A Study to Evaluate the Efficacy and Safety of Daratumumab in Pediatric and Young Adult Participants Greater Than or Equal to (>=)1 and Less Than or Equal to (<=) 30 Years of Age With Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

Precursor Cell Lymphoblastic Leukemia-Lymphoma Clinical Trial

Official title:

An Open-label, Multicenter, Phase 2 Study Evaluating the Efficacy and Safety of Daratumumab in Pediatric and Young Adult Subjects >=1 and <=30 Years of Age With Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03384654
• Other study ID #: CR108432
• Secondary ID: 2017-003377-3454
• Status: Completed
• Phase: Phase 2
• Start date: May 14, 2018
• Est. completion date: September 27, 2022

Study information

• Verified date: December 2023
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy of daratumumab in addition to standard chemotherapy in pediatric participants with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LL) and T-cell ALL/LL as measured by the complete response (CR) rate.

Description:

Screening for eligible participants will be performed within 21 days before administration of the study drug. Participants with B-cell ALL/LL will receive treatment until disease progression, unacceptable toxicity or achievement of CR followed by hematopoietic stem cell transplant (HSCT). Participants with T cell ALL/LL will receive treatment for up to 2 cycles. If disease progression is confirmed, then the participant will discontinue study treatment, complete the End of Treatment Visit, and enter the Posttreatment Period. For those participants who discontinue study drug prior to disease progression, disease evaluations will continue to be performed every 8 weeks until subsequent anticancer therapy is initiated.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: September 27, 2022
• Est. primary completion date: September 22, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 30 Years

Eligibility

Inclusion Criteria:

• Documented acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) as

defined by the criteria below:

1. B-cell cohort: Stage 1; ALL in second or greater relapse or refractory to 2 prior induction regimens with greater than or equal to (>=) 5 percent (%) blasts in the bone marrow and aged 1 to less than (<) 18 years. Stage 2; ALL in second or greater relapse or refractory to 2 prior induction regimens with (>=) 5% blasts in the bone marrow and aged 1 to 30 years. LL in second or greater relapse or refractory to 2 prior induction regimens and biopsy proven and with evidence of measurable disease by radiologic criteria and aged 1 to 30 years.

2. T-cell cohort: Stage 1; ALL in first relapse or refractory to 1 prior induction/consolidation regimen with (>=) 5% blasts in the bone marrow and aged 1 to <18 years. Stage 2; ALL in first relapse or refractory to 1 prior induction/consolidation regimen with (>=) 5% blasts in the bone marrow and aged 1 to 30 years. LL in first relapse or refractory to 1 prior induction/consolidation regimen biopsy proven and with evidence of measurable disease by radiologic criteria and aged 1 to 30 years

• Performance status greater than or equal to (>=) 70 by Lansky scale (for participants less than [<] 16 years of age) or Karnofsky scale (for participants [>=] 16 years of age)
• Adequate hematology laboratory values at Cycle 1 Day 1 pre-dosing defined as follows:

1. Hemoglobin (>=) 7.5 gram per deciliter (g/dL) ([>=] 5 millimole per liter [mmol/L]; prior red blood cell [RBC] transfusion is permitted)

2. Platelet count (>=) 10*10^9 per liter (L) (prior platelet transfusion is permitted)

• Adequate renal function defined as normal serum creatinine for the participant's age or creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2) prior to enrollment
• Adequate liver function prior to enrollment defined as:

1. Alanine aminotransferase level less than or equal to (<=) 2.5* the upper limit of normal (ULN),

2. Aspartate aminotransferase level (<=) 2.5* ULN, and

3. Total bilirubin (<=) 2* ULN or direct bilirubin level (<=) 2.0* ULN

Exclusion Criteria:

• Received an allogeneic hematopoietic transplant within 3 months of screening
• Active acute graft-versus-host disease of any grade or chronic graft-versus-host disease of Grade 2 or higher
• Received immunosuppression post hematopoietic transplant within 1 month of study entry
• Philadelphia chromosome positive (Ph+) B-cell ALL eligible for tyrosine kinase inhibitor therapy
• Has either of the following:

1. Evidence of dyspnea at rest or oxygen saturation (<=) 94 percent (%).

2. Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification

• Received an investigational drug, was vaccinated with live attenuated vaccines, or used an invasive investigational medical device within 4 weeks before the planned first dose of study drug, or is currently being treated in an investigational study
• Known to be seropositive for human immunodeficiency virus (HIV)
• Any one of the following:

1. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with resolved infection (ie, participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded

2. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Daratumumab
Participant will receive daratumumab 16 milligram per kilogram (mg/kg) in cohort 1 and cohort 2.
• Vincristine
Participant will receive vincristine 1.5 milligram per meter square (mg/m^2) in cohort 1 and cohort 2.
• Prednisone
Participant will receive prednisone 40 mg/m^2 in cohort 1 and cohort 2.
• Doxorubicin
Participant will receive doxorubicin 60 mg/m^2 in cohort 2.

