable stage III or stage IV melanoma by clinical or radiographic criteria * Measurable disease by RECIST v1.1 * 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 * Documentation of absence of activating and targetable BRAF or NRAS point mutations * Presence of an oncogenic kinase fusion involving ROS1 or NTRK1/2/3, confirmed by assay by a CLIA-approved laboratory * 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 * Resolution of all acute toxic effects (excluding alopecia) of prior radiotherapy, chemotherapy or surgical procedures to CTCAE v4.03 grade =\< 1 * Absolute neutrophil count \>= 1,000/mm\^3 * Platelets \>= 75,000/mcL * Hemoglobin \>= 8 g/dL (transfusions are allowed) * 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) =\< 3.0 x ULN if no liver metastases are present? =\< 5 x ULN if liver metastases are present * Creatinine OR creatinine clearance within normal limits; \> 40 mL/min (calculated by Cockgraft-Gault) for patients with creatinine levels above ULN
Exclusion criteria
* CAPMATINIB
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Overall Response Rate (ORR) | 24 weeks | Defined as a complete or partial response as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria with confirmatory measurements a minimum of 4 weeks after the response-defining determination. Analysis of study results will include ORR estimations of ALK, NTRK, ROS1, RET, MET, and BRAF rearrangement-positive patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) | Up to 2 years | Clinical benefit rate is defined as the proportion of patients achieving a complete response (CR) or partial response (PR) or stable disease (SD) for \> 24 weeks using the same RECIST 1.1 decision matrix used to calculate ORR. The CBR will be estimated for each arm along with a 95% confidence interval |
| Overall Survival | From treatment start to death, assessed up to 2 years | Overall defined as the time from treatment start to the progression or death and overall survival defined as the time from treatment start to death will be estimated using Kaplan-Meier methodology. |
| Progression Free Survival | up to 2 years | Progression free survival (PFS) defined as the time from treatment start to the progression or death and overall survival defined as the time from treatment start to death will be estimated using Kaplan-Meier methodology |
| Evaluation of the Adverse Effect Profile of Each Kinase Inhibitor | Up to 2 years | Frequencies of toxicities will be tabulated according to CTCAE v4.03 to assess drug safety and tolerability |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm C (Regorafenib) Participants with RET or BRAF mutations | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Arm C (Regorafenib) |
|---|---|
| Age, Customized 60-65 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 1 |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 1 / 1 |
Outcome results
Primary
Confirmed Overall Response Rate (ORR)
Defined as a complete or partial response as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria with confirmatory measurements a minimum of 4 weeks after the response-defining determination. Analysis of study results will include ORR estimations of ALK, NTRK, ROS1, RET, MET, and BRAF rearrangement-positive patients.
Time frame: 24 weeks
Population: Evaluable participants would be those with baseline staging, treatment for at least 8 weeks, and at least one post-baseline staging scan while on treatment. No participants meet the criteria to be considered evaluable for this analysis.
Secondary
Clinical Benefit Rate (CBR)
Clinical benefit rate is defined as the proportion of patients achieving a complete response (CR) or partial response (PR) or stable disease (SD) for \> 24 weeks using the same RECIST 1.1 decision matrix used to calculate ORR. The CBR will be estimated for each arm along with a 95% confidence interval
Time frame: Up to 2 years
Population: Evaluable patients would be those with baseline staging, treatment for at least 8 weeks, and at least one post-baseline staging scan while on treatment. No participants meet the criteria to be considered evaluable for this analysis.
Secondary
Evaluation of the Adverse Effect Profile of Each Kinase Inhibitor
Frequencies of toxicities will be tabulated according to CTCAE v4.03 to assess drug safety and tolerability
Time frame: Up to 2 years
Population: Evaluable patients would be those with baseline staging, treatment for at least 8 weeks, and at least one post-baseline staging scan while on treatment. No participants meet the criteria to be considered evaluable for this analysis.
Secondary
Overall Survival
Overall defined as the time from treatment start to the progression or death and overall survival defined as the time from treatment start to death will be estimated using Kaplan-Meier methodology.
Time frame: From treatment start to death, assessed up to 2 years
Population: Evaluable patients would be those with baseline staging, treatment for at least 8 weeks, and at least one post-baseline staging scan while on treatment. No participants meet the criteria to be considered evaluable for this analysis.
Secondary
Progression Free Survival
Progression free survival (PFS) defined as the time from treatment start to the progression or death and overall survival defined as the time from treatment start to death will be estimated using Kaplan-Meier methodology
Time frame: up to 2 years
Population: Evaluable patients would be those with baseline staging, treatment for at least 8 weeks, and at least one post-baseline staging scan while on treatment. No participants meet the criteria to be considered evaluable for this analysis.