Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Dexamethasone acetate

Blinatumomab

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Blinatumomab will be administered as a continuous intravenous infusion (cIV).

AMG 404 will be administered as an intravenous infusion (IV).

AMG 404

Dexamethasone will be administered orally or intravenously prior to blinatumomab treatment, as needed.

Dexamethasone Premedication

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.

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)

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

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.

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.

Amgen

All-cause mortality was collected for all participants enrolled/randomized in the study. Serious AEs and other AEs were collected for all participants who received at least one dose of study drug.

Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.

Cohort 1: Blinatumomab + AMG 404 (240 mg)

Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.

Cohort 2a: Blinatumomab + AMG 404 (480 mg)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Study Director

DLT Analysis Set: included DLT-evaluable participants in the Safety Analysis Set. A participant was DLT-evaluable if the participant had completed DLT-evaluable period which begins with the first AMG 404 dose and includes 28 days after the second AMG 404 dose is administered or experienced a DLT any time during the DLT-evaluable period.

Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)

TEAEs

Serious TEAEs

Blinatumomab-related TEAEs

AMG 404-related TEAEs

EOIs

Safety Analysis Set: defined as all participants who were enrolled and received at least 1 dose of blinatumomab and AMG 404.

Number of Participants Who Experienced Treatment-Emergent AEs (TEAEs)

Within the First 2 Cycles

Across All Cycles

Percentage of Participants Who Achieved Complete Remission (CR) or CR With Partial Hematological Recovery (CRh) (CR/CRh)

Percentage of Participants Who Achieved CR

Safety Analysis Set: defined as all participants who were enrolled and received at least 1 dose of blinatumomab and AMG 404. Includes only participants who achieved CR within the first 2 cycles of treatment.

Median Duration of CR in Participants Who Achieved CR Within First 2 Cycles

Safety Analysis Set: defined as all participants who were enrolled and received at least 1 dose of blinatumomab and AMG 404. Includes only participants who achieved CR/CRh within the first 2 cycles of treatment.

Median Duration of CR/CRh in Participants Who Achieved CR/CRh Within First 2 Cycles

Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7. Cycle 1 consisted of 42 days.

Cohort 1; Cycle 1: Blinatumomab 9 μg/Day

Blinatumomab cIV was administered at 28 μg/day on Days 8 to 28. Cycle 1 consisted of 42 days. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.

Cohort 1; Cycle 1: Blinatumomab 28 μg/Day

Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.

Cohort 1; Cycle 2: Blinatumomab 28 μg/Day

Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.

Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day

Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.

Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day

Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.

Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day

PK Analysis Set: Defined as all participants in the Safety Analysis Set who have at least 1 PK sample collected. Includes only participants with available data at each timepoint.

Steady-state Concentrations (Css) of Blinatumomab

AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Each cycle consisted of 42 days.

Cohort 1: AMG 404 (240 mg)

AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Cycle 1 consisted of 44 days.

Cohort 2a: AMG 404 (480 mg)

Maximum Observed Concentration (Cmax) of AMG 404

Time to Cmax (Tmax) of AMG 404

Area Under the Plasma Concentration-time Curve From Time 0 to 28 Days Post Infusion (AUC0-28d) of AMG 404

Binding Antibody Positive at Anytime

NAb Positive at Anytime

Safety Analysis Set: defined as all participants who were enrolled and received at least 1 dose of blinatumomab and AMG 404. Includes only participants with available data.

Number of Participants With Incidences of Anti-Blinatumomab Antibodies

Number of Participants With Incidences of Anti-AMG 404 Antibodies

Blinatumomab continuous intravenous infusion (cIV) was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered intravenously (IV) at 240 mg, starting on Cycle 1 Day 11 (C1D11) and dosed every 4 weeks (Q4W) thereafter. Participants could receive up to 5 cycles.

Spots Global Cancer Trial Database for Blinatumomab in Combination With AMG 404 for the Treatment of Adults With Relapsed or Refractory B Cell Precursor ALL

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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