Precursor Cell Lymphoblastic Leukemia-Lymphoma
Conditions
Brief 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.
Detailed 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.
Interventions
DRUGDaratumumab
Participant will receive daratumumab 16 milligram per kilogram (mg/kg) in cohort 1 and cohort 2.
DRUGVincristine
Participant will receive vincristine 1.5 milligram per meter square (mg/m\^2) in cohort 1 and cohort 2.
DRUGPrednisone
Participant will receive prednisone 40 mg/m\^2 in cohort 1 and cohort 2.
DRUGDoxorubicin
Participant will receive doxorubicin 60 mg/m\^2 in cohort 2.
BIOLOGICALPeg-asparaginase
Participant will receive peg-asparaginase 2500 units per meter square (U/m\^2) in cohort 2.
DRUGCyclophosphamide
Participant will receive cyclophosphamide 1 gram per meter square (g/m\^2) once in cohort 2.
DRUGCytarabine
Participant will receive cytarabine 75 mg/m\^2 in cohort 2.
DRUG6-mercaptopurine
Participant will receive 6-mercaptopurine 60 mg/m\^2 orally daily in cohort 2.
DRUGMethotrexate
Participant will receive methotrexate 5 g/m\^2 intravenously (IV) in cohort 2.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 30 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Percentage of Participants With Complete Response (CR) for B-cell Acute Lymphoblastic Leukemia (ALL) | Up to 2 cycles, that is, up to 56 days (each cycle of 28-days) | 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. |
| Cohort 2: Percentage of Participants With Complete Response (CR) for T-cell ALL | End of Cycle 1 (that is, up to 28 days) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse-free Survival (RFS) | Up to 4 years 4 months | 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. |
| Overall Survival (OS) | Up to 4 years 4 months | 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. |
| Minimal Residual Disease (MRD) Negative Rate | Up to 4 years 4 months | 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. |
| Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) | Up to 4 years 4 months | Percentage of participants who received an allogeneic HSCT after treatment with daratumumab were reported. |
| Overall Response Rate (ORR) | Up to 4 years 4 months | 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. |
| Minimum Observed Serum Concentration (Cmin) 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 | Cmin was defined as minimum observed serum concentration of daratumumab. |
| Number of Participants With Anti-daratumumab Antibodies | Up to 4 years 4 months | Number of participants with anti-daratumumab antibodies was reported. |
| Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | 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 | 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. |
| Maximum Observed Serum Concentration (Cmax) 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 | Cmax was defined as maximum observed serum concentration of daratumumab. |
| Event-free Survival (EFS) | Up to 4 years 4 months | 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. |
Countries
Belgium, France, Germany, Israel, Italy, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
