Blinatumomab in Combination With AMG 404 for the Treatment of Adults With Relapsed or Refractory B Cell Precursor ALL

A Phase 1b Open-label Study Investigating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Administration of Blinatumomab in Combination With AMG 404 for the Treatment of Adults With Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (ALL)

The primary objective of this phase 1b study is to evaluate the safety and tolerability of blinatumomab and AMG 404 in combination in adults with R/R B-ALL and to estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AMG 404 when combined with continuous intravenous infusion (cIV) blinatumomab.

Study Overview

• Status: Completed
• Conditions: Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Blinatumomab; Drug: AMG 404; Drug: Dexamethasone Premedication

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • The Royal Melbourne Hospital
• Austria
  • Linz, Austria, 4020
    • Ordensklinikum Linz Elisabethinen
• France
  • Paris, France, 75010
    • Hôpital Saint Louis
  • Pierre Benite, France, 69645
    • Centre Hospitalier Lyon Sud
• Germany
  • Frankfurt am Main, Germany, 60590
    • Klinikum und Fachbereich Medizin Johann Wolfgang Goethe-Universität Frankfurt am Main
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein
  • Regensburg, Germany, 93053
    • Universitaetsklinikum Regensburg
• Italy
  • Bologna, Italy, 40138
    • Azienda Ospedaliera Universitaria di Bologna Policlinico S Orsola Malpighi
  • Brescia, Italy, 25123
    • Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen
• Spain
  • Cataluña
    • Badalona, Cataluña, Spain, 08916
      • Hospital Universitari Germans Trias I Pujol
    • Barcelona, Cataluña, Spain, 08036
      • Hospital Clínic i Provincial de Barcelona
• United Kingdom
  • London, United Kingdom, NW3 2PF
    • University College London
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University Of Chicago
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Age ≥ 18 years at enrollment.
• Greater than or equal to 5% blasts in the bone marrow.
• Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2.
• Negative pregnancy test in women of childbearing potential.

Exclusion Criteria

• Cancer chemotherapy (radiotherapy, chemotherapy, antibody therapy, molecular targeted therapy) within 14 days prior to study Day 1.
• Known hypersensitivity to blinatumomab or AMG 404 or to any component of the product formulation.

