Clinical Trials /

Mocetinostat With Vinorelbine in Children, Adolescents & Young Adults With Refractory and/or Recurrent Rhabdomyosarcoma

NCT04299113

Description:

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.

Related Conditions:
  • Rhabdomyosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Mocetinostat With Vinorelbine in Children, Adolescents & Young Adults With Refractory and/or Recurrent Rhabdomyosarcoma
  • Official Title: A Phase I Dose Escalation/Expansion Clinical Trial of Mocetinostat in Combination With Vinorelbine in Children, Adolescents and Young Adults With Refractory and/or Recurrent Rhabdomyosarcoma (RMS)

Clinical Trial IDs

  • ORG STUDY ID: 19-000353
  • NCT ID: NCT04299113

Conditions

  • Rhabdomyosarcoma

Interventions

DrugSynonymsArms
Vinorelbine3'',4''-Didehydro-4''-deoxy-C''-norvincaleukoblastine, 5''-Nor-Anhydrovinblastine, 71486-22-1, Dihydroxydeoxynorvinkaleukoblastine, nor-5''-Anhydrovinblastine, vinorelbine, VINORELBINETreatment (vinorelbine, mocetinostat)
Mocetinostat726169-73-9, Benzamide, N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]-, MG-0103, MGCD0103, MGCD0103, N-(2-aminophenyl)-4-((4-pyridin-3-ylpyrimidin-2-ylamino)methyl)benzamideTreatment (vinorelbine, mocetinostat)

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (vinorelbine, mocetinostat)ExperimentalParticipants receive mocetinostat in combination with vinorelbine
  • Vinorelbine
  • Mocetinostat

Eligibility Criteria

        Inclusion Criteria:

          -  Willing and able to provide written Institutional Review Board (IRB)/Independent
             Ethics Committee (IEC)-approved informed consent. For subjects < 18 years of age,
             their parents or legal guardians must sign a written informed consent. Assent, when
             appropriate, will be obtained according to institutional guidelines

          -  Have histologically or cytological confirmed diagnosis of rhabdomyosarcoma with
             locally advanced/unresectable, metastatic, refractory or relapsed disease who have
             failed standard therapy and for whom no known curative therapy exists

          -  Measurable disease according to RECIST version 1.1

          -  Prior cancer therapy: Subjects may have received any number of prior therapy regimens.
             In the investigator's opinion, subjects must have tolerated prior cytotoxic therapies
             well and have adequate bone marrow reserve. At the time of treatment initiation, at
             least 3 weeks must have elapsed after prior cytotoxic chemotherapy. At least 7 days
             must have elapsed since completion of any prior non-cytotoxic cancer therapy and any
             associated AEs must have resolved

          -  Prior radiotherapy is allowed if >= 2 weeks have elapsed for local palliative
             radiation therapy (XRT) (small port); >= 6 months must have elapsed if prior total
             body irradiation, craniospinal XRT or if > 50% radiation of the pelvis; > 6 weeks must
             have elapsed if other substantial bone marrow radiation (defined per principal
             investigator's [PI's] discretion). Subjects who have received brain irradiation must
             have completed whole brain radiotherapy and/or gamma knife at least 4 weeks prior to
             enrollment

          -  Subjects with controlled asymptomatic central nervous system (CNS) involvement are
             allowed in absence of therapy with anticonvulsants. Subjects not requiring steroids or
             requiring steroids at a stable dose (=< 4 mg/day dexamethasone or equivalent) for at
             least 2 weeks are eligible

          -  Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
             therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse
             Events (CTCAE) (version 4.03) grade < 1 or to the baseline laboratory values as
             defined below

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 in subjects >=
             17 years old; or Karnofsky/Lansky > 50 in subjects < 16 years old

          -  Subjects age > 18 years for first cohort. Subjects must be > 12 years old for the
             second and subsequent cohorts

          -  Life expectancy of at least 3 months

          -  Absolute neutrophil count (ANC) >= 1000/mm^3 (>= 1.0 x 10^9/L)

          -  Platelets (PLT) >= 100,000/mm^3 (>= 100 x 10^9/L) (transfusion independent, defined as
             not receiving platelet transfusions within a 7 day period prior to screening)

          -  Hemoglobin > 9.0 g/dL (transfusions are allowed)

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance > 60
             mL/min

          -  Total serum bilirubin =< 1.5 x ULN; =< 5 x ULN if Gilbert's syndrome

          -  Liver transaminases (aspartate aminotransferase [AST]/alanine aminotransferase [ALT])
             =< 2.5 x ULN; =< 5 x ULN if liver metastases are present

          -  Pregnancy test if female of child-bearing potential negative within 7 days of starting
             treatment

          -  Cardiac ejection fraction > 50% or shortening fraction > 28% by echocardiography
             (ECHO) or multigated acquisition scan (MUGA)

