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

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.

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.

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.

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.

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.

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.

Pharmacokinetic (PK) parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.

PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.

PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.

PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.

Only samples testing positive for anti-blinatumomab binding antibodies were to be tested for neutralizing antibodies (NAbs) as pre-specified in the protocol.

Only samples testing positive for anti-AMG 404 binding antibodies were to be tested for NAbs as pre-specified in the protocol.