Biological:
• Peg-asparaginase
Participant will receive peg-asparaginase 2500 units per meter square (U/m^2) in cohort 2.

Drug:
• Cyclophosphamide
Participant will receive cyclophosphamide 1 gram per meter square (g/m^2) once in cohort 2.
• Cytarabine
Participant will receive cytarabine 75 mg/m^2 in cohort 2.
• 6-mercaptopurine
Participant will receive 6-mercaptopurine 60 mg/m^2 orally daily in cohort 2.
• Methotrexate
Participant will receive methotrexate 5 g/m^2 intravenously (IV) in cohort 2.

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Gent - UZ GENT	Gent
France	CHU de Bordeaux, Hopital des Enfants	Bordeaux
France	IHOPE - Hospices civils de Lyon	Lyon
France	Hôpital Robert Debré	Paris
France	Hopital trousseau- APHP	Paris
France	Hôpital D'Enfants	Vandoeuvre les Nancy
Germany	Charite-Universitätsmedizin Berlin - Berlin	Berlin
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitätsklinikum Münster	Münster
Israel	Schneider Children's Medical Center	Petach Tiquva
Italy	Istituto Giannina Gaslini	Genova
Italy	Fondazione MBBM, ASST Monza	Monza
Italy	Ospedale Pediatrico Bambin Gesù	Roma
Italy	AOU Città della Salute e della Scienza di Torino, Presidio Ospedale Infantile Regina Margherita	Torino
Netherlands	Princess Maxima Center	Utrecht
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	Hosp. Sant Joan de Deu	Esplugues de Llobregat
Spain	Hosp. Infantil Univ. Nino Jesus	Madrid
Spain	Hosp. Univ. I Politecni La Fe	Valencia
Sweden	Karolinska University Hospital	Stockholm
United Kingdom	Bristol Royal Hospital for Children	Bristol
United Kingdom	Royal Hospital for Sick Children	Glasgow
United Kingdom	Leeds Children's Hospital	Leeds
United Kingdom	Great Ormond Street Hospital	London
United Kingdom	University College London Hospitals	London
United Kingdom	Royal Manchester Children's Hospital	Manchester
United Kingdom	Royal Marsden Hospital	Surrey
United States	C.S. Mott Children's Hospital	Ann Arbor	Michigan
United States	Children'S Healthcare Of Atlanta/Emory Univ. Dept. Of Pediatrics	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas/Children's Blood and Cancer Center	Austin	Texas
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Baylor College of Medicine	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Medical College Of Wisconsin	Milwaukee	Wisconsin
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	New York University Langone Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	Children's Hospital Orange County	Orange	California
United States	Stanford University	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Washington Univeristy School of Medicine/ Pediatrics	Saint Louis	Missouri
United States	University of Utah Primary Children's Medical Center	Salt Lake City	Utah
United States	Stony Brook University Medical Center	Stony Brook	New York

