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

Primary Purpose

Neoplasms, Solid Tumor, Adult, Non-Hodgkin Lymphoma

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
JNJ-64619178
Sponsored by
Janssen Research & Development, LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neoplasms focused on measuring Lower risk MDS, Low risk MDS, Lower-risk MDS, Low-risk MDS, Intermediate 1 risk MDS, Intermediate-1 risk MDS

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Florida Specialist and Cancer Institute
  • Massachusetts General Hospital
  • Ohio State University
  • University of Texas, MD Anderson Cancer Center
  • St. Paul's Hospital
  • University of Toronto
  • Universitaetsklinikum Duesseldorf
  • Goethe Universität Frankfurt
  • Universitaetsklinikum Leipzig
  • Carmel Medical Center
  • Hadassah Medical Center
  • Tel Aviv Sourasky MC
  • Hosp. Univ. Germans Trias I Pujol
  • Hosp. Univ. Vall D Hebron
  • Hosp. Univ. Fund. Jimenez Diaz
  • Clinica Univ. de Navarra
  • Hosp. Clinico Univ. de Salamanca
  • Hosp. Virgen Del Rocio

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Part 1: Dose escalation and RP2D Selection

Part 2:Dose Confirmation and Expansion

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Part 1 and Part 2: Number of Participants with Dose-limiting Toxicities (DLTs)
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)
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
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
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
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
Number of participants with electrocardiogram(ECG) abnormalities will be reported.
Part 1 and Part 2: Maximum Plasma Concentration (Cmax) of JNJ-64619178
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)
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)
Cmin is the minimum observed plasma concentration.
Part 1 and Part 2: Plasma Decay Half-Life (t1/2)
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)
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
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)
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)
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
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
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
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
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
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
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.

Full Information

First Posted
June 20, 2018
Last Updated
October 10, 2023
Sponsor
Janssen Research & Development, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT03573310
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 13, 2018 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Janssen Research & Development, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neoplasms, Solid Tumor, Adult, Non-Hodgkin Lymphoma, Myelodysplastic Syndromes
Keywords
Lower risk MDS, Low risk MDS, Lower-risk MDS, Low-risk MDS, Intermediate 1 risk MDS, Intermediate-1 risk MDS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
114 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part 1: Dose escalation and RP2D Selection
Arm Type
Experimental
Arm Description
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.
Arm Title
Part 2:Dose Confirmation and Expansion
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
JNJ-64619178
Intervention Description
JNJ-64619178 capsules to be administered orally.
Primary Outcome Measure Information:
Title
Part 1 and Part 2: Number of Participants with Dose-limiting Toxicities (DLTs)
Description
DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.
Time Frame
Approximately 3 years
Secondary Outcome Measure Information:
Title
Part 1 and Part 2: Number of Participants with Adverse Events (AE)
Description
AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Number of Participants with AE by Severity
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.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Number of Participants with Abnormal Vital Signs
Description
Number of participants with abnormality in vital signs (temperature, pulse/heart rate, and blood pressure) will be reported.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Number of Participants with Laboratory Abnormalities
Description
Number of participants with laboratory abnormalities (serum chemistry, hematology, and coagulation, and disease-related laboratory abnormalities) will be reported.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Number of Participants with Electrocardiogram (ECG) Abnormalities
Description
Number of participants with electrocardiogram(ECG) abnormalities will be reported.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Maximum Plasma Concentration (Cmax) of JNJ-64619178
Description
Cmax is the maximum observed plasma concentration.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Area Under the Plasma Concentration Versus Time Curve From Time Zero to End of Dosing Interval (AUCtau)
Description
AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Minimum Plasma Concentration (Cmin)
Description
Cmin is the minimum observed plasma concentration.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Plasma Decay Half-Life (t1/2)
Description
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Volume of Distribution at Steady-State Influenced by the Fraction Absorbed (Vss/F)
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.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Apparent Total Systemic Clearance of Drug (CL/F) after Extravascular Administration
Description
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Accumulation Index (RA)
Description
Accumulation Index (RA) is calculated as AUC (0-24) value at steady state divided by AUC (0-24) value after first dose.
Time Frame
Approximately 3 years
Title
Part 1 and Part 2: Plasma Concentration of Symmetric Dimethyl-Arginine (SDMA)
Description
Plasma concentration of symmetric dimethyl-arginine (SDMA) will be evaluated.
Time Frame
Approximately 3 years
Title
Part 1: Percentage of Participants with B cell non-Hodgkin lymphoma (NHL) Showing Overall Response of Partial Response (PR) or Better
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.
Time Frame
Approximately 3 years
Title
Part 1: Percentage of Participants with Solid Tumors Showing Overall Response of PR or Better
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.
Time Frame
Approximately 3 years
Title
Part 1: Duration of Response
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%.
Time Frame
Approximately 3 years
Title
Part 1: Clinical Benefit Rate
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.
Time Frame
Approximately 3 years
Title
Part 2: Red Blood Cell (RBC) Transfusion Independence (TI) Rate
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.
Time Frame
Approximately 3 years
Title
Part 2: Overall Improvement Rate
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.
Time Frame
Approximately 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Janssen Research & Development, LLC Clinical Trial
Organizational Affiliation
Janssen Research & Development, LLC
Official's Role
Study Director
Facility Information:
Facility Name
Florida Specialist and Cancer Institute
City
Sarasota
State/Province
Florida
ZIP/Postal Code
34232
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
University of Texas, MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
St. Paul's Hospital
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6E 1M7
Country
Canada
Facility Name
University of Toronto
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G1Z5
Country
Canada
Facility Name
Universitaetsklinikum Duesseldorf
City
Düsseldorf
ZIP/Postal Code
40225
Country
Germany
Facility Name
Goethe Universität Frankfurt
City
Frankfurt/Main
ZIP/Postal Code
60590
Country
Germany
Facility Name
Universitaetsklinikum Leipzig
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Carmel Medical Center
City
Haifa
ZIP/Postal Code
34362
Country
Israel
Facility Name
Hadassah Medical Center
City
Jerusalem
ZIP/Postal Code
9112001
Country
Israel
Facility Name
Tel Aviv Sourasky MC
City
Tel Aviv
ZIP/Postal Code
6423906
Country
Israel
Facility Name
Hosp. Univ. Germans Trias I Pujol
City
Badalona
ZIP/Postal Code
08916
Country
Spain
Facility Name
Hosp. Univ. Vall D Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hosp. Univ. Fund. Jimenez Diaz
City
Madrid
ZIP/Postal Code
28040
Country
Spain
Facility Name
Clinica Univ. de Navarra
City
Pamplona
ZIP/Postal Code
31008
Country
Spain
Facility Name
Hosp. Clinico Univ. de Salamanca
City
Salamanca
ZIP/Postal Code
37007
Country
Spain
Facility Name
Hosp. Virgen Del Rocio
City
Sevilla
ZIP/Postal Code
41013
Country
Spain

12. IPD Sharing Statement

Learn more about this trial

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

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