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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention / Treatment
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* Drug: Daratumumab
* Drug: Vincristine
* Drug: Prednisone
* Drug: Doxorubicin
* Biological: Peg-asparaginase
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: 6-mercaptopurine
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) as defined by the criteria below: 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. 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: Hemoglobin (>=) 7.5 gram per deciliter (g/dL) ([>=] 5 millimole per liter [mmol/L]; prior red blood cell [RBC] transfusion is permitted) 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: Alanine aminotransferase level less than or equal to (<=) 2.5* the upper limit of normal (ULN), Aspartate aminotransferase level (<=) 2.5* ULN, and 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: Evidence of dyspnea at rest or oxygen saturation (<=) 94 percent (%). 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: 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 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)

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: B-Cell Acute Lymphoblastic Leukemia (ALL)/LL<br>Cohort 1 will include participants with B cell ALL/LL in second or greater relapse or refractory to at least 2 prior induction regimens. Participant will receive daratumumab in combination with vincristine and prednisone. | Drug: Daratumumab<br>* Participant will receive daratumumab 16 milligram per kilogram (mg/kg) in cohort 1 and cohort 2.<br>Drug: Vincristine<br>* Participant will receive vincristine 1.5 milligram per meter square (mg/m^2) in cohort 1 and cohort 2.<br>Drug: Prednisone<br>* Participant will receive prednisone 40 mg/m^2 in cohort 1 and cohort 2.<br>|
| Experimental: Cohort 2: T-Cell ALL/LL<br>Cohort 2 will include participants with T-cell ALL/LL in first relapse or refractory to at least 1 prior induction/consolidation regimen. Participant will receive daratumumab in combination with vincristine, prednisone, doxorubicin and peg-asparaginase in Cycle 1 and daratumumab in combination with cyclophosphamide, cytarabine, 6- mercaptopurine and methotrexate in Cycle 2. | Drug: Daratumumab<br>* Participant will receive daratumumab 16 milligram per kilogram (mg/kg) in cohort 1 and cohort 2.<br>Drug: Vincristine<br>* Participant will receive vincristine 1.5 milligram per meter square (mg/m^2) in cohort 1 and cohort 2.<br>Drug: Prednisone<br>* Participant will receive prednisone 40 mg/m^2 in cohort 1 and cohort 2.<br>Drug: Doxorubicin<br>* Participant will receive doxorubicin 60 mg/m^2 in cohort 2.<br>Biological: Peg-asparaginase<br>* Participant will receive peg-asparaginase 2500 units per meter square (U/m^2) in cohort 2.<br>Drug: Cyclophosphamide<br>* Participant will receive cyclophosphamide 1 gram per meter square (g/m^2) once in cohort 2.<br>Drug: Cytarabine<br>* Participant will receive cytarabine 75 mg/m^2 in cohort 2.<br>Drug: 6-mercaptopurine<br>* Participant will receive 6-mercaptopurine 60 mg/m^2 orally daily in cohort 2.<br>Drug: Methotrexate<br>* Participant will receive methotrexate 5 g/m^2 intravenously (IV) in cohort 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Number of Participants With Anti-daratumumab Antibodies | Number of participants with anti-daratumumab antibodies was reported. | Up to 4 years 4 months | 
| 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 |