MT103-205

Amgen, Inc

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

IHQ medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com

IHQ medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com

Yes

No

Yes

Final

24 May 2016

No

Yes

24 May 2016

No

The purpose of this study is to determine the dose of the bispecific T cell engager blinatumomab (MT103) in pediatric and adolescent patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and to assess whether this dose of blinatumomab is effective.

This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, the GCPs applicable to any region where the study is conducted and in accordance with the ethical principles set forth in the Declaration of Helsinki. All subject/the subject’s legal representative provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.

31 Jan 2012

Yes

Yes

Netherlands: 2

United Kingdom: 1

France: 5

Germany: 29

Italy: 28

United States: 28

93

65

0

0

0

10

59

24

0

0

0

Overall Study (overall period)

Not applicable

Yes

Blinatumomab

MT103

BLINCYTO®, AMG 103

Powder for solution for injection

Intravenous use

Administered by continuous intravenous infusion

Blinatumomab

MT103

BLINCYTO®, AMG 103

Powder for solution for injection

Intravenous use

Administered by continuous intravenous infusion

Blinatumomab

MT103

BLINCYTO®, AMG 103

Powder for solution for injection

Intravenous use

Administered by continuous intravenous infusion

Blinatumomab

MT103

BLINCYTO®, AMG 103

Powder for solution for injection

Intravenous use

Administered by continuous intravenous infusion

Blinatumomab

MT103

BLINCYTO®, AMG 103

Powder for solution for injection

Intravenous use

Administered by continuous intravenous infusion

Blinatumomab

MT103

BLINCYTO®, AMG 103

Powder for solution for injection

Intravenous use

Administered by continuous intravenous infusion

Phase 1: Blinatumomab 5 µg/m²/Day

Phase 1: Blinatumomab 15 µg/m²/Day

Phase 1: Blinatumomab 30 µg/m²/Day

Phase 1: Blinatumomab 15/30 µg/m²/Day

Phase 1: Blinatumomab 5/15 µg/m²/Day

Phase 2: Blinatumomab 5/15 µg/m²/Day

Phase 1: Blinatumomab 5 µg/m²/Day

Phase 1: Blinatumomab 15 µg/m²/Day

Phase 1: Blinatumomab 30 µg/m²/Day

Phase 1: Blinatumomab 15/30 µg/m²/Day

Phase 1: Blinatumomab 5/15 µg/m²/Day

Phase 2: Blinatumomab 5/15 µg/m²/Day

Phase 1: Blinatumomab 5 µg/m²/Day

Participants who received blinatumomab administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day during the first cycle. This analysis set was used for pharmacokinetic (PK) and pharmacodynamic (PD) analyses.

Phase 1: Blinatumomab 15 µg/m²/Day

Participants who received blinatumomab administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day during the first cycle. This analysis set was used for PK and PD analyses.

Phase 1: Blinatumomab 30 µg/m²/Day

Participants who received blinatumomab administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day during the first cycle. This analysis set was used for PK and PD analyses.

Phase 1: Blinatumomab

All participants in phase 1 who received blinatumomab administered as a continuous intravenous infusion at a constant daily flow rate ranging from 5 to 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.

Phase 2: Blinatumomab 5/15 µg/m²/Day

Participants in phase 2 who received blinatumomab administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.

Phase 1+2: Blinatumomab 5/15 µg/m²/Day

All participants in phase 1 and phase 2 who received blinatumomab administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.

The maximum tolerated dose (MTD) was defined as one or fewer out of 6 participants experiencing a dose limiting toxicity (DLT) or the maximum administered dose (MAD). A dose limiting toxicity is any Grade ≥ 3 adverse event related to study drug, Grade 3 fatigue, headache, insomnia, fever, hypotension or infection were not considered dose limiting toxicities. Laboratory parameters of Grade . 3 but not considered as clinically relevant and/or responding to routine medical management, thrombocytopenia, leukopenia (including neutropenia and lymphopenia), and anemia were not considered dose limiting toxicities. Participants in the Phase 1 dose escalation part of the study are included in the analysis.

Primary

Cycle 1, 28 days

Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central laboratory. Complete remission (CR) was defined as • M1 bone marrow (bone marrow blasts < 5%) • No evidence of circulating blasts or extra-medullary disease Complete remission includes participants with incomplete recovery of peripheral blood counts. The full analysis set includes all participants who received any infusion of blinatumomab.

