Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to determine the dose of the bispecific T cell engager blinatumomab (MT103) in pediatric and adolescent patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and to assess whether this dose of blinatumomab is effective.

Detailed Description
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Childhood acute lymphoblastic leukemia (ALL) is a type of cancer of the blood and bone marrow in which the bone marrow makes too many abnormal immature lymphocytes. Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against cluster of differentiation (CD)19 expressing cells. The purpose of this study is to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of escalating doses of blinatumomab in pediatric and adolescent patients with relapsed/refractory B-precursor ALL, to select a dose and to investigate the efficacy and safety of that dose of blinatumomab in the above-mentioned patient population. The phase 1 part of the study included the evaluation of four dose levels of blinatumomab with comprehensive PK/PD assessments and was separated in 2 parts: Phase 1 dose evaluation/escalation part to define the recommended phase 2 dose of blinatumomab in patients aged 2 to 17 years Phase 1 PK expansion part in patients aged < 18 years to further assess PK/PD at the recommended phase 2 dose. In this part additional participants were enrolled to ensure that 6 patients in each of the 2 older age groups (2-6 and 7-17 years) were analyzed for PK before recruitment of infants < 2 years of age began. In the phase 2 extension cohort (efficacy phase) of the study, eligible participants less than 18 years were enrolled according to a two-stage design and received blinatumomab at the recommended dose level (5/15 μg/m²/day). The study consisted of a screening period, a treatment period, and an End of Core Study visit 30 days after last dose of study medication. A treatment cycle consisted of a continuous intravenous (cIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks. Participants who achieved complete remission (CR) within 2 cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Instead of consolidation cycles with blinatumomab, participants could be withdrawn from blinatumomab treatment to receive chemotherapy or allogeneic HSCT as early as the first cycle, at the discretion of the investigator. After the last treatment cycle and End of Core Study visit, all participants were followed for efficacy and survival for up to 24 months after treatment start. Participants who suffered a hematological relapse of B-precursor ALL during their follow-up period (at least 3 months after completion of treatment) had the possibility for retreatment with blinatumomab.

Official Title
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A Single-Arm Multicenter Phase II Study Preceded by Dose Evaluation to Investigate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab (MT103) in Pediatric and Adolescent Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: Blinatumomab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Morphologic evidence of B-precursor ALL with > 25% blasts in bone marrow (M3) at study enrolment Age less than 18 years at enrollment Relapsed/refractory disease: Second or later bone marrow relapse, Any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT), or Refractory to other treatments: Patients in first relapse must have failed to achieve a CR following full standard reinduction chemotherapy regimen of at least 4 weeks duration. Patients who have not achieved a first remission must have failed a full standard induction regimen Karnofsky performance status more than or equal to 50% for patients more than or equal to 16 years and Lansky Performance Status (LPS) of more than or equal to 50% for patients less than 16 years Organ function requirements: All patients must have adequate renal and liver functions Exclusion Criteria: Active acute or extensive chronic graft-versus-host disease (GvHD) Immunosuppressive agents to prevent or treat GvHD within 2 weeks prior to blinatumomab treatment Evidence for current central nervous system (CNS) involvement by ALL (CNS 2, CNS 3) or testicular involvement by ALL History of relevant CNS pathology or current relevant CNS pathology History of autoimmune disease with potential CNS involvement or current autoimmune disease Any HSCT within 3 months prior to blinatumomab treatment Cancer chemotherapy within 2 weeks prior to blinatumomab treatment (except for intrathecal chemotherapy and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, glucocorticoids) Chemotherapy related toxicities that haven't resolved to less than or equal to Grade 2 Radiotherapy within 2 weeks prior to blinatumomab treatment Immunotherapy (e.g. rituximab, alemtuzumab) within 6 weeks prior to blinatumomab treatment Any investigational product within 4 weeks prior to study entry Previous treatment with blinatumomab Active severe infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti-HCV positive)

