A Study of Subcutaneous Blinatumomab Administration in Acute Lymphoblastic Leukemia (ALL) Patients

Study Overview
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Brief Summary
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The study aims to evaluate the safety, efficacy, and tolerability of subcutaneous (SC) blinatumomab for treatment of Acute Lymphoblastic Leukemia (ALL), to determine the maximum tolerated dose (MTD), and recommended phase 2 dose(s) (RP2D) of SC administered blinatumomab. It will also conduct a clinical PK evaluation of SC1 and SC2 blinatumomab formulations.

Official Title
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A Phase 1/2 Open-label Study to Investigate the Safety, Efficacy, and Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the Treatment of Adults With Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL)

Conditions
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B Cell Precursor Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Blinatumomab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or older. Participants with B-precursor ALL with any of the following: Either refractory to primary induction therapy or refractory to at least 1 salvage therapy OR In untreated first, second, third or greater relapse or refractory relapse First Relapse is defined as achievement of first Complete Remission (CR) [CR1] during upfront therapy then relapse during or after continuation therapy Primary Refractory disease is defined as the absence of CR after standard induction therapy Refractory relapse is defined as lack of CR after salvage treatment Second relapse or later relapse is defined as relapse after achieving a second CR (CR2) in first or later salvage Refractory to salvage is defined as no attainment of CR after salvage Relapsed or Refractory at any time after first salvage therapy. Relapse at any time after allogenic hematopoietic stem cell transplant (HSCT). Greater than or equal to 5% blasts in the Bone Marrow (Exception: Isolated Non-central nervous system (CNS) extramedullary disease [EMD]). Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2. Participants with relapse or refractory B Cell ALL Ph+ disease and that are intolerant or refractory to prior tyrosine kinase inhibitors (TKIs) are eligible. The above is a summary, other inclusion criteria details may apply. Exclusion Criteria: Active ALL in the central nervous system (CNS). Presence of greater than 5 white blood cells per cubic millimeter in cerebrospinal fluid (CSF) with lymphoblasts present and/or clinical signs of CNS leukemia. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis or severe (≥ grade 3) CNS events including immune effector cell-associated neurotoxicity syndrome (ICANS) from prior chimeric antigen receptor T-cell (CAR T) or other T cell engager therapies. Isolated Extramedullary (EM) Disease Symptoms and/or signs that indicate an acute or uncontrolled chronic infection, any other disease or condition that could be exacerbated by the treatment or would complicate protocol compliance. Testicular leukemia History of malignancy (with certain exceptions) other than ALL within 3 years prior to start of protocol-specified therapy. Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy. Cancer chemotherapy within 2 weeks before the start of protocol-specified therapy (with certain exceptions). Immunotherapy within 4 weeks before start of protocol-specified therapy. Prior failed cluster of differentiation (CD19) directed therapy such as prior blinatumomab or CD19 CAR T cells will be allowed, if treatment ended more than 4 weeks prior to start of protocol therapy therapy and no prior CNS complications. Currently receiving treatment in or less than 30 days since ending treatment on another investigational study(ies). Abnormal screening laboratory parameters. Female participant: Expected to breastfeed during treatment and for 96 hours after the last dose of treatment. The above is a summary, other exclusion criteria details may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Phase: Blinatumomab Subcutaneous Formulation 1 (SC1)<br>Cohorts of at least 3 participants each will be treated with escalating doses of bilinatumomab to determine the maximum tolerated dose (MTD). The MTD will be defined as the dose for which the estimate of the toxicity rate from an isotonic regression (Yan et al, 2017) is closest to the target toxicity rate. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy will be assessed. | Drug: Blinatumomab<br>* Blinatumomab will be administered as a subcutaneous (SC) injection.<br>* Other names: Blincyto®;|