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Belgium,  France,  Germany,  Israel,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cohort 1: Percentage of Participants With Complete Response (CR) for B-cell Acute Lymphoblastic Leukemia (ALL)	Complete response based on the modified National Comprehensive Cancer Network (NCCN) criteria was defined as: less than 5 percent (%) blasts in the bone marrow; no evidence of circulating blasts or extramedullary disease; full recovery of peripheral blood counts: platelets greater than (>)100*10^9 cells/liter (L) and absolute neutrophil count (ANC) >1.0*10^9 cells/L. This outcome measure was planned to be analyzed for specified arm only.	Up to 2 cycles, that is, up to 56 days (each cycle of 28-days)
Primary	Cohort 2: Percentage of Participants With Complete Response (CR) for T-cell ALL	Complete response based on the modified NCCN criteria was defined as: less than 5% blasts in the bone marrow; no evidence of circulating blasts or extramedullary disease; full recovery of peripheral blood counts: platelets >100*10^9 cells/L and ANC >1.0*10^9 cells/L. This outcome measure was planned to be analyzed for specified arms only.	End of Cycle 1 (that is, up to 28 days)
Secondary	Overall Response Rate (ORR)	For ALL participants, ORR was defined as percentage of participants who achieved CR or CR with only partial hematological recovery(CRi) as per NCCN criteria. CR for ALL: less than 5% blasts in bone marrow; no evidence of circulating blasts or extramedullary disease; full recovery of peripheral blood counts: platelets >100*10^9 cells/L and ANC >1.0*10^9 cells/L. CRi for ALL: less than 5% blasts in bone marrow; no evidence of circulating blasts or extramedullary disease; partial recovery of peripheral blood counts not meeting criteria for CR. For LL participants, ORR was defined as percentage of participants who had CR or PR during or after treatment administration but prior to start of subsequent anti-cancer therapy or allogeneic hematopoietic stem cell transplant(HSCT). CR for LL: disappearance of all evidence of disease from all sites. PR for LL: decrease of >=50% in sum of products of diameter of lesions of up to 6 of largest dominant nodes or nodal masses with no new lesions.	Up to 4 years 4 months
Secondary	Event-free Survival (EFS)	EFS was defined as the time (in months) from the date of first treatment to the first documented treatment failure (that is [ie], disease progression) or date of relapse from CR or death due to any cause, whichever occurred first. Per NCCN criteria, relapse from CR is defined as: reappearance of leukemia blasts in the peripheral blood or >5% blasts in the bone marrow; reappearance of extramedullary disease or new extramedullary disease. Progressive disease: increase of at least 25% in the absolute number of circulating peripheral or bone marrow blasts, or development of new extramedullary disease. Kaplan-Meier method was used for the analysis.	Up to 4 years 4 months
Secondary	Relapse-free Survival (RFS)	RFS was defined as the time (in months) from CR to relapse from CR, or disease progression or death due to any cause, whichever occurred first. For ALL, as per NCCN criteria, relapse from CR is defined as: reappearance of leukemia blasts in the peripheral blood or >5% blasts in the bone marrow, or reappearance of extramedullary disease or new extramedullary disease. Progressive disease: increase of at least 25% in absolute number of circulating peripheral or bone marrow blasts, or development of new extramedullary disease. Kaplan-Meier method was used for analysis.	Up to 4 years 4 months
Secondary	Overall Survival (OS)	OS was defined as the time (in months) from the date of first study drug administration to the date of death due to any cause. Kaplan-Meier method was used for the analysis. Participants who died after consent withdrawal were considered as having an OS event.	Up to 4 years 4 months
Secondary	Minimal Residual Disease (MRD) Negative Rate	MRD negative rate was defined as the percentage of participants who were considered MRD negative after MRD testing by bone marrow aspirate at any timepoint after first study treatment administration and before disease progression or starting subsequent anti-cancer therapy or allogeneic hematopoietic stem cell transplant (HSCT). MRD negative was defined as less than (<) 0.01% abnormal population counts to nucleated mononuclear cells when measured by flow cytometry.	Up to 4 years 4 months
Secondary	Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT)	Percentage of participants who received an allogeneic HSCT after treatment with daratumumab were reported.	Up to 4 years 4 months
Secondary	Maximum Observed Serum Concentration (Cmax) of Daratumumab	Cmax was defined as maximum observed serum concentration of daratumumab.	Cohort 1: B-cell ALL: End of infusion (EOI) on Day 1 of Cycle 2; Cohort 2: T-cell ALL (1-17 years): EOI on Day 22 of Cycle 2; Cohort 2: T-cell ALL (18-30 years): EOI on Day 1 of Cycle 2; Cohort 2: T-cell LL (1-30 years): EOI on Day 22 of Cycle 2
Secondary	Minimum Observed Serum Concentration (Cmin) of Daratumumab	Cmin was defined as minimum observed serum concentration of daratumumab.	Cohort 1: B-cell ALL: Predose on Day 1 of Cycle 2; Cohort 2: T-cell ALL (1-17 years): Predose on Day 22 of Cycle 2; Cohort 2: T-cell ALL (18-30 years): Predose on Day 1 of Cycle 2; Cohort 2: T-cell LL (1-30 years): Predose on Day 22 of Cycle 2
Secondary	Number of Participants With Anti-daratumumab Antibodies	Number of participants with anti-daratumumab antibodies was reported.	Up to 4 years 4 months
Secondary	Concentration of Daratumumab in Cerebrospinal Fluid (CSF)	Concentration of daratumumab in CSF was reported. '0' in the number analyzed field signifies that none of the participants were available for the analysis at the specified time points.	Pre-dose on Cohort 1: Cycles 1 and 2: Day 1; Cohort 2: Cycle 1 Day 1 and Day 15 and Cycle 2 Day 2 and Day 15