          -  Females of child-bearing potential must have a negative pregnancy test during
             screening and be neither breastfeeding nor intending to become pregnant during study
             participation. Females of childbearing potential must agree to avoid pregnancy during
             the study and commit to abstinence from heterosexual intercourse or agree to use two
             methods of birth control (one highly effective method and one additional effective
             method) at least 4 weeks before the start of protocol therapy, for the duration of
             study participation, and for 6 months after the last dose of mocetinostat

          -  Males with partner(s) of childbearing potential must take appropriate precautions to
             avoid fathering a child from the screening period until 90 days after receiving the
             last dose of mocetinostat. They must commit to abstinence from heterosexual
             intercourse or agree to use appropriate barrier contraception

          -  Prior to enrollment of females or males of reproductive potential, the investigator
             must document confirmation of the subject's understanding of the possible teratogenic
             effects of mocetinostat

          -  Willingness and ability to comply with scheduled visits, treatment plan, laboratory
             tests and other study procedures

        Exclusion Criteria:

          -  Current participation in another therapeutic clinical trial

          -  Symptomatic brain metastases

          -  History of previous cancer (non RMS), except squamous cell or basal-cell carcinoma of
             the skin or any in situ carcinoma that has been completely resected, which required
             therapy within the previous 3 years. Other low grade cancers can be reviewed and
             allowed at the discretion of the PI

          -  Incomplete recovery from any surgery (other than central venous catheter or port
             placement) prior to treatment

          -  Any of the following in the past 6 months: pericarditis, pericardial effusion,
             symptomatic congestive heart failure, cerebrovascular accident or transient ischemic
             attack, pulmonary embolism, deep vein thrombosis, symptomatic bradycardia, requirement
             for anti-arrhythmic medication

          -  History of prolonged corrected QT (QTc) interval (e.g., repeated demonstration of a
             QTc interval > 450 milliseconds, unless associated with the use of medications known
             to prolong the QTc interval). QTc will be calculated using the Bazett formula (RR
             interval = 60/heart rate; QTI corrected = QT interval/sqr[RRinterval])

          -  History of additional risk factors for torsade de pointes (e.g., heart failure, family
             history of long QT syndrome)

          -  Use of concomitant medications that increase or possibly increase the risk to prolong
             the QTc interval and/or induce torsades de pointes ventricular arrhythmia

          -  Females who are breastfeeding/lactating

          -  Known active infections (e.g., bacterial, fungal, viral including hepatitis and human
             immunodeficiency virus [HIV] positivity)

          -  Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration or may interfere with the interpretation of study results and, in
             the judgment of the investigator, would make the subject inappropriate for entry into
             this study or compromise protocol objectives in the opinion of the investigator and/or
             the sponsor
      
Maximum Eligible Age:35 Years
Minimum Eligible Age:13 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To describe any dose-limiting toxicity (DLT)
Time Frame:1 year
Safety Issue:
Description:Percentage of subjects with dose-limiting toxicities (DLTs) as assessed by NCI CTCAE (Version 4.03)

Secondary Outcome Measures

Measure:To determine the Recommended Phase 2 Dose (RP2D) for mocetinostat in combination with vinorelbine
Time Frame:1 year
Safety Issue:
Description:The RP2D may be determined by the MTD or optimal target inhibition with an acceptable safety profile
Measure:Incidence of Adverse Events (AEs) as assessed by NCI CTCAE (Version 4.03)
Time Frame:1 year
Safety Issue:
Description:Assess incidence of all AEs by NCI CTCAE (Version 4.03) grades 1-5
Measure:Objective Tumor Response
Time Frame:2 years
Safety Issue:
Description:Measured using RECIST, Version 1.1
Measure:Progression Free Survival (PFS)
Time Frame:2 years
Safety Issue:
Description:Estimated using Kaplan-Meier methodology
Measure:Disease Control (DC)
Time Frame:2 years
Safety Issue:
Description:Proportion of subjects with a confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) according to RECIST v1.1
Measure:Duration of Response (DOR)
Time Frame:2 years
Safety Issue:
Description:Measured from the first date a response is identified (either CR or PR) until the date of disease progression
Measure:Area under the Plasma Concentration versus Time Curve (AUC) of mocetinostat
Time Frame:2 years
Safety Issue:
Description:Continuous variables will be summarized with means, standard deviations, medians, minimums, and maximums
Measure:Clearance (CL) of mocetinostat
Time Frame:2 years
Safety Issue:
Description:Continuous variables will be summarized with means, standard deviations, medians, minimums, and maximums
Measure:Half-Life [T1/2] of mocetinostat
Time Frame:2 years
Safety Issue:
Description:Continuous variables will be summarized with means, standard deviations, medians, minimums, and maximums
Measure:Volume of Distribution (Vd) of mocetinostat
Time Frame:2 years
Safety Issue:
Description:Continuous variables will be summarized with means, standard deviations, medians, minimums, and maximums

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

Trial Keywords

  • Locally Advanced Rhabdomyosarcoma
  • Recurrent Rhabdomyosarcoma
  • Refractory Rhabdomyosarcoma
  • Unresectable Rhabdomyosarcoma

Last Updated

March 4, 2020