This phase I trial studies the side effects and best dose of mocetinostat when given together with vinorelbine to see how well it works in treating children, adolescents, and young adults with rhabdomyosarcoma that has spread to nearby tissues or lymph nodes and cannot be removed by surgery (locally advanced unresectable) or has spread to other places in the body (metastatic), and does not respond to treatment (refractory) or has come back (relapsed). Mocetinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as vinorelbine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving mocetinostat and vinorelbine may work better in treating children, adolescents, and young adults with rhabdomyosarcoma compared to vinorelbine alone.
PRIMARY OBJECTIVES: I. To determine the first cycle dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and a biologically effective and recommended phase 2 dose (RP2D) of mocetinostat administered orally three times per week for a total of 9 doses per 21 day cycle given in combination with vinorelbine on days 1, 8, 15 of 21 day cycles in subjects with refractory or recurrent rhabdomyosarcoma (RMS). (Phase 1 Dose Escalation) II. To determine the progression-free survival (PFS), defined as time from first dose of vinorelbine to tumor progression or death due to any cause, at the RP2D of mocetinostat administered orally three times per week starting on day 3 for a total of 9 doses per 21 day cycle given in combination with vinorelbine on days 1, 8, 15 of a 21 day cycle in subjects with refractory or recurrent RMS. (Expansion Cohort) SECONDARY OBJECTIVES: I. Safety profile of mocetinostat in combination with vinorelbine as characterized by adverse event (AE) type, severity, timing and relationship to study drugs, as well as laboratory abnormalities in the first and subsequent treatment cycles. (Phase 1 Dose Escalation) II. Pharmacokinetics (PK) of mocetinostat in plasma. (Phase 1 Dose Escalation) III. Clinical benefit rate (CBR = complete response \[CR\] + partial response \[PR\] and stable disease \[SD\]) of mocetinostat + vinorelbine in metastatic/refractory/unresectable RMS. (Phase 1 Dose Escalation) IV. Antitumor activity of mocetinostat + vinorelbine in refractory/recurrent RMS as measured by overall response rate (ORR), duration of response (DOR), disease control (DC), duration of disease control, as well as progression-free survival (PFS). (Phase 1 Dose Escalation) V. Pharmacodynamics of mocetinostat on molecular targets in surrogate tissue. (Phase 1 Dose Escalation and Expansion Cohort) VI. Exploratory biomarker development to enable prediction of drug toxicity, tumor response and the mechanism(s) of acquired study drug resistance. (Phase 1 Dose Escalation and Expansion Cohort) VII. Obtain RMS tissue biological samples pre-treatment and at progression to assess for differences in gene expression by next gen (generation) sequencing and ribonucleic acid (RNA) sequencing (seq). (Phase 1 Dose Escalation and Expansion Cohort) VIII. Antitumor activity of mocetinostat + vinorelbine in metastatic/refractory RMS as measured by overall response rate (ORR) and duration of response (DOR), disease control (DC), duration of disease control, as well as progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. (Expansion Cohort) IX. Safety and tolerability of mocetinostat and vinorelbine as characterized by adverse event type, severity, timing and relationship to study drug, as well as laboratory abnormalities. (Expansion Cohort) OUTLINE: This is a phase I, dose-escalation study of mocetinostat followed by additional studies.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
38
Given IV
Given PO
Rebecca Phelan
Los Angeles, California, United States
To describe any dose-limiting toxicity (DLT)
Percentage of subjects with dose-limiting toxicities (DLTs) as assessed by NCI CTCAE (Version 4.03)
Time frame: 1 year
To determine the maximum tolerated dose (MTD) or highest protocol defined doses (in the absence of exceeding the MTD)
The MTD is the highest dose associated with first-cycle DLT in \< 33% of subjects
Time frame: 1 year
To determine the Recommended Phase 2 Dose (RP2D) for mocetinostat in combination with vinorelbine
The RP2D may be determined by the MTD or optimal target inhibition with an acceptable safety profile
Time frame: 1 year
Incidence of Adverse Events (AEs) as assessed by NCI CTCAE (Version 4.03)
Assess incidence of all AEs by NCI CTCAE (Version 4.03) grades 1-5
Time frame: 1 year
Objective Tumor Response
Measured using RECIST, Version 1.1
Time frame: 2 years
Progression Free Survival (PFS)
Estimated using Kaplan-Meier methodology
Time frame: 2 years
Disease Control (DC)
Proportion of subjects with a confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) according to RECIST v1.1
Time frame: 2 years
Duration of Response (DOR)
Measured from the first date a response is identified (either CR or PR) until the date of disease progression
Time frame: 2 years
Area under the Plasma Concentration versus Time Curve (AUC) of mocetinostat
Continuous variables will be summarized with means, standard deviations, medians, minimums, and maximums
Time frame: 2 years
Clearance (CL) of mocetinostat
Continuous variables will be summarized with means, standard deviations, medians, minimums, and maximums
Time frame: 2 years
Half-Life [T1/2] of mocetinostat
Continuous variables will be summarized with means, standard deviations, medians, minimums, and maximums
Time frame: 2 years
Volume of Distribution (Vd) of mocetinostat
Continuous variables will be summarized with means, standard deviations, medians, minimums, and maximums
Time frame: 2 years
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