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

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)

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.

Study Overview

• Status: Completed
• Conditions: Acute Lymphoblastic Leukemia
• Intervention / Treatment: Biological: Blinatumomab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • St. Anna Kinderspital
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G1X8
      • Hospital for Sick Children
• France
  • Besancon, France, 25030
    • (CHU Besancon) Hopital Saint-Jaques
  • Marseille, France
    • Hôpital de la Timone (Enfants)
  • Paris Cedex 19, France, 75935
    • Hôpital Robert Debré (AP-HP)
• Germany
  • Berlin, Germany, 13353
    • Charité Campus Virchow Klinikum, Otto-Heubner-Centrum (OHC) für Kinder- und Jugendmedizin
  • Düsseldorf, Germany, 40225
    • Universitatsklinikum Dusseldorf
  • Essen, Germany
    • Universitatsklinikum Essen
  • Frankfurt am Main, Germany, 60590
    • Klinikum der Johann Wolfgang Goethe-Universität Frankfurt/Main
  • Hamburg, Germany
    • Universitatsklinikum Hamburg-Eppendorf
  • Hannover, Germany
    • Medizinische Hochschule Hannover
  • Kiel, Germany
    • Universitätsklinikum Schleswig-Holstein Campus Kiel
  • München, Germany, 80337
    • Klinikum der Universität München, Dr. von Haunersches Kinderspital
  • Tübingen, Germany, 72076
    • Universitätsklinik für Kinder- und Jugendmedizin Tübingen
  • Würzburg, Germany
    • Universitatsklinikum Wurzburg
• Italy
  • Monza, Italy, 20052
    • University of Milano-Bicocca, Hospital San Gerardo
  • Padova, Italy
    • Dipartimento della Donna e del Bambino
  • Rome, Italy, 00165
    • The Bambino Gesù Children's Hospital
• Netherlands
  • Rotterdam, Netherlands, 3015 GJ
    • Erasmus MC, Sophia Children's Hospital
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Denver
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta at Egleston
  • Missouri
    • ST. Louis, Missouri, United States
      • Washington University
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Memphis, Tennessee, United States, 38105-3678
      • St Jude Children's Research Hospital
  • Texas
    • Dallas, Texas, United States, 75390-9063
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030-2399
      • Texas Children's Cancer Center/ Baylor
  • Utah
    • Salt Lake City, Utah, United States
      • Primary Children's Medical Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Blinatumomab; 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; Administered by continuous intravenous infusion; Other Names: BLINCYTO®; MT103; AMG103

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Amgen Research (Munich) GmbH
• Investigators: Study Chair: Arend von Stackelberg, MD, Charite University, Berlin, Germany; Study Chair: Lia Gore, MD, Children's Hospital Denver, USA

Publications and helpful links

General Publications

• von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM, Barnette P, Messina C, Michel G, DuBois SG, Hu K, Zhu M, Whitlock JA, Gore L. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016 Dec 20;34(36):4381-4389. doi: 10.1200/JCO.2016.67.3301. Epub 2016 Oct 31.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): May 1, 2016

Study Registration Dates

• First Submitted: October 28, 2011
• First Submitted That Met QC Criteria: November 10, 2011
• First Posted (Estimate): November 16, 2011

Study Record Updates

• Last Update Posted (Estimate): February 8, 2017
• Last Update Submitted That Met QC Criteria: December 16, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Neoplasms; ALL; Leukemia; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphatic Diseases; Leukemia, Lymphoid; Neoplasms by Histologic Type; Antibodies, Bispecific; relapsed, refractory B-precursor ALL; Precursor Cell Lymphoblastic Leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Antineoplastic Agents; Blinatumomab
• Other Study ID Numbers: MT103-205; 2010-024264-18 (EudraCT Number)