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Blinatumomab

Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter.

Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. For pediatric participants the initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.

Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter.

Continuous intravenous infusion over four weeks per treatment cycle

This is an open-label, combined 2-part multicenter study to evaluate the efficacy, safety, and tolerability of blinatumomab in adult and pediatric Japanese patients with relapsed/refractory B-precursor ALL.

The Phase 1b part will investigate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of blinatumomab to determine the maximum tolerated dose (MTD) in both adult and pediatric Japanese patients with relapsed/refractory B-precursor ALL. The Phase 2 part will assess the safety and efficacy of the recommended dose level of blinatumomab identified in the Phase 1b portion of the study in the adult study population.

In June 2017 protocol amendment 4 extended the study to include an expansion cohort of approximately 65 participants to investigate the safety of blinatumomab in participants who did not participate in Phase 1b or Phase 2 of the study. Adult and pediatric patients in the expansion cohort may receive up to 5 cycles of investigational blinatomumab and may receive commercial blinatomumab after a minimum of 2 cycles of the investigational drug.

Study of Blinatumomab in Japanese Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)

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

Dose-limiting toxicities (DLTs) were defined as any Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade ≥ 3 adverse event related to blinatumomab, excluding specific CTCAE grade ≥ 3 adverse events considered consistent with the current known safety profile of blinatumomab, CTCAE grade ≥ 3 fever or infection, and laboratory parameters of CTCAE grade ≥ 3 not considered clinically relevant and/or responding to routine medical management.

Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory.

Hematological remissions were defined by the following criteria:

* Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets \> 100,000/µl and absolute neutrophil count (ANC) \> 1,000/µl.
* Complete Remission With Partial Hematological Recovery (CRh\*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets \> 50,000/µl and ANC \> 500/µl.

TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period.

The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death.

The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab.

Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory.

Hematological remissions were defined by the following criteria:

* Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets \> 100,000/µl and absolute neutrophil count (ANC) \> 1,000/µl.
* Complete Remission With Partial Hematological Recovery (CRh\*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets \> 50,000/µl and ANC \> 500/µl

M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease.

Duration of response was calculated from the date of bone marrow aspiration when response (CR/CRh\*) was detected for the first time during the first 2 cycles of treatment until the earlier of the following events:

* the date of bone marrow aspiration at which hematological relapse or progressive disease (PD) was first detected,
* the date of diagnosis on which the hematological or extra medullary relapse was documented,
* the date of death if patient died due to PD
* the date of end of induction phase if primary reason for treatment termination was hematological or extramedullary relapse.

For a responder who did not report an event and was alive during the study, the end date of duration (censoring) was based on the date of the last available bone marrow aspiration prior to the data cutoff date for the analysis. Participants with response who did not report an event and who died due to reasons other than PD, were censored on the date of death, with death treated as a competing risk.

Relapse-free survival (RFS) was defined for participants who achieved a response (CR/CRh\*) during the first 2 cycles of treatment. RFS was calculated from the date of bone marrow aspiration when response was detected for the first time to the date of bone marrow aspiration at which hematological relapse was first detected or the date of diagnosis on which the hematological or extra medullary relapse was documented or the date of death due to any cause, whichever was earlier. Participants who did not experience hematological relapse and did not die were censored on the date of the last available bone marrow aspiration prior to the data cutoff date for the analysis.

Overall survival (OS) was calculated from the start date of blinatumomab infusion in the first treatment cycle. All deaths were counted as events on the date of death.

Participants still alive were censored on the last documented visit date or the date of the last phone contact when the participant was last known to have been alive. For participants who withdrew their informed consent, only information until the date of withdrawal was used in the analysis.

Best response was defined as one of the following:

CR: ≤ 5% blasts in the bone marrow (BM); No evidence of disease; Full recovery of peripheral blood counts: Platelets \> 100,000/µl, and absolute neutrophil count (ANC) \> 1,000/µl

CRh\*: ≤ 5% blasts in BM; No evidence of disease; Partial recovery of peripheral blood counts: Platelets \> 50,000/µl, and ANC \> 500/µl

CRi: CR with incomplete count recovery without CRh\*

Blast free hypoplastic or aplastic BM: ≤ 5 % blasts in BM; No evidence of disease; Insufficient recovery of peripheral blood counts: platelets ≤ 50,000/µl and/or ANC ≤ 500/µl

Partial Remission: BM blasts \> 5 to \< 25% with at least a 50% reduction from baseline

Hematological Relapse: \> 5% blasts in BM or blasts in peripheral blood after documented CR/CRh\* during the study

PD: An increase from baseline of ≥ 25% of BM blasts or an absolute increase of ≥ 5,000 cells/µL in the number of circulating leukemia cells.

Participants who were eligible for allogeneic HSCT were those who achieved remission (complete response or complete response with partial recovery of peripheral blood counts) after 2 cycles of blinatumomab treatment, and no further anti-leukemic medication was given before HSCT.

The analysis of 100-day mortality after allogeneic HSCT was assessed for all participants who received an allogeneic HSCT while in any CR following treatment with blinatumomab. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT.

Participants still alive alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive.

The 100-day mortality rate after allogeneic HSCT was defined as the percentage of participants having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods.

The steady-state concentration (Css) of serum blinatumomab was summarized as the average of the observed concentrations collected after 5 half-lives or after 24 hours from the start of continuous IV infusion.