After enrollment of 47 participants, one participant in Cohort 1: B-cell acute lymphoblastic leukemia (ALL) (1-17 Years) was withdrawn prior to receiving treatment, and thus only 46 participants were treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: B-cell ALL (1-17 Years) Participants with relapsed/refractory B-cell ALL received intrathecal methotrexate (MTX) 8 milligrams (mg): 1 to less than (\<) 2 years, 10 mg: 2 to \<3 years, 12 mg: 3 to \<9 years and 15 mg: greater than or equal to (\>=) 9 years on Cycle 1 Day 1 (for all participants) and Cycle 2 and later Day 1 each Cycle (for CNS negative participants); for CNS positive participants: along with MTX, hydrocortisone (HC)/cytarabine (ARA-C) was administered per local standard practice; daratumumab 16 milligrams per kilogram (mg/kg) as intravenous (IV) infusion weekly on Days 1, 8, 15 and 22 of Cycles 1 and 2 then every 2 weeks on Days 1, 15 of Cycle 3 to 6 and every 4 weeks on Day 1 of Cycle 7 and onward; vincristine 1.5 milligrams per meter square (mg/m\^2) IV injection/infusion once weekly on Days 1, 8, 15 and 22 of Cycle 1, then every 2 weeks on Days 1 and 15 of Cycle 2 and every 4 weeks on Day 1 of Cycle 3 and onward; prednisone 40 mg/m\^2 orally daily on Day 1 to 28 of Cycle 1 and on Day 1 to 5 of Cycle 2 onward. Participants received treatment until disease progression, unacceptable toxicity, or proceeding hematopoietic stem cell transplant after complete response (CR), whichever came first (maximum duration: 2.3 months). | 7 |
| Cohort 2: T-Cell ALL (1-17 Years) Participants with relapsed/refractory T-cell ALL received intrathecal MTX 8 mg: 1 to \<2 years, 10 mg: 2 to \<3 years, 12 mg: 3 to \<9 years and 15 mg: \>=9 years on Cycle 1 Day 1 (all participants) and Cycle 1 Days 15, and 22 (CNS negative participants);for CNS positive participants, along with MTX, HC/ARA-C was administered per local standard practice; daratumumab 16 mg/kg IV infusion weekly on Days 1, 8, 15 and 22 of Cycle 1; doxorubicin 60 mg/m\^2 IV infusion once on Day 1; vincristine 1.5 mg/m\^2 IV injection/infusion once weekly on Days 1, 8, 15 and 22 on Cycle 1; prednisone 40 mg/m\^2 as 2 doses (20 mg/m\^2 per dose) orally daily on Day 1 to 28 on Cycle 1; peg-asparaginase 2500 units per meter square (U/m\^2) as intramuscular (IM) injection/IV infusion on Days 2, 16 of Cycle 1. In Cycle 2, participants received intrathecal MTX 8 mg: 1 to \<2 years, 10 mg: 2 to \<3 years, 12 mg: 3 to \<9 years and 15 mg: \>=9 years on Cycle 2 Days 2 and 15 (CNS negative participants); MTX, HC/ARA-C was administered on Days 2 and 15 per local standard practice (CNS positive participants); daratumumab 16 mg/kg IV infusion weekly on Days 1, 8, 15 and 22; MTX 5 g/m\^2 as IV once on Day 2, cyclophosphamide IV 1 g/m\^2 once on Day 15; cytarabine 75 mg/m\^2 IV/subcutaneous (SC) on Day 16 to 19 and Days 23 to 26; 6-mercaptopurine 60 mg/m\^2 orally daily on Days 15 to 28 (maximum duration: 2.9 months). | 24 |
| Cohort 2: T-Cell ALL (18-30 Years) Participants with relapsed/refractory T-cell ALL in Cycle 1 received intrathecal MTX 8 mg: 1 to \<2 years, 10 mg: 2 to \<3 years, 12 mg: 3 to \<9 years and 15 mg: \>=9 years on Cycle 1 Day 1 (all participants) and on Cycle 1 Days 15 and 22 (CNS negative participants); for CNS positive participants, along with MTX, HC/ARA-C was administered per local standard practice; daratumumab 16 mg/kg IV infusion weekly on Days 1, 8, 15 and 22 of Cycle 1; doxorubicin 60 mg/m\^2 IV once on Day 1 of Cycle 1; vincristine 1.5 mg/m\^2 IV injection/infusion once weekly on Days 1, 8, 15 and 22 of Cycle 1; prednisone 40 mg/m\^2 as 2 doses (20 mg/m\^2 per dose) orally daily on Days 1 to 28 and peg-asparaginase 2500 U/m\^2 as IM injection/IV infusion on Days 2 and 16 of Cycle 1. In Cycle 2, participants received intrathecal MTX 8 mg: 1 to \<2 years, 10 mg: 2 to \<3 years, 12 mg: 3 to \<9 years and 15 mg:\>=9 years on Days 2 and 15 (CNS negative participants); MTX, HC/ARA-C was administered on Days 2 and 15 per local standard practice (CNS positive participants); daratumumab 16 mg/kg IV infusion weekly on Days 1, 8, 15 and 22; MTX 5 g/m\^2 as IV once on Day 2, cyclophosphamide 1g/m\^2 