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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 and Adolescents With Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL) and Minimal Residual Disease Positive (MRD+) B-ALL

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

Oda Kazunori

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

clinicaltrials_japan@amgen.com

Local Contact

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

+81-80-7217-8592

clinicaltrials_japan@amgen.com

Recruiting

Jan. 04, 2021

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. 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).
2. Ph-IIRa and Ph-IIMa: Aged >= 17 years at time of informed consent.
3. Ph-IIRb and Ph-IIMb: Age >= 12 years and < 17 years at time of informed consent.
4. Ph-IIR, Ph-IIC, Dose escalation, Dose Expansion: Participants with R/R B-precursor ALL.
5. Relapsed or Refractory B-precursor ALL at any time after first salvage therapy.
6. Relapsed B-precursor ALL at any time after allogenic hematopoietic stem cell transplant (HSCT).
7. Ph-IIR, Ph-IIC, Dose escalation, Dose expansion: Greater than or equal to 5% blasts in the Bone Marrow per local assessment.
8. Ph-IIM: Subjects must have B-precursor ALL and bone marrow blasts (BMB) >= 0.01% and < 5% per local assessment.
9. Ph-IIM: Availability of an appropriate archival BM specimen from initial or relapse diagnosis and the screening BM sample.
10. Participants aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2.
11. Participants aged 16 to < 18 years old: Karnofsky Performance Score >= 50%.
12. Participants aged < 16 years old: Lansky Performance Score >= 50%.
13. Any Ph+ participant intolerant or refractory to prior tyrosine kinase inhibitors (TKIs) are eligible.
14. Ph-IIM: BM function as follows:
Absolute Neutrophil Count (ANC) >= 500/uL
Platelet count >= 50 000/uL (transfusion permitted)
Hemoglobin level >= 9 g/dL (transfusion permitted)
The above is a summary, other inclusion criteria details may apply.

1. 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.
2. 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.
3. Isolated Extramedullary (EM) Disease.
4. For Ph-IIM only: Current EM disease or presence of circulating leukemia blasts.
5. Current autoimmune disease or history of autoimmune disease with potential CNS involvement.
6. Active acute or chronic graft versus host disease requiring systemic treatment with immunosuppressive medication.
7. 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.
8. Testicular leukemia.
9. History of malignancy (with certain exceptions) other than ALL within 3 years prior to start of protocol-specified therapy.
10. Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy.
11. Cancer chemotherapy within 2 weeks before the start of protocol-specified therapy (with certain exceptions).
12. Immunotherapy within 4 weeks before start of protocol-specified therapy.
13. 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.
14. 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(ies).
15. Abnormal screening laboratory parameters.
16. 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.

Both

B Cell Precursor Acute Lymphoblastic Leukemia

Experimental: Dose Escalation Phase: Blinatumomab Subcutaneous Formulation 1 (SC1)
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.
Intervention: Drug: Blinatumomab

Experimental: Dose Expansion Phase: Blinatumomab SC1
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 aimto further assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy.
Intervention: Drug: Blinatumomab

Experimental: Ph-IIC: Clinical PK Evaluation of SC Blinatumomab Formulations
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 SC1and SC2 formulations at the preliminary RP2D determined from the dose expansion phase, in participants with R/R B-ALL.
Intervention: Drug: Blinatumomab

Experimental: Ph-IIR: Efficacy of SC Blinatumomab in Participants with R/R B-ALL
The efficacy of SC blinatumomab (in the SC2 formulation) will be evaluated in adults and adolescents with R/R B-ALL.
Interventions: Drug: Blinatumomab

Experimental: Ph-IIM: Efficacy of SC Blinatumomab in Participants with MRD+ B-ALL
The efficacy of SC blinatumomab (in the SC2 formulation) will be evaluated in adults and adolescents with MRD+ B-ALL.
Interventions: Drug: Blinatumomab

1. Dose Escalation Phase: Number of participants who experience dose limiting toxicities (DLTs) [Time Frame: Up to 29 days]
2. Dose Escalation Phase: Number of participants who experience one or more treatment-emergent adverse events (TEAEs) [Time Frame: Up to approximately 28 weeks]
3. Dose Escalation Phase: Number of participants who experience one or more serious TEAEs [Time Frame: Up to approximately 28 weeks]
4. Dose Escalation Phase: Number of participants who experience one or more treatment-related TEAEs [Time Frame: Up to approximately 28 weeks]
5. Dose Escalation Phase: Number of participants who experience one or more adverse events (AEs) of Interest (AEIs) [Time Frame: Up to approximately 28 weeks]
6. Dose Expansion and Phase 2 (Ph-IIR cohort): Number of participants who achieve complete remission (CR) / complete remission with partial hematological recovery (CRh) [Time Frame: Up to 10 weeks]
7. Phase 2 Ph-IIC cohort: Maximum concentration (Cmax) of blinatumomab SC1 and SC2 [Time Frame: Up to approximately 4 weeks]
8. Phase 2 Ph-IIC cohort: Average concentration (Cavg) of blinatumomab SC1 and SC2 [Time Frame: Up to approximately 4 weeks]
9. Phase 2 Ph-IIC cohort: Time to reach maximum concentration (Tmax) of blinatumomab SC1 and SC2 [Time Frame: Up to approximately 4 weeks]
10. Phase 2 Ph-IIC cohort: Area under the concentration-time curve (AUC) of blinatumomab SC1 and SC2 [Time Frame: Up to approximately 4 weeks]
11. Phase 2 Ph-IIM cohort: Number of participants who achieve CR with MRD-negative response [Time Frame: Up to 10 weeks]

