Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Melanoma, Cutaneous Malignant

Skin Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Entrectinib

Ceritinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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.

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.

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.

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.

Capmatinib

Laboratory Biomarker Analysis

Regorafenib

Adil Daud

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.

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.

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

A Phase II Trial of Targeted Kinase Fusion Inhibition in Unresectable Stage III/IV BRAF/NRAS Wild-Type Melanoma

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.

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 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 (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

Frequencies of toxicities will be tabulated according to CTCAE v4.03 to assess drug safety and tolerability

University of California, San Francisco

Principal Investigator

Analyses will be performed for all participants having received at least one dose of study drug. Only one participant was enrolled on this trial to Arm C (Regorafenib) for a total of 3 months. Adverse Events reported are for single accrued participant

Arm C (Regorafenib)

60-65 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Only 1 participant was enrolled on this protocol to Arm C (regorafenib). 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 protocol.

Only 1 participant was enrolled on this study to Arm C (regorafenib) based on the participants mutation profile. The study was terminated after one accrual due to lack of funding.

Dr. Adil Daud

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.

Confirmed Overall Response Rate (ORR)

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.

Clinical Benefit Rate (CBR)

Overall Survival

Progression Free Survival

Evaluation of the Adverse Effect Profile of Each Kinase Inhibitor

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

Capmatinib: Given orally

Laboratory Biomarker Analysis: Correlative studies

Arm A (Capmatinib)

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

Ceritinib: Given PO

Laboratory Biomarker Analysis: Correlative studies

Arm B (Ceritinib)

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.

Laboratory Biomarker Analysis: Correlative studies

Regorafenib: Given PO

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.

Entrectinib: Given PO

Laboratory Biomarker Analysis: Correlative studies

Arm D (Entrectinib)

Overall Study

Neoplasms, Second Primary

Patients receive brigatinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

90 mg orally QD for 7 days followed by 180 mg orally QD continuously thereafter. One cycle of therapy will consist of 28 days of treatment.

Brigatinib

Quality-of-Life Assessment

Questionnaire Administration

Sameek Roychowdhury, MD

This phase II trial studies how well brigatinib works in treating patients with ALK and ROS1 gene alterations and solid cancers that have spread to nearby tissue and lymph nodes or other places in the body. Brigatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To evaluate the overall response rate (ORR) of brigatinib in patients with advanced solid tumors harboring genomic alterations in ALK (excluding lung) and ROS1 (all solid tumors).

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of brigatinib in patients with advanced solid tumors harboring genomic alterations in ALK (excluding lung) and ROS1 (all solid tumors).

II. To assess progression free survival (PFS) and overall survival (OS) in patients with advanced ALK or ROS1 mutated solid tumors treated with brigatinib.

III. To assess sensitivity and durability of response to brigatinib in different solid tumor types.

IV. To assess the role of intertumoral and intratumoral heterogeneity in the development of resistance to brigatinib.

V. To identify candidate genomic (including circulating tumor deoxyribonucleic acid \[DNA\]) and proteomic biomarkers of tumor sensitivity and resistance to brigatinib using high-throughput approaches (exome, transcriptome, reverse phase protein array \[RPPA\]).

TERTIARY OBJECTIVES:

I. Correlation of brigatinib exposure with efficacy and safety. II. Correlation of tumor and plasma biomarkers with brigatinib efficacy and safety.

OUTLINE:

Patients receive brigatinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 52 weeks.

Brigatinib in Treating Patients With ALK and ROS1 Gene Alterations and Locally Advanced or Metastatic Solid Cancers

Phase II Study of Brigatinib for Advanced Solid Cancers Harboring Genomic Alterations in ALK (Excluding Lung) and ROS1 Oncogenes

Brigatinib exposure will be compared to RECIST measurements and adverse events measured using CTCAE v4.