once on Day 15; cytarabine 75 mg/m\^2 IV/SC on Days 16 to 19 and Days 23 to 26; and 6-mercaptopurine 60 mg/m\^2 orally daily on Days 15 to 28 (maximum duration: 2.1 months). | 5 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) Participants with relapsed/refractory T-cell LL in Cycle 1 received intrathecal MTX 8 mg: 1 to \<2 years, 10 mg: 2 to \<3 years, 12 mg: 3 to \<9 years and 15 mg: \>=9 years on Cycle 1 Day 1 (all participants) and on Cycle 1 Days 15 and 22 (CNS negative participants); for CNS positive participants, along with MTX, HC/ARA-C was administered per local standard practice; daratumumab 16 mg/kg IV infusion weekly on Days 1, 8, 15 and 22 of Cycle 1; doxorubicin 60 mg/m\^2 IV once on Day 1 of Cycle 1; vincristine 1.5 mg/m\^2 IV injection/infusion weekly on Days 1, 8, 15 and 22 of Cycle 1; prednisone 40 mg/m\^2 as 2 doses (20 mg/m\^2 per dose) orally daily on Days 1 to 28 and peg-asparaginase 2500 U/m\^2 as IM injection/IV infusion on Days 2 and 16 of Cycle 1. In Cycle 2, participants received intrathecal MTX 8 mg: 1 to \<2 years, 10 mg: 2 to \<3 years, 12 mg: 3 to \<9 years and 15 mg:\>=9 years on Days 2 and 15 (CNS negative participants); MTX, HC/ARA-C was administered by on Days 2 and 15 per local standard practice (CNS positive participants); daratumumab 16 mg/kg IV infusion weekly on Days 1, 8, 15 and 22; MTX 5 g/m\^2 as IV once on Day 2, cyclophosphamide 1g/m\^2 once on Day 15; cytarabine 75 mg/m\^2 IV/SC on Days 16 to 19 and Days 23 to 26; and 6-mercaptopurine 60 mg/m\^2 orally daily on Days 15 to 28 (maximum duration: 2.3 months). | 10 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 2: T-Cell ALL (1-17 Years) | Cohort 2: T-Cell ALL (18-30 Years) | Cohort 1: B-cell ALL (1-17 Years) | Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 9.8 years STANDARD_DEVIATION 4.17 | 22.2 years STANDARD_DEVIATION 2.77 | 8.1 years STANDARD_DEVIATION 5.01 | 13.5 years STANDARD_DEVIATION 5.68 | 11.7 years STANDARD_DEVIATION 6.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 3 Participants | 4 Participants | 7 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 2 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 0 Participants | 2 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) White | 18 Participants | 2 Participants | 5 Participants | 8 Participants | 33 Participants |
| Region of Enrollment BELGIUM | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment FRANCE | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 5 Participants |
| Region of Enrollment GERMANY | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment ISRAEL | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment ITALY | 4 Participants | 0 Participants | 2 Participants | 0 Participants | 6 Participants |
| Region of Enrollment NETHERLANDS | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment SPAIN | 5 Participants | 1 Participants | 2 Participants | 4 Participants | 12 Participants |
| Region of Enrollment UNITED KINGDOM | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 5 Participants |
| Region of Enrollment UNITED STATES | 4 Participants | 3 Participants | 1 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Female | 10 Participants | 0 Participants | 4 Participants | 1 Participants | 15 Participants |
| Sex: Female, Male Male | 14 Participants | 5 Participants | 3 Participants | 9 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 7 | 14 / 24 | 3 / 5 | 8 / 10 |
| other Total, other adverse events | 7 / 7 | 24 / 24 | 5 / 5 | 10 / 10 |
| serious Total, serious adverse events | 3 / 7 | 16 / 24 | 4 / 5 | 7 / 10 |
Outcome results
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.
