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

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Transitional Cell

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Lung Neoplasms

Ureteral Neoplasms

Neoplasms, Glandular and Epithelial

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Neoplasms, Squamous Cell

Head and Neck Neoplasms

Carcinoma, Bronchogenic

Bronchial Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Ureteral Diseases

Urologic Diseases

Male Urogenital Diseases

Transitional Cell Carcinoma

Pembrolizumab

Abexinostat

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Histone Deacetylase Inhibitors

Participants receive abexinostat PO BID on days -7 to -4 of the lead-in period, and days 1-4, 8-11 of each treatment cycle and pembrolizumab over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Participants with primary resistance to prior anti-PD-1/PD-L1 will receive abexinostat PO BID on days -7 to -4 of the lead-in period, and days 1-4, 8-11 of each treatment cycle and pembrolizumab over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Participants with acquired resistance, defined as treatment duration on prior CPI for greater than 6 months with evidence of clinical benefit (tumor regression or disease stabilization) with subsequent disease progression will receive abexinostat PO BID on days -7 to -4 of the lead-in period, and days 1-4, 8-11 of each treatment cycle and pembrolizumab over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Given orally (PO) twice a day (BID) days 1-4, 8-11 of every 21 day cycle

Rahul Aggarwal, MD

This phase I trial studies the best dose and side effects of abexinostat and how well it works with given together with pembrolizumab in treating participants with microsatellite instability (MSI) solid tumors that have spread to other places in the body. Abexinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving abexinostat and pembrolizumab may work better in treating participants with solid tumors.

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated and recommended phase 2 dose of abexinostat in combination with anti-PD-1/PD-L1 checkpoint inhibitor (CPI). (Dose escalation)

II. To determine the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in patients treated with abexinostat in combination with CPI in patients with prior primary (cohort A) or acquired (cohort B) resistance to prior CPI treatment. (Dose expansion)

SECONDARY OBJECTIVES:

I. To determine the objective response rate and median duration of response (DoR) by immune modified (i)RECIST criteria.

II. To determine the median progression-free survival (PFS).

III. To further characterize the safety profile of the treatment combination.

OUTLINE: This is a dose-escalation study of abexinostat.

Participants receive abexinostat orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (IV) on over 30 minutes day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 90 days.

Abexinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumor Malignancies

A Phase 1b Dose Escalation/Expansion Study of Abexinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumor Malignancies

Starting at dose level 1, if 2/3 patients have a dose-limiting toxicity (DLT), the dose will be de-escalated to dose -1. If 0/3 patients experience a DLT, 3 patients will be treated at the next dose level. If DLT attributable to the treatment is experienced in 1/3 patients, three more patients (for a total of six patients) will be treated at that dose level. If no additional DLTs are observed at the expanded dose level (i.e. 1/6 with DLT), the dose will be escalated. Escalation will terminate as soon as two or more patients experience any DLT attributable to study drugs, at a given dose level. If de-escalation is necessary, 3 patients will be enrolled on the next lower dose cohort. If 1 or less DLTs is observed in this cohort, this will be the MTD.

Objective response rate (ORR) by RECIST 1.1 criteria in patients treated with abexinostat in combination with (CPI) immune checkpoint inhibition in patients with prior primary or acquired resistance to prior CPI treatment.

Objective response rate (ORR) by iRECIST. The criteria are identical to those of RECIST 1.1 but have been adapted to account for instances where an increase in tumor burden, or the appearance of new lesions, does not reflect true tumor progression. Immuno response evaluation criteria in solid tumours (iRECIST) ORR requires the confirmation of progression and uses the terms unconfirmed progression (iUPD) and confirmed progression (iCPD).

The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR), whichever is first recorded, until the first date that recurrent or progressive disease is objectively documented.

The duration of overall response is measured from the time measurement criteria are met for CR (complete response) or PR (partial response), whichever is first recorded, until the first date that recurrent or progressive disease is objectively documented. The criteria are identical to those of RECIST 1.1 but have been adapted to account for instances where an increase in tumor burden, or the appearance of new lesions, does not reflect true tumor progression. iRECIST requires the confirmation of progression and uses the terms iUPD (unconfirmed progression) and iCPD (confirmed progression).

PFS is defined as the time from the date of initiation of study treatment to the date measurement criteria are first met for radiographic progressive disease (PD) or death from any cause, whichever occurs first.

Percentages of participants experiencing adverse events by preferred term will be summarized by NCI-CTCAE version 5

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
Abexinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumor Malignancies	NCT03590054	Stage III Cutan... Stage IV Cutane... Locally Advance... Locally Advance... Metastatic Head... Metastatic Mali... Metastatic Mela... Metastatic Urot... Non-Small Cell ... Stage IB Lung C... Stage III Cutan... Stage III Lung ... Stage III Urete... Stage IIIA Lung... Stage IIIB Lung... Stage IIIC Lung... Stage IV Cutane... Stage IV Lung C... Stage IV Ureter... Stage IVA Lung ... Stage IVB Lung ...	Abexinostat Pembrolizumab	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

Spots Global Cancer Trial Database for stage iii cutaneous melanoma