E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adults with relapsed or refractory B-precursor ALL (R/R B-ALL) |
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E.1.1.1 | Medical condition in easily understood language |
Acute Lymphoblastic Leukemia – a cancer of the blood and marrow |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000844 |
E.1.2 | Term | Acute lymphoblastic leukaemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063621 |
E.1.2 | Term | Acute lymphoblastic leukaemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Dose Escalation -Evaluate the safety and tolerability of subcutaneous (SC) blinatumomab for treatment of Relapsed or Refractory B cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL) -Determine the maximum tolerated dose (MTD) and preliminary recommended phase 2 dose(s)(RP2D) of SC administered blinatumomab
Dose Expansion and Phase 2 (Ph-IIR and Ph-IIM cohorts) -Evaluate the efficacy of SC blinatumomab
Phase 2 Ph-IIC (SC1 and SC2 Cohorts) -Evaluate the PK following SC administration of SC1 and SC2 blinatumomab formulations |
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E.2.2 | Secondary objectives of the trial |
Dose Escalation -Determine PK following SC blinatumomab -Evaluate the efficacy of SC blinatumomab -Evaluate the immunogenicity of SC blinatumomab
Dose Expansion and Phase 2 (Ph-IIR and Ph-IIM cohorts) -Determine PK following SC blinatumomab -Evaluate the immunogenicity of SC blinatumomab -Evaluate the relapse-free survival (RFS) induced by SC blinatumomab -Evaluate the effect of SC blinatumomab on overall survival and on the duration of complete response -Evaluate the safety and tolerability of SC blinatumomab -Evaluate patient-reported outcomes and quality of life outcomes with SC blinatumomab
Phase 2 Ph-IIC (SC1 and SC2 Cohorts) -Evaluate the efficacy and immunogenicity, safety and tolerability of SC blinatumomab -Evaluate the relapse free survival (RFS) induced by SC blinatumomab -Evaluate the effect of SC blinatumomab on OS and duration of complete response -Evaluate patient-reported outcomes and quality of life outcomes with SC blinatumomab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects are eligible to be included in the study only if all of the following criteria apply: 101 Subject has provided informed consent prior to initiation of any study specific activities/procedures and/or the subject's legally acceptable 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. 111 Subjects enrolled in SC1 and SC2 comparison cohort (Ph-IIC) must provide consent to participate in the additional PK sample collection requirements. 102 Age ≥ 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. 103 Subjects 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 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 104 Relapsed or Refractory at any time after first salvage therapy 105 Relapse at any time after allogenic HSCT. 106 Greater than or equal to 5% blasts in the BM. (Exception: Isolated Non CNS extramedullary disease [EMD]). 107 Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2. 108 Subjects with relapse or refractory B Cell ALL Ph+ disease and that are intolerant or refractory to prior tyrosine kinase inhibitors (TKIs) are 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. |
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E.4 | Principal exclusion criteria |
Disease Related - 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. Other Medical Conditions - 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 including ICANS from prior CD19 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 - 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). Prior/Concurrent Clinical Study Experience - Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study. Other investigational studies are not permitted while participating in this study. Diagnostic Assessments - 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 < 60 mL/min Other Exclusions - Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 96 hours after the last dose of protocol-specified therapy. - 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 protocol-specified therapy. - 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
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E.5 End points |
E.5.1 | Primary end point(s) |
Dose Escalation • Dose limiting toxicities (DLTs), treatment-emergent adverse events serious (TEAE), treatment-related TEAE, and adverse events.
Dose Expansion and Phase 2 (Ph-IIR and Ph-IIM cohorts) • CR/CRh within the first 2 cycles for Ph2a and Ph-IIR cohorts (R/R B-ALL) and CR with MRD < 0.01% within the first 2 cycles for Ph-IIM cohort (MRD B-ALL)
Phase 2 Ph-IIC (SC1 and SC2 Cohorts) •Blinatumomab PK parameters following SC administration including, but not limited to Cmax, average concentration (Cavg),tmax, and AUC |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Dose escalation Unless otherwise specified, statistical analyses of safety endpoints will be done using subjects from the safety analysis set. Subject incidence of DLT will be tabulated overall and by planned cohort. Safety data will be reviewed on an ongoing basis.
