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

Phase 1

Completed

Conditions: Acute Lymphoblastic Leukemia

Interventions: Drug: Blinatumomab
Drug: AMG 404
Drug: Dexamethasone Premedication

Registration Number: NCT04524455

Lead Sponsor: Amgen

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Blinatumomab and AMG 404	Dexamethasone Premedication	-
Blinatumomab and AMG 404	AMG 404	-
Blinatumomab and AMG 404	Blinatumomab	-

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)	Cohort 1: Up to 67 days; Cohort 2a: Up to 56 days	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.
Number of Participants Who Experienced Treatment-Emergent AEs (TEAEs)	Median (min, max) overall duration from first dose until 30 days after last dose is: 83.4 (40.2, 274.1) days	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.

Secondary Outcome Measures

Name	Time	Method
Maximum Observed Concentration (Cmax) of AMG 404	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)	PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.
Time to Cmax (Tmax) of AMG 404	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)	PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.
Area Under the Plasma Concentration-time Curve From Time 0 to 28 Days Post Infusion (AUC0-28d) of AMG 404	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)	PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.
Percentage of Participants Who Achieved Complete Remission (CR) or CR With Partial Hematological Recovery (CRh) (CR/CRh)	Within the first 2 cycles: Up to approximately 86 days; across all cycles: Up to approximately 274 days	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.
Median Duration of CR/CRh in Participants Who Achieved CR/CRh Within First 2 Cycles	Up to approximately 274 days	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.
Steady-state Concentrations (Css) of Blinatumomab	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	Pharmacokinetic (PK) parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.
Number of Participants With Incidences of Anti-AMG 404 Antibodies	Up to approximately 274 days	Only samples testing positive for anti-AMG 404 binding antibodies were to be tested for NAbs as pre-specified in the protocol.
Percentage of Participants Who Achieved CR	Within the first 2 cycles: Up to approximately 86 days; across all cycles: Up to approximately 274 days	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.
Number of Participants With Incidences of Anti-Blinatumomab Antibodies	Up to approximately 274 days	Only samples testing positive for anti-blinatumomab binding antibodies were to be tested for neutralizing antibodies (NAbs) as pre-specified in the protocol.
Median Duration of CR in Participants Who Achieved CR Within First 2 Cycles	Up to approximately 274 days	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.

Trial Locations

Locations (19): Centre Hospitalier Lyon Sud
🇫🇷
Pierre Benite, France
Hospital Universitari Germans Trias i Pujol
🇪🇸
Badalona, Cataluña, Spain
Universitätsklinikum Schleswig-Holstein
🇩🇪
Kiel, Germany
Hôpital Saint Louis
🇫🇷
Paris, France
Cleveland Clinic Taussig Cancer Center
🇺🇸
Cleveland, Ohio, United States
Ordensklinikum Linz Elisabethinen
🇦🇹
Linz, Austria
Hospital Clinic i Provincial de Barcelona
🇪🇸
Barcelona, Cataluña, Spain
Klinikum und Fachbereich Medizin Johann Wolfgang Goethe-Universität Frankfurt am Main
🇩🇪
Frankfurt am Main, Germany
University of Chicago
🇺🇸
Chicago, Illinois, United States
Icahn School of Medicine at Mount Sinai
🇺🇸
New York, New York, United States
The Royal Melbourne Hospital
🇦🇺
Parkville, Victoria, Australia
Royal Adelaide Hospital
🇦🇺
Adelaide, South Australia, Australia
Universitaetsklinikum Regensburg
🇩🇪
Regensburg, Germany
University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Azienda Ospedaliera Universitaria di Bologna Policlinico S Orsola Malpighi
🇮🇹
Bologna, Italy
Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
🇮🇹
Brescia, Italy
Universitair Medisch Centrum Groningen
🇳🇱
Groningen, Netherlands
City of Hope National Medical Center
🇺🇸
Duarte, California, United States
University College London
🇬🇧
London, United Kingdom