Ages Eligible for Study
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Maximum Age: 17 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinatumomab<br>Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate over 4 weeks followed by a treatment-free interval of 2 weeks. Doses ranged between 5 and 30 µg/m²/day. Each participant received up to five cycles of treatment. | Biological: Blinatumomab<br>* Administered by continuous intravenous infusion<br>* Other names: BLINCYTO®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Number of Participants With Dose-limiting Toxicities (DLTs) | The maximum tolerated dose (MTD) was defined as one or fewer out of 6 participants experiencing a dose limiting toxicity (DLT) or the maximum administered dose (MAD). A dose limiting toxicity is any Grade ≥ 3 adverse event related to study drug, Grade 3 fatigue, headache, insomnia, fever, hypotension or infection were not considered dose limiting toxicities. Laboratory parameters of Grade ≥ 3 but not considered as clinically relevant and/or responding to routine medical management, thrombocytopenia, leukopenia (including neutropenia and lymphopenia), and anemia were not considered dose limiting toxicities. | Cycle 1, 28 days | 
| Percentage of Participants With Complete Remission in the First Two Cycles | Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central laboratory. Complete remission (CR) was defined as M1 bone marrow (bone marrow blasts < 5%) No evidence of circulating blasts or extra-medullary disease Complete remission includes participants with incomplete recovery of peripheral blood counts. | Cycles 1 and 2 (12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | The severity (or intensity) of adverse events (AEs) was assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v4.03 and according to the following: Grade 1 - Mild adverse event; Grade 2 - Moderate adverse event; Grade 3 - Severe and undesirable adverse event; Grade 4 - Life-threatening or disabling adverse event; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. | From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle, median treatment duration was 28 days | 
| Steady State Concentration of Blinatumomab | Blinatumomab serum concentrations were quantified in all patients during the first 2 treatment cycles in the phase 1 part of the study only. Blinatumomab concentrations were quantified using a validated bioassay, the lower limit of quantification was 50 pg/mL. Steady state serum concentration (Css) was presumed on day 1, approximately 5 half-lives after the start of the IV infusion. The steady state serum concentration reported is the mean of the observed concentrations collected after during cycles 1 and 2. | Cycles 1 and 2 during the IV infusion on day 3 (at least 48 hours after start of infusion) and days 8, 15 and 22 (steady state) and day 29 at End of Infusion (EoI) and 2, 4, and 8 hours after EoI for ages ≥ 2 years. | 
| Time to Hematological Relapse (Duration of Response) | Time to hematological relapse was measured only for participants in remission and was measured from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their date of death. Hematological relapse is defined as the proportion of blasts in bone marrow > 25% following documented remission, or extramedullary relapse. Time to hematological relapse was analyzed by Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method. | Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.5 months for phase 2. | 
| Overall Survival | Overall survival (OS) was measured for all participants from the first treatment of blinatumomab until death due to any cause or the date of the last follow-up. Participants who did not die were censored on the last documented visit date or the date of the last contact when the patient was last known to have been alive. For patients who withdrew their informed consent only information until the date of withdrawal was analyzed. Overall survival was estimated using Kaplan-Meier methods. The median follow-up time with respect to overall survival was calculated by the reverse Kaplan-Meier method. | Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.6 months for phase 2. | 
| Relapse-free Survival | Relapse-free survival (RFS) was assessed for participants who achieved a complete remission during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to any cause. Participants without a documented relapse (hematological or extramedullary) or who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Relapse free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan-Meier method. | Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.5 months for phase 2. | 
| Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant During Blinatumomab Induced Remission | The percentage of participants who received allogeneic hematopoietic stem cell transplantation (HSCT) while in remission due to treatment with blinatumomab during the first two cycles, and received no further anti-leukemic medication before HSCT. | Up to the data cut-off date of 12 January 2015; Maximum duration on study was 24 months in phase 1 and 15 months for phase 2. | 
| Number of Participants Who Developed Anti-blinatumomab Antibodies | Antibodies to blinatumomab were detected using an electrochemiluminescence (ECL)-based assay. | Predose up until 30 days after last dose of study medication; median treatment duration was 28 days. | 
| Serum Cytokine Peak Levels | The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-ɣ) using cytometric bead assays. The limit of detection of the assay (LOD) was 20 pg/mL and the lower limit of quantification (LLOQ) was 125 pg/mL. Data below LOD were set to 10 pg/mL while data < LOQ and > LOD were reported as measured. | Cycle 1 and 2 day 1 (prior to infusion, 2 and 6 hours after infusion start), day 2 and day 3. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALL, relapsed, refractory B-precursor ALL, Leukemia, Leukemia, Lymphoid, Precursor Cell Lymphoblastic Leukemia, Neoplasms by Histologic Type, Neoplasms, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Antibodies, Bispecific