Dose expansion and Phase 2 (Ph-IIR and Ph-IIM cohorts) The proportion of subjects with a response to treatment (CR/CRh within the first 2 cycles for Ph2a and Ph-IIR cohorts [R/R B‑ALL] and CR with MRD < 0.01% within the first 2 cycles for Ph-IIM cohort [MRD+ B-ALL]) and 95% CI will be tabulated overall and by cohort. |
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E.5.2 | Secondary end point(s) |
Dose Escalation • Blinatumomab PK parameters following SC administration including, but not limited to, minimum concentration over the dosing interval (Cmin), maximum concentration (Cmax), time to maximum concentration (Tmax), area under the concentration-time curve (AUC) • Complete remission/complete remission with partial hematological recovery/(CR/CRh) within the first 2 cycles • Anti-blinatumomab antibody formation
Dose Expansion and Phase 2 (Ph-IIR and Ph-IIM cohorts) • Blinatumomab PK parameters following SC administration including, but not limited to Cmin, Cmax, Tmax, and AUC • Anti-blinatumomab antibody formation • RFS in subjects who achieve response (CR/CRh within the first 2 cycles for Ph2a and Ph-IIR cohorts and CR with MRD<0.01% within the first 2 cycles for Ph-IIM cohort) is defined as the time from the first achievement of this response until date of the first relapse including extramedullary relapse, or death due to any cause, whichever occurs first • Overall survival (OS) is calculated from the time of the start of first dose of SC blinatumomab until death due to any cause • Duration of complete response is defined as the time from the first onset of response (CR/CRh within the first 2 cycles for Ph2a and Ph-IIR cohorts and CR with MRD <0.01% within the first 2 cycles for Ph-IIM cohort) until the relapse including extramedullary relapse. • TEAEs, serious TEAEs, treatment related TEAEs, and adverse events • Summary scores at each assessment and change from baseline as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ C30)
Phase 2 Ph-IIC (SC1 and SC2 Cohorts) •Complete remission/complete remission with partial hematological recovery (CR/CRh) within the first 2 cycles •Anti blinatumomab antibody formation •RFS in subjects who achieve response (CR/CRh within the first 2 cycles) is defined as the time from the first achievement of this response until date of the first relapse including extramedullary relapse, or death due to any cause, whichever occurs first •OS is calculated from the time of the start of first dose of SC blinatumomab until death due to any cause •Duration of complete response is defined as the time from the first onset of response (CR/CRh within the first 2 cycles) until relapse including extramedullary relapse •TEAEs, serious TEAEs, treatment related TEAEs, and adverse events • Summary scores at each assessment and change from baseline as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ C30) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Dose escalation Proportion of subjects with response to treatment(CR,CRh)and 95%CI will be tabulated overall and by dose level. Dose expansion Summaries of OS,RFS,duration of complete response,duration of MRD response will be reported overall and by cohort. Analysis for RFS and duration of complete response will be performed for subjects with response(CR/CRh within the first 2cycles for Ph2a, Ph-IIC and Ph-IIR and CR with MRD<0.01% within the first 2cycles for Ph-IIM).Number of subjects with events,number of subjects censored,KM estimates at select time points,KM quartiles(when estimable)and their 95%CI,and KMcurves will be provided for OS,RFS,duration of response,and duration of MRD response. Subject incidence of DLT will be tabulated overall and by planned cohort. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
dose-finding study to investigate the PK, safety, and clinical activity of escalating dose levels |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Japan |
Turkey |
United States |
Austria |
France |
Germany |
Italy |
Netherlands |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The date when the last subject is assessed or receives an intervention for the final collection of data for the primary endpoint(s), for the purposes of conducting the final analysis, whether the study concluded as planned in the protocol or was terminated early. The date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (LSLV), following any additional parts in the study (eg,additional antibody testing long-term follow-up),as applicable. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 6 |