Phase 1/2 Study of Subcutaneous Blinatumomab in Adults and Adolescents with Relapsed/Refractory or MRD+ B-cell Precursor Acute Lymphoblastic Leukemia
- Trial ID
- 2023-506136-32-00
- Protocol
- 20180257
- Sponsor
- Amgen Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the safety and tolerability of subcutaneous blinatumomab administration in patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) or minimal residual disease positive (MRD+) B-ALL. This includes determining the maximum tolerated dose (MTD) and the preliminary recommended phase 2 dose (RP2D) during dose escalation, as well as assessing efficacy across various patient cohorts. 5, 4
Secondary objectives include:
- Assessment of pharmacokinetics (PK) following subcutaneous administration. 6
- Evaluation of immunogenicity.
- Monitoring of relapse-free survival (RFS), duration of response (DoR), overall survival, and the rate of MRD-negative response.
- Evaluation of the duration of molecular response and duration of complete response.
- Assessment of patient-reported outcomes, quality of life, side effect bother, and reported pain in adolescents.
Participants
This clinical trial involves a total of 144 participants diagnosed with B-cell precursor acute lymphoblastic leukemia (B-ALL). The study population includes both male and female individuals, including vulnerable groups. Participants are categorized into specific cohorts based on disease status, such as relapsed or refractory (R/R) B-ALL and minimal residual disease positive (MRD+) B-ALL. Age requirements vary by study phase, ranging from pediatric patients aged 12 years and older to adults. Eligibility for the R/R cohort is determined by performance status, measured by the Eastern Cooperative Oncology Group (ECOG) scale, the Karnofsky Performance Score, or the Lansky Performance Score. Key inclusion criteria for the MRD+ cohort include specific bone marrow blasts percentages and required hematological parameters, such as minimum absolute neutrophil count, platelet count, and hemoglobin levels. The study objectives include:
- Evaluation of the safety and tolerability of subcutaneous blinatumomab.
- Determination of the maximum tolerated dose and preliminary recommended phase 2 dose.
- Assessment of the efficacy of the subcutaneous formulation.
- Evaluation of the pharmacokinetics following subcutaneous administration.
Plans and Procedures
This Phase 1/2, open-label study is designed to investigate the safety, efficacy, and pharmacokinetics of subcutaneous blinatumomab administration in adults and adolescents with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) and minimal residual disease positive (MRD+) B-ALL. The research methodology includes a dose escalation phase to determine the maximum tolerated dose and recommended phase 2 dose, followed by a dose expansion phase. The study incorporates several cohorts, including a comparison of two subcutaneous formulations (SC1 and SC2) to evaluate pharmacokinetic parameters, a relapsed/refractory cohort, and an MRD-positive cohort to assess efficacy. The trial is estimated to take place between October 2025 and May 2029. Study procedures involve an initial screening visit to assess eligibility, which includes evaluations of bone marrow status and performance status. Subsequent study activities involve treatment administration and monitoring for dose-limiting toxicities and adverse events. Participants may be subject to early termination based on clinical safety or investigator discretion.
Treatment
The experimental treatment consists of blinatumomab, provided as a solution for injection via subcutaneous administration. Two specific formulations, referred to as Blinatumomab SC1 and Blinatumomab SC2, are evaluated for safety, efficacy, and pharmacokinetics in patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia.
Background therapies utilized during the study include cytarabine and cyclophosphamide, both administered through intravenous routes. Additional auxiliary medications consist of dexamethasone and vincristine sulfate via intravenous administration, methotrexate administered intravenously, and levetiracetam administered via the oral route.
Efficacy
Efficacy in patients with relapsed or refractory B cell precursor acute lymphoblastic leukemia is evaluated through several parameters. In the dose expansion and phase 2 cohorts, the primary clinical endpoints include complete remission (CR) or complete remission with partial hematological recovery (CR/CRh) within the first 2 cycles. For the minimal residual disease positive (MRD+) cohort, efficacy is also assessed by the achievement of an MRD negative response, defined as MRD < 10⁻⁴, within the first 2 cycles.
Secondary efficacy measures include:
- Relapse-free survival (RFS), measured from the first achievement of response or the first dose of subcutaneous blinatumomab until the date of the first relapse or death from any cause.
- Overall survival (OS), calculated from the initiation of the first dose of subcutaneous blinatumomab until death.
- Duration of response, defined from the first onset of response until hematologic relapse or death.
- Duration of molecular response, measured from the onset of molecular response until hematologic relapse, molecular relapse, or death.
- Pharmacokinetics (PK) parameters, including Cmax, Cavg, Tmax, AUC, and Cmin.