Cycle 1, day 2 values represent steady-state concentration after CIV with the initial dose of blinatumomab (9 µg/day for adults and 5 µg/m²/day for pediatric patients). All other time points were measured after the dose step to 28 µg/day (adults) / 15 µg/m²/day (pediatric participants).

Systemic clearance (CL) was calculated as CL = R0/Css, where R0 is the infusion rate (µg/hour or µg/m²/hour).

Antibodies to blinatumomab were detected using an electrochemiluminescence (ECL)-based assay.

The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL.

For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).

Amgen Astellas Biopharma K.K.

Amgen

All-cause mortality is reported for all participants enrolled/randomized in the study. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.

Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.

Phase 1b: Blinatumomab 9/28 μg/Day (Adults)

Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.

Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)

Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.

Phase 2: Blinatumomab 9/28 μg/Day (Adults)

Expansion Cohort: Blinatumomab 9/28 μg/Day (Adults)

Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.

Expansion Cohort: Blinatumomab 5/15 µg/m²/Day (Pediatric)

Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.

Total

Age, Customized

Sex: Female, Male

Race/Ethnicity, Customized

Study Director

Phase 1b participants in who received any infusion of blinatumomab.

Phase 1b: Number of Participants With Dose-limiting Toxicities

Phase 2 participants who received any infusion of blinatumomab.

Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Phase 1b adult participants who received any infusion of blinatumomab.

Phase 1b Adults: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Phase 1b pediatric participants who received any infusion of blinatumomab.

Phase 1b Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment

Phase 1b and Phase 2 participants who received any infusion of blinatumomab and achieved CR/CRh\* during the first 2 cycles of treatment.

Phase 1b and Phase 2: Duration of Response

Phase 1b and Phase 2: Relapse-free Survival

Phase 1b and Phase 2 participants who received any infusion of blinatumomab.

Phase 1b and Phase 2: Overall Survival

Phase 2: Best Overall Response Within 2 Cycles of Treatment

Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission

Phase 2 participants who received an allogeneic HSCT.

Phase 2: 100-Day Mortality After Allogeneic HSCT

All TEAEs

TEAEs ≥ Grade 3

TEAEs ≥ Grade 4

Serious TEAEs (STEAEs)

TEAEs Leading to Blinatumomab Interruption

STEAEs Leading to Blinatumomab Interruption

TEAEs Leading to Blinatumomab Discontinuation

STEAEs Leading to Blinatumomab Discontinuation

Fatal TEAEs

All Treatment-Related (TR) TEAEs

TR TEAEs ≥ Grade 3

TR TEAEs ≥ Grade 4

TR STEAEs

TR TEAEs Leading to Blinatumomab Interruption

TR STEAEs Leading to Blinatumomab Interruption

TR TEAEs Leading to Blinatumomab Discontinuation

TR STEAEs Leading to Blinatumomab Discontinuation

TR Fatal TEAEs

Phase 1b and Phase 2: Number of Participants With TEAEs

Cycle 1 before dose step

Cycle 1 after dose step

Cycle 2

Cycle 3+

Blinatumomab 9/28 μg/Day (Phase 1b and Phase 2 Adults)

Blinatumomab 5/15 µg/m²/Day (Phase 1b and Phase 2 Pediatric)

Blinatumomab 9/28 μg/Day (Phase 1b Only Adults)

Blinatumomab 5/15 µg/m²/Day (Phase 1b Only Pediatric)

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected, with available data at each time point.

Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected.

Phase 1b and Phase 2: Systemic Clearance of Blinatumomab

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected with available data.

Phase 1b and Phase 2: Terminal Half-life of Blinatumomab

Phase 1b and Phase 2: Volume of Distribution of Blinatumomab

Phase 1b and Phase 2: Number of Participants Who Developed Anti-Blinatumomab Antibodies

Cycle 1, day 1, 2 hours after start of infusion

Cycle 1, day 1, 6 hours after start of infusion

Cycle 1, day 1, 10 hours after start of infusion

Cycle 1, day 1, 24 hours after start of infusion

Cycle 1, day 8, 2 hours after start of infusion

Cycle 1, day 8, 6 hours after start of infusion

Cycle 1, day 8, 10 hours after start of infusion

Cycle 2, day 1, 6 hours after start of infusion

Cycle 3, day 1, 6 hours after start of infusion

Cycle 4, day 1, 6 hours after start of infusion

Cycle 5, day 1, 6 hours after start of infusion

Phase 1b and Phase 2: Blinatumomab 9/28 μg/Day (Adults)

Phase 1b and Phase 2: Blinatumomab 5/15 µg/m²/Day (Pediatric)

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacodynamic sample collected, with available data at each time point.

Phase 1b and Phase 2: Interleukin-2 Concentration

Phase 1b and Phase 2: Interleukin-6 Concentration

Phase 1b and Phase 2: Interleukin-10 Concentration

Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration

Phase 1b participants who received any infusion of blinatumomab and had at least one pharmacodynamic sample collected, with available data at each time point.

Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration

TEAEs Leading to Interruption of Blinatumomab

STEAEs Leading to Interruption of Blinatumomab

Expansion Cohort participants in the who received any infusion of blinatumomab.

Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

Expansion Cohort adult participants who received any infusion of blinatumomab.

Expansion Cohort Adult: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Expansion Cohort pediatric participants who received any infusion of blinatumomab.

Spots Global Cancer Trial Database for relapsed refractory b precursor acute lymphoblastic leukemia