Clinical trial NCT01471782: Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Lymphoblastic Leukemia
Keywords: 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
Lead sponsor: Amgen Research (Munich) GmbH
Sponsor class: INDUSTRY
First posted: 2011-11-16
Enrollment: 93
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Phase I: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1, 28 days
measure: Percentage of Participants With Complete Remission in the First Two Cycles
timeFrame: Cycles 1 and 2 (12 weeks)
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 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
measure: Steady State Concentration of Blinatumomab
timeFrame: 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.
measure: Time to Hematological Relapse (Duration of Response)
timeFrame: 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.
measure: Overall Survival
timeFrame: 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.
measure: Relapse-free Survival
timeFrame: 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.
measure: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant During Blinatumomab Induced Remission
timeFrame: 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.
measure: Number of Participants Who Developed Anti-blinatumomab Antibodies
timeFrame: Predose up until 30 days after last dose of study medication; median treatment duration was 28 days.
measure: Serum Cytokine Peak Levels
timeFrame: Cycle 1 and 2 day 1 (prior to infusion, 2 and 6 hours after infusion start), day 2 and day 3.
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Denver
state: Colorado
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta at Egleston
state: Georgia
city: ST. Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Cancer Center/ Baylor
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Vienna
country: Austria
facility: St. Anna Kinderspital
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Besancon
country: France
facility: (CHU Besancon) Hopital Saint-Jaques
city: Marseille
country: France
facility: Hôpital de la Timone (Enfants)
city: Paris Cedex 19
country: France
facility: Hopital Robert Debré (AP-HP)
city: Berlin
country: Germany
facility: Charité Campus Virchow Klinikum, Otto-Heubner-Centrum (OHC) für Kinder- und Jugendmedizin
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt am Main
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universität Frankfurt/Main
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein Campus Kiel
city: München
country: Germany
facility: Klinikum der Universität München, Dr. von Haunersches Kinderspital
city: Tübingen
country: Germany
facility: Universitätsklinik für Kinder- und Jugendmedizin Tübingen
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Monza
country: Italy
facility: University of Milano-Bicocca, Hospital San Gerardo
city: Padova
country: Italy
facility: Dipartimento della Donna e del Bambino
city: Rome
country: Italy
facility: The Bambino Gesù Children's Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus MC, Sophia Children's Hospital
Study officials:
affiliation: Charite University, Berlin, Germany
name: Arend von Stackelberg, MD
role: STUDY_CHAIR
affiliation: Children's Hospital Denver, USA
name: Lia Gore, MD
role: STUDY_CHAIR
References:
citation: 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.