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 and AMG 404	Drug: Blinatumomab; Blinatumomab will be administered as a continuous intravenous infusion (cIV).; Other Names: Blincyto; Drug: AMG 404; AMG 404 will be administered as an intravenous infusion (IV).; Drug: Dexamethasone Premedication; Dexamethasone will be administered orally or intravenously prior to blinatumomab treatment, as needed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)	Investigators determined whether an adverse event (AE) qualified as a DLT per pre-specified protocol defined criteria. An AE was defined as any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment.	Cohort 1: Up to 67 days; Cohort 2a: Up to 56 days
Number of Participants Who Experienced Treatment-Emergent AEs (TEAEs)	A TEAE was defined as any AE starting on or after first dose of blinatumomab or AMG 404. The investigator used clinical judgment to assess causal relationship. A serious AE (SAE) was defined as any AE that: results in death,; immediately life-threatening,; requires in-patient hospitalization or prolongation of existing hospitalization,; results in persistent or significant disability/incapacity,; is a congenital anomaly/birth defect, and/or; other medically important serious AE. AEs of interest (EOIs) for blinatumomab included capillary leak syndrome, cytokine release syndrome, decreased immunoglobulins, elevated liver enzyme, embolic and thrombotic events, immunogenicity, infections, infusion reactions without considering duration, leukoencephalopathy, progressive multifocal leukoencephalopathy, neurologic events, neutropenia and febrile neutropenia, pancreatitis, and tumor lysis syndrome. EOIs for AMG 404 included non-infectious diarrhea and hemorrhages.	Median (min, max) overall duration from first dose until 30 days after last dose is: 83.4 (40.2, 274.1) days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Complete Remission (CR) or CR With Partial Hematological Recovery (CRh) (CR/CRh)	Hematological remissions were defined by the following criteria: CR: Less than 5% blasts in the bone marrow (BM); No evidence of disease; Full recovery of peripheral blood (PB) counts:; Platelets > 100 000/μl; Absolute neutrophil count (ANC) > 1000/μl CR with only CRh: Less than 5% blasts in the BM; No evidence of disease; Partial recovery of PB counts:; Platelets > 50 000/μl and; ANC > 500/μl Percentage of participants with CR/CRh were summarized along with corresponding 95% exact confidence interval (CI) using the Clopper-Pearson method.	Within the first 2 cycles: Up to approximately 86 days; across all cycles: Up to approximately 274 days
Percentage of Participants Who Achieved CR	Hematological remissions were defined by the following criteria: CR: Less than 5% blasts in the BM; No evidence of disease; Full recovery of PB counts:; Platelets > 100 000/μl; ANC > 1000/μl Percentage of participants with CR were summarized along with corresponding 95% exact CI using the Clopper-Pearson method.	Within the first 2 cycles: Up to approximately 86 days; across all cycles: Up to approximately 274 days
Median Duration of CR in Participants Who Achieved CR Within First 2 Cycles	Duration of CR was calculated from the date CR was first achieved within the first 2 cycles until the earliest date of disease assessment indicating a relapse event or death due to any cause, whichever occurred first. Months were calculated as days from date of CR to event/censor date, divided by 30.5. Median time to event and 95% CI was summarized using the Kaplan-Meier (KM) method.	Up to approximately 274 days
Median Duration of CR/CRh in Participants Who Achieved CR/CRh Within First 2 Cycles	Duration of CR/CRh was calculated from the date CR/CRh was first achieved within the first 2 cycles until the earliest date of disease assessment indicating a relapse event or death due to any cause, whichever occurred first. Months were calculated as days from date of CR/CRh to event/censor date, divided by 30.5. Median time to event and 95% CI was summarized using the KM method.	Up to approximately 274 days
Steady-state Concentrations (Css) of Blinatumomab	Pharmacokinetic (PK) parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.	Cohort 1: C1D1 and D8 (predose, 2 to 24 h postdose), and D11, D18 and D29; C2D1 (predose, 2 to 24 h postdose) and D29. Cohort 2a: C1D3 and D10 (predose, 2 to 48 h postdose), and D29, D30 and D31; C2D1 (predose, 2 to 24 h postdose), D13 and D29
Maximum Observed Concentration (Cmax) of AMG 404	PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.	Cohort 1: C1D11 (predose, end of infusion to 48 h postdose), D18, D29, and D39 (predose and end of infusion). Cohort 2a: C1D1 (predose, end of infusion to 168 h postdose), D12 and D29 (predose and end of infusion)
Time to Cmax (Tmax) of AMG 404	PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.	Cohort 1: C1D11 (predose, end of infusion to 48 h postdose), D18, D29, and D39 (predose and end of infusion). Cohort 2a: C1D1 (predose, end of infusion to 168 h postdose), D12 and D29 (predose and end of infusion)
Area Under the Plasma Concentration-time Curve From Time 0 to 28 Days Post Infusion (AUC0-28d) of AMG 404	PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.	Cohort 1: C1D11 (predose, end of infusion to 48 h postdose), D18, D29, and D39 (predose and end of infusion). Cohort 2a: C1D1 (predose, end of infusion to 168 h postdose), D12 and D29 (predose and end of infusion)
Number of Participants With Incidences of Anti-Blinatumomab Antibodies	Only samples testing positive for anti-blinatumomab binding antibodies were to be tested for neutralizing antibodies (NAbs) as pre-specified in the protocol.	Up to approximately 274 days
Number of Participants With Incidences of Anti-AMG 404 Antibodies	Only samples testing positive for anti-AMG 404 binding antibodies were to be tested for NAbs as pre-specified in the protocol.	Up to approximately 274 days

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2020
• Primary Completion (Actual): January 24, 2023
• Study Completion (Actual): January 24, 2023

Study Registration Dates

• First Submitted: August 20, 2020
• First Submitted That Met QC Criteria: August 20, 2020
• First Posted (Actual): August 24, 2020

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: October 11, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Leukemia; Blinatumomab; AMG 404
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Blinatumomab
• Other Study ID Numbers: 20190177

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No