Time frame: Up to 2 cycles, that is, up to 56 days (each cycle of 28-days)
Population: The all treated analysis set included all enrolled participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Cohort 1: Percentage of Participants With Complete Response (CR) for B-cell Acute Lymphoblastic Leukemia (ALL) | 0 Percentage of participants |
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.
Time frame: End of Cycle 1 (that is, up to 28 days)
Population: The all treated analysis set included all enrolled participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Cohort 2: Percentage of Participants With Complete Response (CR) for T-cell ALL | 41.7 Percentage of participants |
| Cohort 2: T-Cell ALL (18-30 Years) | Cohort 2: Percentage of Participants With Complete Response (CR) for T-cell ALL | 60.0 Percentage of participants |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Cohort 2: Percentage of Participants With Complete Response (CR) for T-cell ALL | 30.0 Percentage of participants |
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.
Time frame: 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
Population: The CSF PK evaluable analysis set included all enrolled participants who received at least 1 dose of daratumumab and provided at least 1 post-infusion CSF sample for daratumumab concentrations. Here, 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and 'n' (number analyzed) represent number of participants evaluable for specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 1 Day 1 predose | NA mcg/mL | — |
| Cohort 1: B-cell ALL (1-17 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 2 Day 1 predose | 0.573 mcg/mL | Standard Deviation 0.545 |
| Cohort 2: T-Cell ALL (18-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 1 Day 1 predose | NA mcg/mL | — |
| Cohort 2: T-Cell ALL (18-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 1 Day 15 predose | 0.907 mcg/mL | Standard Deviation 1.96 |
| Cohort 2: T-Cell ALL (18-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 2 Day 2 predose | 0.915 mcg/mL | Standard Deviation 0.916 |
| Cohort 2: T-Cell ALL (18-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 2 Day 15 predose | 0.934 mcg/mL | Standard Deviation 0.549 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 2 Day 15 predose | 0.163 mcg/mL | — |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 2 Day 2 predose | 0.296 mcg/mL | Standard Deviation 0.191 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 1 Day 1 predose | NA mcg/mL | — |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 1 Day 15 predose | 0.319 mcg/mL | Standard Deviation 0.203 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 2 Day 2 predose | 1.23 mcg/mL | Standard Deviation 0.728 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 2 Day 15 predose | 1.06 mcg/mL | Standard Deviation 0.282 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 1 Day 15 predose | 0.456 mcg/mL | Standard Deviation 0.28 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Concentration of Daratumumab in Cerebrospinal Fluid (CSF) | Cycle 1 Day 1 predose | NA mcg/mL | — |
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.
Time frame: Up to 4 years 4 months
Population: The all treated analysis set included all enrolled participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Event-free Survival (EFS) | 1.1 Months |
| Cohort 2: T-Cell ALL (18-30 Years) | Event-free Survival (EFS) | 8.9 Months |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Event-free Survival (EFS) | 10.3 Months |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Event-free Survival (EFS) | 2.9 Months |
Secondary
Maximum Observed Serum Concentration (Cmax) of Daratumumab
Cmax was defined as maximum observed serum concentration of daratumumab.
Time frame: 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
Population: The serum pharmacokinetics (PK) evaluable analysis set included all enrolled participants who received at least 1 dose of daratumumab and provided at least 1 post-infusion blood sample for serum daratumumab concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | 494 Micrograms per milliliter (mcg/mL) | Standard Deviation 184 |
| Cohort 2: T-Cell ALL (18-30 Years) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | 763 Micrograms per milliliter (mcg/mL) | Standard Deviation 185 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | 501 Micrograms per milliliter (mcg/mL) | Standard Deviation 347 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Maximum Observed Serum Concentration (Cmax) of Daratumumab | 758 Micrograms per milliliter (mcg/mL) | Standard Deviation 157 |
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.
