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

Sponsor

Janssen Research & Development, LLC (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03573310

Collaborator

(none)

114

Enrollment

Locations

Arms

65.5

Anticipated Duration (Months)

6.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Neoplasms Solid Tumor, Adult Non-Hodgkin Lymphoma Myelodysplastic Syndromes	Drug: JNJ-64619178	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

114 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jul 13, 2018

Anticipated Primary Completion Date :

Dec 28, 2023

Anticipated Study Completion Date :

Dec 29, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Dose escalation and RP2D Selection Participants 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.	Drug: JNJ-64619178 JNJ-64619178 capsules to be administered orally.
Experimental: Part 2:Dose Confirmation and Expansion Participants 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.	Drug: JNJ-64619178 JNJ-64619178 capsules to be administered orally.

Arm

Intervention/Treatment

Experimental: Part 1: Dose escalation and RP2D Selection

Participants 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.

Drug: JNJ-64619178

JNJ-64619178 capsules to be administered orally.

Experimental: Part 2:Dose Confirmation and Expansion

Participants 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.

Drug: JNJ-64619178

JNJ-64619178 capsules to be administered orally.

Outcome Measures

Primary Outcome Measures

Part 1 and Part 2: Number of Participants with Dose-limiting Toxicities (DLTs) [Approximately 3 years]
DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.

Secondary Outcome Measures

Part 1 and Part 2: Number of Participants with Adverse Events (AE) [Approximately 3 years]
AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship.
Part 1 and Part 2: Number of Participants with AE by Severity [Approximately 3 years]
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.
Part 1 and Part 2: Number of Participants with Abnormal Vital Signs [Approximately 3 years]
Number of participants with abnormality in vital signs (temperature, pulse/heart rate, and blood pressure) will be reported.
Part 1 and Part 2: Number of Participants with Laboratory Abnormalities [Approximately 3 years]
Number of participants with laboratory abnormalities (serum chemistry, hematology, and coagulation, and disease-related laboratory abnormalities) will be reported.
Part 1 and Part 2: Number of Participants with Electrocardiogram (ECG) Abnormalities [Approximately 3 years]
Number of participants with electrocardiogram(ECG) abnormalities will be reported.
Part 1 and Part 2: Maximum Plasma Concentration (Cmax) of JNJ-64619178 [Approximately 3 years]
Cmax is the maximum observed plasma concentration.
Part 1 and Part 2: Area Under the Plasma Concentration Versus Time Curve From Time Zero to End of Dosing Interval (AUCtau) [Approximately 3 years]
AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval.
Part 1 and Part 2: Minimum Plasma Concentration (Cmin) [Approximately 3 years]
Cmin is the minimum observed plasma concentration.
Part 1 and Part 2: Plasma Decay Half-Life (t1/2) [Approximately 3 years]
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Part 1 and Part 2: Volume of Distribution at Steady-State Influenced by the Fraction Absorbed (Vss/F) [Approximately 3 years]
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.
Part 1 and Part 2: Apparent Total Systemic Clearance of Drug (CL/F) after Extravascular Administration [Approximately 3 years]
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Part 1 and Part 2: Accumulation Index (RA) [Approximately 3 years]
Accumulation Index (RA) is calculated as AUC (0-24) value at steady state divided by AUC (0-24) value after first dose.
Part 1 and Part 2: Plasma Concentration of Symmetric Dimethyl-Arginine (SDMA) [Approximately 3 years]
Plasma concentration of symmetric dimethyl-arginine (SDMA) will be evaluated.
Part 1: Percentage of Participants with B cell non-Hodgkin lymphoma (NHL) Showing Overall Response of Partial Response (PR) or Better [Approximately 3 years]
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.
Part 1: Percentage of Participants with Solid Tumors Showing Overall Response of PR or Better [Approximately 3 years]
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.
Part 1: Duration of Response [Approximately 3 years]
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%.
Part 1: Clinical Benefit Rate [Approximately 3 years]
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.
Part 2: Red Blood Cell (RBC) Transfusion Independence (TI) Rate [Approximately 3 years]
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.
Part 2: Overall Improvement Rate [Approximately 3 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Specialist and Cancer Institute	Sarasota	Florida	United States	34232
2	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
3	Ohio State University	Columbus	Ohio	United States	43210
4	University of Texas, MD Anderson Cancer Center	Houston	Texas	United States	77030
5	University of Toronto	Toronto		Canada	M5G1Z5
6	St. Paul's Hospital	Vancouver		Canada	V6E 1M7
7	Universitaetsklinikum Duesseldorf	Düsseldorf		Germany	40225
8	Goethe Universität Frankfurt	Frankfurt/Main		Germany	60590
9	Universitatsklinikum Leipzig	Leipzig		Germany	04103
10	Carmel Medical Center	Haifa		Israel	34362
11	Hadassah Medical Center	Jerusalem		Israel	9112001
12	Tel Aviv Sourasky MC	Tel Aviv		Israel	6423906
13	Hosp. Univ. Germans Trias I Pujol	Badalona		Spain	08916
14	Hosp. Univ. Vall D Hebron	Barcelona		Spain	08035
15	Hosp. Univ. Fund. Jimenez Diaz	Madrid		Spain	28040
16	Clinica Univ. de Navarra	Pamplona		Spain	31008
17	Hosp. Clinico Univ. de Salamanca	Salamanca		Spain	37007
18	Hosp. Virgen Del Rocio	Sevilla		Spain	41013