Clinical Trials /

A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS

NCT03573310

Description:

The purpose of the study is to identify the maximum tolerated dose (MTD) of JNJ-64619178 in participants with relapsed/refractory B cell non-Hodgkin lymphoma (NHL) or advanced solid tumors and also to identify the recommended Phase 2 dose(s) (RP2Ds) of JNJ-64619178 for NHL and advanced solid tumors (Part 1) and to confirm the tolerability of JNJ-64619178 in participants with lower risk myelodysplastic syndromes (MDS) (Part 2).

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Malignant Solid Tumor
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS
  • Official Title: A Phase 1, First-in-Human, Open-Label Study of the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-64619178, an Inhibitor of Protein Arginine Methyltransferase 5 (PRMT5) in Subjects With Advanced Cancers

Clinical Trial IDs

  • ORG STUDY ID: CR108485
  • SECONDARY ID: 64619178EDI1001
  • SECONDARY ID: 2018-000067-87
  • NCT ID: NCT03573310

Conditions

  • Neoplasms
  • Solid Tumor, Adult
  • Non-Hodgkin Lymphoma
  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
JNJ-64619178Part 1: Dose escalation and RP2D Selection

Purpose

The purpose of the study is to identify the maximum tolerated dose (MTD) of JNJ-64619178 in participants with relapsed/refractory B cell non-Hodgkin lymphoma (NHL) or advanced solid tumors and also to identify the recommended Phase 2 dose(s) (RP2Ds) of JNJ-64619178 for NHL and advanced solid tumors (Part 1) and to confirm the tolerability of JNJ-64619178 in participants with lower risk myelodysplastic syndromes (MDS) (Part 2).

Detailed Description

      The study is designed to determine the maximum tolerated dose (MTD) of JNJ-64619178, and to
      select a dose(s) and regimen(s) that may be used in future clinical development. Study
      evaluations will include safety, pharmacokinetics, biomarkers and efficacy evaluations
      (Disease Assessments). Adverse events will be evaluated throughout the study. The study is
      divided into 4 periods: a screening phase, a pharmacokinetic run-in phase, a treatment phase,
      and a post treatment follow-up phase. An end-of-treatment visit will be completed less than
      or equal (<=) 30 days (+7 days) after the last dose of study drug or prior to the start of a
      new anticancer therapy, whichever comes first.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1: Dose escalation and RP2D SelectionExperimentalParticipants with solid tumors or non-Hodgkin lymphoma (NHL) will receive JNJ-64619178 orally as per the assigned sequential cohorts and doses will be escalated based on the review of all available data including, but not limited to, pharmacokinetic, pharmacodynamic, safety, and clinical activity. One or more recommended Phase 2 dose(s) (RP2Ds) may be determined for further exploration.
  • JNJ-64619178
Part 2:Dose Confirmation and ExpansionExperimentalParticipants with myelodysplastic syndromes (MDS) will receive JNJ-64619178 at a dose less than or equal to the RP2D selected in Part 1 for 24 weeks, or longer if there is evidence of clinical benefit. The dose level of JNJ-64619178 may be adjusted based on observed toxicities.
  • JNJ-64619178

Eligibility Criteria

        Inclusion Criteria:

          -  B cell non-Hodgkin lymphoma (NHL) or solid tumors, or lower risk MDS

          -  At least 1 measurable site of disease for B cell-NHL and solid tumors

          -  Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1

          -  Adequate organ function

          -  Women of childbearing potential must have a negative highly sensitive serum
             (beta-human chorionic gonadotropin [beta-hCG]) at screening and prior to the first
             dose of study drug. Women must agree not to donate eggs (ova, oocytes) for the
             purposes of assisted reproduction during the study and for a period of 90 days after
             receiving the last dose of study drug

        Exclusion Criteria:

          -  History of, or known, central nervous system (CNS) involvement

          -  Prior solid organ transplantation

          -  Either of the following: a) Received an autologous stem cell transplant less than or
             equal (<=) 9 months before the first dose of study drug B) Prior treatment with
             allogenic stem cell transplant

          -  History of malignancy (other than the disease under study) within 3 years before the
             first administration of study drug. Exceptions include squamous and basal cell
             carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the
             opinion of the investigator, with concurrence with the sponsor's medical monitor, is
             considered cured with minimal risk of recurrence within 3 years

          -  Known allergies, hypersensitivity, or intolerance to JNJ-64619178 or its excipient
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1 and Part 2: Number of Participants with Dose-limiting Toxicities (DLTs)
Time Frame:Approximately 3 years
Safety Issue:
Description:DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.