- Anti-blinatumomab antibody formation.
Patient-reported outcomes are collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) for subjects aged 17 years or older, and the PedsQL Generic Core Scale for subjects aged 12 to less than 17 years. Additionally, the Functional Assessment of Chronic Illness Therapy (FACIT) GP5 item is used to measure side effect bother, and the Numeric Rating Scale (NRS-11) is utilized to assess pain differences before and after injection in specific age groups.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 101 Subject has provided informed consent before initiation of any study specific activities/procedures and/or the subject’s legally authorized representative has provided informed consent prior to any study specific activities/procedures being initiated when the subject has any kind of condition that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent or the subject’s legally authorized representative has provided informed consent when the participant is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines before any study-specific activities/procedures being initiated.
- (Disease Status) 108 A Ph+ subject intolerant or refractory to prior tyrosine kinase inhibitors (TKIs) is eligible.
- 109 For subjects in the MRD cohorts only (cohort Ph-IIM), BMB must be <5% and ≥0.1%. This will replace inclusion criterion #106 for subjects in this cohort
- 112 Subjects with Isolated (< 5% BMB) Non CNS Extra Medullary Disease (EMD) are eligible in phase 2 cohorts Ph-IIR and Ph-IIM only.
- 111 Ph-IIC only: Subject enrolled in SC1 and SC2 comparison cohort (Ph-IIC) must provide consent to participate in the additional PK sample collection requirements.
- 102 (Age requirement) Ph-IIC, Dose Escalation and Dose Expansion: Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years) at time of informed consent.
- Disease status: All subjects must fulfill at least 1 of inclusion criteria 103, 104, or 105 for eligibility. For Ph-IIM cohort (subjects with MRD+ ALL [phase 2]) only: Subjects will be eligible for Ph-IIM if they have B-ALL and meet the MRD criteria defined in inclusion criterion #109 below. With the exception of disease status criteria (ie, inclusion criteria #103, #104, #105, #106), Ph-IIM cohort subjects must satisfy all other inclusion criteria to be eligible.
- (Disease History) Ph-IIR, Ph IIC, Dose escalation, Dose Expansion: subjects must fulfill at least 1 of inclusion criteria 103, 104, or 105 for eligibility. 103 Subjects with B precursor ALL with any of the following: • Either refractory to primary induction therapy or relapse after 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 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.
- (Disease History) Ph-IIR, Ph IIC, Dose escalation, Dose Expansion: subjects must fulfill at least 1 of inclusion criteria 103, 104, or 105 for eligibility. 104 Relapsed or Refractory B precursor ALL at any time after first salvage therapy
- (Disease History) Ph-IIR, Ph IIC, Dose escalation, Dose Expansion: subjects must fulfill at least 1 of inclusion criteria 103, 104, or 105 for eligibility. 105 Relapsed B precursor ALL at any time after allogeneic HSCT.
- (Disease Status) 106 Ph IIR, Ph IIC, Dose escalation, Dose expansion: Greater than or equal to 5% blasts in the BM per local assessment.
- 107 Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.
- 114 (Age requirement) Ph-IIRa and Ph-IIMa: Age ≥ 17 years at time of informed consent.
- 113 (Age requirement) Ph-IIRb and Ph-IIMb: Age ≥ 12 years and <17 years at time of informed consent.
- 107 (Performance Status Requirement) Age ≥ 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
- 115 (Performance Status Requirement) Age 16 to <18 years old: Karnofsky Performance Score ≥ 50%
- 116 (Performance Status Requirement) Age < 16 years old: Lansky Performance Score ≥ 50%
- (Disease Status) 117 Ph IIM: Subjects must have B precursor ALL and BMB ≥ 0.01% and <5% per local assessment.
- (Disease Status) 118 Ph IIM: Availability of an appropriate archival bone marrow specimen from initial or relapse diagnosis and the screening BM sample.
- (Bone Marrow Function) 119 Ph-IIM: Bone marrow function as defined below: • Absolute Neutrophil Count (ANC) ≥500/µL • Platelet count ≥50,000/ µL (transfusion permitted) • Hemoglobin level ≥ 9g/dL (transfusion permitted)
- (Other) 120 Ph-IIRb extended cohort: Weight <45 kg at screening
Exclusion Criteria
- Active ALL in the CNS. Presence of > 5 white blood cells (WBC) per cubic millimeter in cerebrospinal fluid (CSF) with lymphoblasts present (confirmed by CSF analysis) 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 or event 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 (excluding headache) including ICANS from prior CART or other T cell engager therapies.
- 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.
- Known hypersensitivity to blinatumomab or to any component of the product formulation.
- Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus or hepatitis C virus.