| Experimental: Dose Expansion Phase: Blinatumomab SC1<br>Up to 4 cohorts of participants with R/R B-ALL will be enrolled to the preliminary recommended phase 2 dose (RP2D) and schedule determined from dose escalation phase. Each cohort will aim to further assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. | Drug: Blinatumomab<br>* Blinatumomab will be administered as a subcutaneous (SC) injection.<br>* Other names: Blincyto®;|
| Experimental: Ph-IIC: Clinical PK Evaluation of SC Blinatumomab Formulations<br>1 cohort of participants will be enrolled into the Ph-IIC arm. The clinical PK evaluation cohort (Ph-IIC) will be conducted to compare the PK of SC1 and SC2 formulations at the RP2D determined from the dose expansion phase, in participants with R/R B-ALL. | Drug: Blinatumomab<br>* Blinatumomab will be administered as a subcutaneous (SC) injection.<br>* Other names: Blincyto®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Phase: Number of participants who experience dose limiting toxicities (DLTs) |  | Up to 29 days | 
| Dose Escalation Phase: Number of participants who experience one or more treatment-emergent adverse events (TEAEs) |  | Up to approximately 28 weeks | 
| Dose Escalation Phase: Number of participants who experience one or more serious TEAEs |  | Up to approximately 28 weeks | 
| Dose Escalation Phase: Number of participants who experience one or more treatment-related treatment-emergent adverse events |  | Up to approximately 28 weeks | 
| Dose Escalation Phase: Number of participants who experience one or more adverse events (AEs) |  | Up to approximately 28 weeks | 
| Dose Expansion Phase (R/R B-ALL): Number of participants who achieve complete remission (CR) |  | Up to 68 days | 
| Dose Expansion Phase (R/R B-ALL): Number of participants who achieve complete remission with partial hematological recovery (CRh) |  | Up to 68 days | 
| Phase 2 Ph-IIC: Maximum concentration (Cmax) of blinatumomab SC1 and SC2 |  | Up to approximately 4 weeks | 
| Phase 2 Ph-IIC: Average concentration (Cavg) of blinatumomab SC1 and SC2 |  | Up to approximately 4 weeks | 
| Phase 2 Ph-IIC: Time to reach maximum concentration (Tmax) of blinatumomab SC1 and SC2 |  | Up to approximately 4 weeks | 
| Phase 2 Ph-IIC: Area under the concentration-time curve (AUC) of blinatumomab SC1 and SC2 |  | Up to approximately 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Phase: Minimum concentration over the dosing interval (Cmin) of blinatumomab |  | Up to approximately 28 weeks | 
| Dose Escalation Phase: Cmax of blinatumomab |  | Up to approximately 28 weeks | 
| Dose Escalation Phase: Tmax of blinatumomab |  | Up to approximately 28 weeks | 
| Dose Escalation Phase: AUC of blinatumomab |  | Up to approximately 28 weeks | 
| Dose Escalation Phase and Phase 2 (Ph-IIC cohort): Number of participants who achieve CR/CRh |  | Up to 68 days | 
| Dose Escalation, Dose Expansion, and Ph-IIC: Number of participants with incidence of anti-blinatumomab antibody formation |  | Up to approximately 28 weeks | 
| Dose Expansion Phase: Cmin of blinatumomab |  | Up to approximately 28 weeks | 
| Dose Expansion Phase: Cmax of blinatumomab |  | Up to approximately 28 weeks | 
| Dose Expansion Phase: Tmax of blinatumomab |  | Up to approximately 28 weeks | 
| Dose Expansion Phase: AUC of blinatumomab |  | Up to approximately 28 weeks | 
| Dose Expansion Phase and Phase 2 (Ph-IIC cohort): Relapse-Free Survival in participants who achieve CR/CRh within the first 2 cycles(R/R B-ALL) |  | Up to 68 days | 
| Dose Expansion Phase and Phase 2 (Ph-IIC cohort): Overall survival (OS) |  | Up to approximately 28 weeks | 
| Dose Expansion Phase and Phase 2 (Ph-IIC cohort): Duration of complete response |  | Up to approximately 28 weeks | 
| Dose Expansion Phase and Phase 2 (Ph-IIC cohort): Number of participants who experience one or more TEAEs |  | Up to approximately 28 weeks | 
| Dose Expansion Phase and Phase 2 (Ph-IIC cohort): Number of participants who experience one or more serious treatment-emergent adverse event |  | Up to approximately 28 weeks | 
| Dose Expansion Phase and Phase 2 (Ph-IIC cohort): Number of participants who experience one or more treatment-related treatment-emergent adverse events |  | Up to approximately 28 weeks | 
| Dose Expansion Phase and Phase 2 (Ph-IIC cohort): Number of participants who experience one or more AEs |  | Up to approximately 28 weeks | 
| Dose Expansion Phase and Phase 2 (Ph-IIC cohort): Summary scores of quality of life at each assessment as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) |  | Baseline (Day 1) up to approximately 28 weeks | 
| Dose Expansion Phase and Phase 2 (Ph-IIC cohort): Change from baseline of quality of life as assessed by the EORTC QLQ-C30 |  | Baseline (Day 1) up to approximately 28 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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R/R B-ALL, Blincyto®, AMG 103, Blinatumomab, Acute lymphoblastic leukemia (ALL)