Time frame: Up to 4 years 4 months
Population: The all treated analysis set included all enrolled participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Minimal Residual Disease (MRD) Negative Rate | 0 Percentage of participants |
| Cohort 2: T-Cell ALL (18-30 Years) | Minimal Residual Disease (MRD) Negative Rate | 45.8 Percentage of participants |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Minimal Residual Disease (MRD) Negative Rate | 20.0 Percentage of participants |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Minimal Residual Disease (MRD) Negative Rate | 50.0 Percentage of participants |
Secondary
Minimum Observed Serum Concentration (Cmin) of Daratumumab
Cmin was defined as minimum observed serum concentration of daratumumab.
Time frame: 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
Population: The serum PK evaluable analysis set included all enrolled participants who received at least 1 dose of daratumumab and provided at least 1 post-infusion blood sample for serum daratumumab concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Minimum Observed Serum Concentration (Cmin) of Daratumumab | 172 mcg/mL | Standard Deviation 115 |
| Cohort 2: T-Cell ALL (18-30 Years) | Minimum Observed Serum Concentration (Cmin) of Daratumumab | 369 mcg/mL | Standard Deviation 105 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Minimum Observed Serum Concentration (Cmin) of Daratumumab | 172 mcg/mL | Standard Deviation 177 |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Minimum Observed Serum Concentration (Cmin) of Daratumumab | 365 mcg/mL | Standard Deviation 204 |
Secondary
Number of Participants With Anti-daratumumab Antibodies
Number of participants with anti-daratumumab antibodies was reported.
Time frame: Up to 4 years 4 months
Population: The immunogenicity evaluable analysis set included all enrolled participants who received at least 1 dose of daratumumab and had at least 1 post-infusion sample for detection of anti-daratumumab antibodies.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Number of Participants With Anti-daratumumab Antibodies | 0 Participants |
| Cohort 2: T-Cell ALL (18-30 Years) | Number of Participants With Anti-daratumumab Antibodies | 0 Participants |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Number of Participants With Anti-daratumumab Antibodies | 0 Participants |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Number of Participants With Anti-daratumumab Antibodies | 0 Participants |
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.
Time frame: Up to 4 years 4 months
Population: The all treated analysis set included all enrolled participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Overall Response Rate (ORR) | 14.3 Percentage of participants |
| Cohort 2: T-Cell ALL (18-30 Years) | Overall Response Rate (ORR) | 83.3 Percentage of participants |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Overall Response Rate (ORR) | 80.0 Percentage of participants |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Overall Response Rate (ORR) | 50.0 Percentage of participants |
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.
Time frame: Up to 4 years 4 months
Population: The all treated analysis set included all enrolled participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Overall Survival (OS) | 3.2 Months |
| Cohort 2: T-Cell ALL (18-30 Years) | Overall Survival (OS) | 10.9 Months |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Overall Survival (OS) | 12.0 Months |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Overall Survival (OS) | 4.2 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.
Time frame: Up to 4 years 4 months
Population: The all treated analysis set included all enrolled participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: B-cell ALL (1-17 Years) | Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) | 14.3 Percentage of participants |
| Cohort 2: T-Cell ALL (18-30 Years) | Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) | 75.0 Percentage of participants |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) | 60.0 Percentage of participants |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) | 30.0 Percentage of participants |
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.
Time frame: Up to 4 years 4 months
Population: The response evaluable analysis set included all enrolled participants who received at least 1 dose of daratumumab and had at least 1 adequate post-baseline disease assessment. Here, 'N' (number of participants analysed) signifies all treated participants who achieved a complete response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2: T-Cell ALL (18-30 Years) | Relapse-free Survival (RFS) | 19.4 Months |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Relapse-free Survival (RFS) | 9.4 Months |
| Cohort 2: T-Cell Lymphoblastic Leukemia (LL) (1-30 Years) | Relapse-free Survival (RFS) | NA Months |