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 Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
17
Blinatumomab will be administered as a continuous intravenous infusion (cIV).
AMG 404 will be administered as an intravenous infusion (IV).
Dexamethasone will be administered orally or intravenously prior to blinatumomab treatment, as needed.
City of Hope National Medical Center
Duarte, California, United States
University of Chicago
Chicago, Illinois, United States
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.
Time frame: 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.
Time frame: Median (min, max) overall duration from first dose until 30 days after last dose is: 83.4 (40.2, 274.1) days
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.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Icahn School of Medicine at Mount Sinai
New York, New York, United States
Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, United States
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Royal Adelaide Hospital
Adelaide, South Australia, Australia
The Royal Melbourne Hospital
Parkville, Victoria, Australia
Ordensklinikum Linz Elisabethinen
Linz, Austria
Hôpital Saint Louis
Paris, France
Centre Hospitalier Lyon Sud
Pierre-Bénite, France
...and 9 more locations
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to approximately 274 days