Secondary Outcome Measures

Measure:Part 1 and Part 2: Number of Participants with Adverse Events (AE)
Time Frame:Approximately 3 years
Safety Issue:
Description:AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship.
Measure:Part 1 and Part 2: Number of Participants with AE by Severity
Time Frame:Approximately 3 years
Safety Issue:
Description:Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Severity scale ranges from Grade 1 (Mild) to Grade 4 (Life-threatening). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event.
Measure:Part 1 and Part 2: Number of Participants with Abnormal Vital Signs
Time Frame:Approximately 3 years
Safety Issue:
Description:Number of participants with abnormality in vital signs (temperature, pulse/heart rate, and blood pressure) will be reported.
Measure:Part 1 and Part 2: Number of Participants with Laboratory Abnormalities
Time Frame:Approximately 3 years
Safety Issue:
Description:Number of participants with laboratory abnormalities (serum chemistry, hematology, and coagulation, and disease-related laboratory abnormalities) will be reported.
Measure:Part 1 and Part 2: Number of Participants with Electrocardiogram (ECG) Abnormalities
Time Frame:Approximately 3 years
Safety Issue:
Description:Number of participants with electrocardiogram(ECG) abnormalities will be reported.
Measure:Part 1 and Part 2: Maximum Plasma Concentration (Cmax) of JNJ-64619178
Time Frame:Approximately 3 years
Safety Issue:
Description:Cmax is the maximum observed plasma concentration.
Measure:Part 1 and Part 2: Area Under the Plasma Concentration Versus Time Curve From Time Zero to End of Dosing Interval (AUCtau)
Time Frame:Approximately 3 years
Safety Issue:
Description:AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval.
Measure:Part 1 and Part 2: Minimum Plasma Concentration (Cmin)
Time Frame:Approximately 3 years
Safety Issue:
Description:Cmin is the minimum observed plasma concentration.
Measure:Part 1 and Part 2: Plasma Decay Half-Life (t1/2)
Time Frame:Approximately 3 years
Safety Issue:
Description:Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Measure:Part 1 and Part 2: Volume of Distribution at Steady-State Influenced by the Fraction Absorbed (Vss/F)
Time Frame:Approximately 3 years
Safety Issue:
Description:Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady state which is estimated by (D/AUC[0-infinity])* (AUMC[0-infinity])/(AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. All these parameters will be assessed as influenced by the fraction absorbed.
Measure:Part 1 and Part 2: Apparent Total Systemic Clearance of Drug (CL/F) after Extravascular Administration
Time Frame:Approximately 3 years
Safety Issue:
Description:Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Measure:Part 1 and Part 2: Accumulation Index (RA)
Time Frame:Approximately 3 years
Safety Issue:
Description:Accumulation Index (RA) is calculated as AUC (0-24) value at steady state divided by AUC (0-24) value after first dose.
Measure:Part 1 and Part 2: Plasma Concentration of Symmetric Dimethyl-Arginine (SDMA)
Time Frame:Approximately 3 years
Safety Issue:
Description:Plasma concentration of symmetric dimethyl-arginine (SDMA) will be evaluated.
Measure:Part 1: Percentage of Participants with B cell non-Hodgkin lymphoma (NHL) Showing Overall Response of Partial Response (PR) or Better
Time Frame:Approximately 3 years
Safety Issue:
Description:Overall response rate (ORR) is defined as the percentage of participants who have a PR or better. Per Lugano classification, PR is defined as greater than or equal (>=) 50 percent (%) decrease in size of target lesions.
Measure:Part 1: Percentage of Participants with Solid Tumors Showing Overall Response of PR or Better
Time Frame:Approximately 3 years
Safety Issue:
Description:Overall response rate (ORR) is defined as the percentage of participants who have a PR or better. PR criteria in solid tumors (RECIST) is >= 30 percent (%) decrease in the sum of the diameters of all index lesions compared with baseline in 2 observations at least 4 weeks apart, in absence of new lesions or unequivocal progression of non-index lesions.
Measure:Part 1: Duration of Response
Time Frame:Approximately 3 years
Safety Issue:
Description:Duration of response (DOR) will be calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease (PD), as defined in the disease-specific response criteria, or death due to any cause, whichever occurs first. PD (per RECIST 1.1) defined as at least 20% increase in the sum of the longest diameters of index lesions or unequivocal progression of non-index lesions. Per Lugano classification, PD: target lesions larger; clear progression of non-target lesions; or new tumor lesions; new or recurrent bone marrow involvement; splenomegaly + 2 centimeter (cm) or +50%.
Measure:Part 1: Clinical Benefit Rate
Time Frame:Approximately 3 years
Safety Issue:
Description:Clinical benefit rate is defined as percentage of participants who have a complete response (CR), PR and sustained stable disease of 12 weeks or more. Sustained stable disease of 12 weeks or more is defined as participants with stable disease assessment maintained for about 12 weeks or longer from baseline. Per Lugano classification CR is defined as no detectable disease by computed tomography (CT) or positron emission tomography (PET)/CT scan. Evaluation criteria as per RECIST 1.1 for CR is defined as disappearance of all lesions in 2 consecutive observations not less than 4 weeks apart.
Measure:Part 2: Red Blood Cell (RBC) Transfusion Independence (TI) Rate
Time Frame:Approximately 3 years
Safety Issue:
Description:Percentage of participants with TI, defined as being without any transfusion during any consecutive 8 weeks (56 days) between the first dose of study drug and treatment discontinuation.
Measure:Part 2: Overall Improvement Rate
Time Frame:Approximately 3 years
Safety Issue:
Description:Overall improvement rate is defined as the percentage of participants achieving complete remission (bone marrow: less than or equal to (<=)5% myeloblasts with normal maturation of all cell lines; Peripheral blood: hemoglobin >=11 gram per deciliter (g/dL); platelets >=100*109/liter(L); neutrophils >=1.0*109/L; blasts, 0%), partial remission (All complete remission criteria if abnormal before treatment except: Bone marrow blasts decreased by >=50% over pretreatment but still >5% Cellularity and morphology not relevant), or hematologic improvement (HI) (Erythroid response [pretreatment, <11 g/dL]; Platelet response (pretreatment, <100*10^9/L); Neutrophil response (pretreatment, <1*10^9/L); Progression or relapse after HI) according to modified International Working Group (IWG) criteria.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Janssen Research & Development, LLC

Trial Keywords

  • Lower risk MDS
  • Low risk MDS
  • Lower-risk MDS
  • Low-risk MDS
  • Intermediate 1 risk MDS
  • Intermediate-1 risk MDS

Last Updated

November 14, 2019