A Study of Subcutaneous Blinatumomab Administration in Participants With R/R and MRD+ B-ALL

Amgen

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: B Cell Precursor Acute Lymphoblastic Leukemia

Treatments: Drug: Blinatumomab

Study type: Interventional

Funder types: Industry

Identifiers

NCT04521231

20180257

2023-506136-32 (EudraCT Number)

Details and patient eligibility

About

The Phase I part of the study aims to evaluate the safety, efficacy, and tolerability of subcutaneous (SC) blinatumomab for treatment of Relapsed or Refractory B cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL), to determine the maximum tolerated dose (MTD), and recommended phase 2 dose(s) (RP2D) of SC administered blinatumomab.

The Phase II part of the study will evaluate the safety, efficacy, and tolerability of SC blinatumomab for treatment of R/R B-ALL and Minimum Residual Disease Positive (MRD+) B-ALL in participants 12 years old and greater. It will also conduct a clinical pharmacokinetic (PK) evaluation of SC1 and SC2 blinatumomab formulations.

Enrollment: 281 estimated patients

Sex: All

Ages: 12+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Ph-IIC, Dose Escalation and Dose Expansion: Aged 18 years or older (or same or greater than legal age within the country if it is older than 18 years).

• Ph-IIRa and Ph-IIMa: Aged ≥ 17 years at time of informed consent.

• Ph-IIRb and Ph-IIMb: Age ≥ 12 years and < 17 years at time of informed consent.

• Ph-IIR, Ph-IIC, Dose escalation, Dose Expansion: Participants with R/R B-precursor ALL.

• Relapsed or Refractory B-precursor ALL at any time after first salvage therapy.

• Relapsed B-precursor ALL at any time after allogenic hematopoietic stem cell transplant (HSCT).

• Ph-IIR, Ph-IIC, Dose escalation, Dose expansion: Greater than or equal to 5% blasts in the Bone Marrow per local assessment.

• Ph-IIM: B-precursor ALL and bone marrow blasts (BMB) ≥ 0.01% and < 5% per local assessment.

• Ph-IIM: Availability of an appropriate archival BM specimen from initial or relapse diagnosis and the screening BM sample.

• Participants aged ≥ 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2.

• Participants aged 16 to < 18 years old: Karnofsky Performance Score ≥ 50%.

• Participants aged < 16 years old: Lansky Performance Score ≥ 50%.

• Any Ph+ participant intolerant or refractory to prior tyrosine kinase inhibitors (TKIs) are eligible.

• Ph-IIM: BM function as follows:

  • Absolute Neutrophil Count (ANC) ≥ 500/μL
  • Platelet count ≥ 50 000/μL (transfusion permitted)
  • Hemoglobin level ≥ 9 g/dL (transfusion permitted)

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. If CSF leukemia is present subjects will have to receive intrathecal therapy and have documented negative CSF prior to enrolling.
• History or presence of clinically relevant CNS pathology (excluding headache) 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.
• For Ph-IIM only: Current EM disease or presence of circulating leukemia blasts.
• Current autoimmune disease or history of autoimmune disease with potential CNS involvement.
• Active acute or chronic graft versus host disease requiring systemic treatment with immunosuppressive medication.
• 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 (with demonstrated continued CD19+ expression), if treatment ended more than 4 weeks prior to start of protocol therapy and no prior CNS complications.
• Currently receiving treatment in or less than 30 days or 5 half-lives since ending treatment on another investigational study(ies).
• Abnormal screening laboratory parameters.
• Female participant: Pregnant or breastfeeding or planning to become pregnant or donate eggs, or expected to breastfeed during treatment and for 96 hours after the last dose of investigational product (SC blinatumomab).

The above is a summary, other exclusion criteria details may apply.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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281 participants in 5 patient groups

Dose Escalation Phase: Blinatumomab Subcutaneous Formulation 1 (SC1)

Experimental group

Description:

Cohorts of at least 3 adult participants with R/R B-ALL will be treated with escalating doses of blinatumomab 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.

Treatment:

Drug: Blinatumomab

Dose Expansion Phase: Blinatumomab SC1

Experimental group

Description:

Up to 4 cohorts of adult participants with R/R B-ALL will be enrolled at different dose levels to support identification of the RP2D. Each cohort will aim to further assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy.

Treatment:

Drug: Blinatumomab

Ph-IIC: Clinical PK Evaluation of SC Blinatumomab Formulations

Experimental group

Description:

1 cohort of adult 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 preliminary RP2D determined from the dose expansion phase, in participants with R/R B-ALL.

Treatment:

Drug: Blinatumomab

Ph-IIR: Efficacy of SC Blinatumomab in Participants with R/R B-ALL

Experimental group

Description:

The efficacy of SC blinatumomab (in the SC2 formulation) will be evaluated in adults and adolescents with R/R B-ALL.

Treatment:

Drug: Blinatumomab

Ph-IIM: Efficacy of SC Blinatumomab in Participants with MRD+ B-ALL

Experimental group

Description:

The efficacy of SC blinatumomab (in the SC2 formulation) will be evaluated in adults and adolescents with MRD+ B-ALL.

Treatment:

Drug: Blinatumomab