Correlative and protein markers will be summarized univariately in a quantitative manner and also summarized by clinical outcome group (e.g. response vs. no response). Graphical analyses will be largely used to assess potential patterns and relationships; e.g. side-by-side boxplots to assess differences in continuous marker levels between those with vs. without the clinical improvement (e.g. response versus no response). Will correlate with efficacy and safety.

Response for tumors will be assessed using the RECIST 1.1 criteria (using computed tomography scans or calipers by clinical exam) where response will be defined as a partial or complete response. Will be calculated with 95% binomial confidence intervals for the estimate of the proportion of responses.

Will be assessed by central independent review committee per RECIST version 1.1.

Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.

Kaplan-Meier curves will be used to estimate the survival distributions of overall survival.

Kaplan-Meier curves will be used to estimate the survival distributions of progression-free survival.

Will be calculated by the number of patients who have achieve a response and/or are progression-free and alive at 6 months divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for clinical benefit rate will be calculated.

The logistical aspects of the trial will be evaluated and summarized. Disease group-specific outcomes will also be summarized and described, although we will not be powered for any formal evaluation within a disease or histology subset.

The logistical aspects of the trial will be evaluated and summarized. Disease group-specific outcomes will also be summarized and described, although we will not be powered for any formal evaluation within a disease or histology subset. Genes will be evaluated in aggregate from whole exome and transcriptome sequencing.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Capmatinib, Ceritinib, Regorafenib, or Entrectinib in Treating Patients With BRAF/NRAS Wild-Type Stage III-IV Melanoma	NCT02587650	ALK Fusion Prot... BRAF wt Allele Invasive Skin M... MET Fusion Gene... NRAS wt Allele NTRK1 Fusion Po... NTRK2 Fusion Po... NTRK3 Fusion Po... RET Fusion Posi... ROS1 Fusion Pos... Stage III Cutan... Stage IIIA Cuta... Stage IIIB Cuta... Stage IIIC Cuta... Stage IV Cutane...	Capmatinib Ceritinib Entrectinib Laboratory Biom... Regorafenib	18 Years -	University of California, San Francisco
Capmatinib, Ceritinib, Regorafenib, or Entrectinib in Treating Patients With BRAF/NRAS Wild-Type Stage III-IV Melanoma	NCT02587650	ALK Fusion Prot... BRAF wt Allele Invasive Skin M... MET Fusion Gene... NRAS wt Allele NTRK1 Fusion Po... NTRK2 Fusion Po... NTRK3 Fusion Po... RET Fusion Posi... ROS1 Fusion Pos... Stage III Cutan... Stage IIIA Cuta... Stage IIIB Cuta... Stage IIIC Cuta... Stage IV Cutane...	Capmatinib Ceritinib Entrectinib Laboratory Biom... Regorafenib	18 Years -	University of California, San Francisco
Capmatinib, Ceritinib, Regorafenib, or Entrectinib in Treating Patients With BRAF/NRAS Wild-Type Stage III-IV Melanoma	NCT02587650	ALK Fusion Prot... BRAF wt Allele Invasive Skin M... MET Fusion Gene... NRAS wt Allele NTRK1 Fusion Po... NTRK2 Fusion Po... NTRK3 Fusion Po... RET Fusion Posi... ROS1 Fusion Pos... Stage III Cutan... Stage IIIA Cuta... Stage IIIB Cuta... Stage IIIC Cuta... Stage IV Cutane...	Capmatinib Ceritinib Entrectinib Laboratory Biom... Regorafenib	18 Years -	University of California, San Francisco
Brigatinib in Treating Patients With ALK and ROS1 Gene Alterations and Locally Advanced or Metastatic Solid Cancers	NCT03868423	Advanced Malign... ALK Fusion Prot... ALK Gene Amplif... ALK Gene Mutati... Locally Advance... Metastatic Mali... Metastatic Mali... Metastatic Mali... ROS1 Fusion Pos... ROS1 Gene Ampli... ROS1 Gene Mutat...	Brigatinib Laboratory Biom... Quality-of-Life... Questionnaire A...	18 Years -	Ohio State University Comprehensive Cancer Center

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