- Symptoms and/or clinical signs and/or radiological and/or sonographic signs that indicate an acute or uncontrolled chronic infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol.
- History of malignancy other than ALL within 3 years prior to start of protocol-specified therapy except for: Malignancy treated with curative intent and with no known active disease present for 3 years before enrollment and felt to be at low risk for recurrence by the treating physician. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. Adequately treated cervical carcinoma in situ without evidence of disease. Adequately treated breast ductal carcinoma in situ without evidence of disease. Prostatic intraepithelial neoplasia without evidence of prostate cancer.
- Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy
- Isolated EM disease For Ph-IIM only: Current EM disease or presence of circulating leukemia blasts
- Testicular leukemia
- Cancer chemotherapy within 2 weeks before the start of protocolspecified therapy. With the exception of intrathecal chemotherapy and/or low dose maintenance therapy for example vinca alkaloids, mercaptopurine, methotrexate, or hydroxyurea (any low dose chemotherapy as stated above must be discontinued before starting prephase) or pre-phase chemotherapy and/or dexamethasone.
- Immunotherapy (eg, rituximab, alemtuzumab) within 4 weeks before start of protocol-specified therapy. Prior failed CD19 directed therapy such as prior blinatumomab or CD19 CAR T cells will be allowed (with demonstrated continued CD19+ expression), if treatment ended > 4 weeks prior to start of protocol therapy. and no prior CNS complications (see exclusion criteria 202).
- Currently receiving treatment in another investigational device or drug study, or less than 30 days or 5 half-lives since ending treatment on another investigational device or drug study. Other investigational or observational studies are not permitted while participating in this study
- Dose Escalation, Dose Expansion, Ph IIC: Abnormal screening laboratory values as defined below: - Total bilirubin more than 3.0 mg/dL prior to start of treatment (unless related to Gilbert’s or Meulengracht disease) - Estimated Creatinine clearance less than 60 mL/min.
- Female subject is pregnant or breastfeeding or planning to become pregnant or donate eggs or breastfeed during treatment and for an additional 96 hours after the last dose of investigational product (SC blinatumomab)
- Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 96 hours after the last dose of investigational product (SC blinatumomab).
- Female subjects of childbearing potential with a positive pregnancy test assessed during Screening by a serum pregnancy test and/or urine pregnancy test.
- Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s awareness. Completion of patient reported outcomes questionnaires is not required and will not be prohibitive to enrollment in case patient has intellectual disability or cognitive impairment or in case instrument is unavailable in subject’s language
- Immunotherapy (eg, rituximab, alemtuzumab) within 4 weeks before start of protocol-specified therapy.
- Prior failed CD19 directed therapy such as prior blinatumomab or CD19 CAR T cells will be allowed (with demonstrated continued CD19+ expression) if treatment ended > 4 weeks prior to start of protocol therapy and no prior CNS complications
- Ph IIR and Ph IIM: Abnormal screening laboratory values as defined below: - Total bilirubin > 3.0 mg/dL prior to start of treatment (unless related to Gilbert’s or Meulengracht disease). - Estimated Creatinine clearance < 30 mL/min per the Cockcroft-Gault equation for subjects ≥ 18 years and estimated Glomerular Filtration Rate (eGFR)< 30 mL/min per 1.73 m2 per the Revised Schwartz equation for subjects 12 to < 18 years.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Yet Recruiting | 31 Oct 2025 | 2 |
 France | Not Yet Recruiting | 31 Oct 2025 | 7 |
 Germany | Not Yet Recruiting | 31 Oct 2025 | 8 |
 Italy | Not Yet Recruiting | 31 Oct 2025 | 18 |
 The Netherlands | Not Yet Recruiting | 31 Oct 2025 | — |
 Romania | Not Yet Recruiting | 31 Oct 2025 | 3 |
 Spain | Not Yet Recruiting | 31 Oct 2025 | 18 |
| Netherlands | — | — | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DEXAMETHASONE | Other | — | INTRAVENOUS | — | — | SUB07017MIG |
Blinatumomab SC2 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | — | — | PRD10785712 |
LEVETIRACETAM | Other | — | ORAL | — | — | SUB08459MIG |
VINCRISTINE SULFATE | Other | — | INTRAVENOUS | — | — | SUB05101MIG |
Blinatumomab SC1 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | — | — | PRD10785709 |
METHOTREXATE | Other | — | INTRAVENOUS | — | — | SUB08856MIG |
CYCLOPHOSPHAMIDE | Other | — | INTRAVENOUS | — | — | SUB06859MIG |
CYTARABINE | Other | — | INTRAVENOUS | — | — | SUB06880MIG |