1. Dose Escalation and Dose Expansion Phase: Minimum concentration over the dosing interval (Cmin) of blinatumomab [Time Frame: Up to approximately 10weeks]
2. Dose Escalation and Dose Expansion Phase: Cmax of blinatumomab [Time Frame: Up to approximately 10 weeks]
3. Dose Escalation and Dose Expansion Phase: Tmax of blinatumomab [Time Frame: Up to approximately 10 weeks]
4. Dose Escalation and Dose Expansion Phase: AUC of blinatumomab [Time Frame: Up to approximately 10 weeks]
5. Dose Escalation Phase and Phase 2 (Ph-IIC cohort): Number of participants who achieve CR/CRh [Time Frame: Up to 10 weeks]
6. Dose Escalation Phase, Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Number of participants with incidence of anti-blinatumomab antibody formation [Time Frame: Up to approximately 28 weeks]
7. Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Overall survival (OS) [Time Frame: Up to approximately 2 years]
8. Dose Expansion Phase and Phase 2 (Ph-IIR cohort and Ph-IIC cohort): Duration of response [Time Frame: Up to approximately 2 years]
9. Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Relapse free survival [Time Frame: Up to approximately 2 years]
10. Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Number of participants who experience one or more TEAEs [Time Frame:Up to approximately 28 weeks]
11. Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Number of participants who experience one or more serious treatment-emergent adverse event [Time Frame: Up to approximately 2 years]
12. Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Number of participants who experience one or more treatment-related treatment-emergent adverse events [Time Frame: Up to approximately 28 weeks]
13. Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Number of participants who experience one or more AEIs [Time Frame: Up to approximately 28 weeks]
14. Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Summary scores of quality of life at each assessment as assessed by the EORTC QLQ-C30 for participants aged >= 17 years at the time of consent [Time Frame: Baseline (Day 1) up to approximately 28 weeks]
The EORTC QLQ-C30 is defined as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.
15. Dose Expansion Phase and Phase 2 (Ph-IIR cohort, Ph-IIM cohort and Ph-IIC cohort): Change from baseline of quality of life as assessed by the EORTC QLQ-C30for participants aged >= 17 years at the time of consent [Time Frame: Baseline (Day 1) up to approximately 28 weeks]
16. Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Summary scores of quality of life at each assessment as assessed by PedsQL Generic Core Scale for participants aged 12 to < 17 years at time of consent [Time Frame: Baseline (Day 1) up to approximately 28 weeks]
17. Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Change from baseline of quality of life as assessed by PedsQL Generic Core Scale for participants aged 12 to < 17years at time of consent [Time Frame: Baseline (Day 1) up to approximately 28 weeks]
18. Phase 2 (Ph-IIR cohort): Number of participants who achieve CR [Time Frame: Up to 10 weeks]
19. Phase 2 (Ph-IIR cohort): Number of participants who achieve CR, CRh, CRi (complete remission with incomplete hematological recovery) or blast free hypoplastic or aplastic bone marrow (BM) [Time Frame: Up to 10 weeks]
20. Phase 2 (Ph-IIM cohort): Number of participants who achieve CR, CRh, CRi or blast free hypoplastic or aplastic BM with MRD-negative response [Time Frame: Up to 10 weeks]
21. Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Number of participants who achieve CR or CRh with MRD-negative response [Time Frame: Up to 10 weeks]
22. Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Duration of molecular response [Time Frame: Up to approximately 2 years]
23. Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Cmax of blinatumomab for participants participating in intense PK sampling assessment [Time Frame: Up to approximately 4 weeks]
24. Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Tmax of blinatumomab for participants participating in intense PK sampling assessment [Time Frame: Up to approximately 4 weeks]
25. Phase 2 (Ph-IIR cohort and Ph-IIM cohort): AUC of blinatumomab for participants participating in intense PK sampling assessment [Time Frame: Up to approximately 4 weeks]
26. Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Blinatumomab serum concentrations for participants not participating in intense PK sampling assessment [Time Frame: Up to approximately 4 weeks]
27. Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Proportion of time on treatment with high side effect bother from baseline to end of treatment as measured by Functional Assessment of Chronic Illness Therapy (FACIT) GP5 item for participants aged >= 17 years [Time Frame: Baseline (Day 1) up to approximately 28 weeks]
This endpoint applies to participants aged >= 17 years at time of consent.
28. Phase 2 (Ph-IIR cohort and Ph-IIM cohort): Pain difference between pain score before and after injection as reported using the Numeric Rating Scale (NRS-11) for participants aged 12 to < 17 years at time of consent [Time Frame: Up to approximately 28 weeks]

Feb. 01, 2023

Yes

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

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