Primary

Cycles 1 and 2 (12 weeks)

The severity (or intensity) of adverse events (AEs) was assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v4.03 and according to the following: Grade 1 - Mild adverse event; Grade 2 – Moderate adverse event; Grade 3 – Severe and undesirable adverse event; Grade 4 - Life-threatening or disabling adverse event; 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.

Secondary

From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle, median treatment duration was 28 days.

Blinatumomab serum concentrations were quantified in all patients at baseline (predose) and during the first 2 treatment cycles in the phase 1 part of the study only. Blinatumomab concentrations were quantified using a validated bioassay, the lower limit of quantification was 50 pg/mL. The analysis includes Phase 1 participants with available blinatumomab concentration data.

Secondary

Cycles 1 and 2 predose, during the IV infusion on day 3 (at least 48 hours after start of infusion) and days 8, 15 and 22 (steady state) and day 29 at End of Infusion (EoI) and 2, 4, and 8 hours after EoI for ages ≥ 2 years.

Time to hematological relapse was measured only for participants in remission and was measured from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their date of death. Hematological relapse is defined as the proportion of blasts in bone marrow > 25% following documented remission, or extramedullary relapse. Time to hematological relapse was analyzed by Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method. "99999" indicates data that could not be estimated due to the low number of events.

Secondary

Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.5 months for phase 2.

Relapse-free survival (RFS) was assessed for participants who achieved a complete remission during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to any cause. Participants without a documented relapse (hematological or extramedullary) or who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Relapse free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan-Meier method.

Secondary

Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.5 months for phase 2.

Relapse-free survival (RFS) was assessed for participants who achieved a complete remission during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to any cause. Participants without a documented relapse (hematological or extramedullary) or who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Relapse free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan-Meier method.

Secondary

Up to the end of the follow-up period; median overall observation time was 23.1 months.

Overall survival (OS) was measured for all participants from the first treatment of blinatumomab until death due to any cause or the date of the last follow-up. Participants who did not die were censored on the last documented visit date or the date of the last contact when the patient was last known to have been alive. For patients who withdrew their informed consent only information until the date of withdrawal was analyzed. Overall survival was estimated using Kaplan-Meier methods. The median follow-up time with respect to overall survival was calculated by the reverse Kaplan-Meier method.

Secondary

Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.6 months for phase 2.

Overall survival (OS) was measured for all participants from the first treatment of blinatumomab until death due to any cause or the date of the last follow-up. Participants who did not die were censored on the last documented visit date or the date of the last contact when the patient was last known to have been alive. For patients who withdrew their informed consent only information until the date of withdrawal was analyzed. Overall survival was estimated using Kaplan-Meier methods. The median follow-up time with respect to overall survival was calculated by the reverse Kaplan-Meier method.

Secondary

Up to the end of the follow-up period; median overall observation time was 23.8 months.

The percentage of participants who received allogeneic hematopoietic stem cell transplantation (HSCT) while in remission due to treatment with blinatumomab during the first two cycles, and received no further anti-leukemic medication before HSCT.

Secondary

Up to the data cut-off date of 12 January 2015; Maximum duration on study was 24 months in phase 1 and 15 months for phase 2.

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

Secondary

Predose up until 30 days after last dose of study medication; median treatment duration was 28 days.

The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-γ) using cytometric bead assays. The limit of detection of the assay (LOD) was 20 pg/mL and the lower limit of quantification (LLOQ) was 125 pg/mL. Data below LOD were set to 10 pg/mL while data < LOQ and > LOD were reported as measured. Serum IL-4 levels were below detection limit (< 20 pg/mL) at all time points in all participants studied.

Secondary

Cycle 1 and 2 day 1 (prior to infusion, 2 and 6 hours after infusion start), day 2 and day 3.

From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle, median treatment duration was 28 days.

17.1

Phase 1: Blinatumomab 5 µg/m²/Day

Phase 1: Blinatumomab 15 µg/m²/Day

Phase 1+2: Blinatumomab 5/15 µg/m²/Day

Phase 1: Blinatumomab 15/30 µg/m²/Day

Phase 1: Blinatumomab 30 µg/m²/Day