Study of Blinatumomab in Japanese Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This is an open-label, combined 2-part multicenter study to evaluate the efficacy, safety, and tolerability of blinatumomab in adult and pediatric Japanese patients with relapsed/refractory B-precursor ALL.

Detailed Description
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The Phase 1b part will investigate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of blinatumomab to determine the maximum tolerated dose (MTD) in both adult and pediatric Japanese patients with relapsed/refractory B-precursor ALL. The Phase 2 part will assess the safety and efficacy of the recommended dose level of blinatumomab identified in the Phase 1b portion of the study in the adult study population. In June 2017 protocol amendment 4 extended the study to include an expansion cohort of approximately 65 participants to investigate the safety of blinatumomab in participants who did not participate in Phase 1b or Phase 2 of the study. Adult and pediatric patients in the expansion cohort may receive up to 5 cycles of investigational blinatomumab and may receive commercial blinatomumab after a minimum of 2 cycles of the investigational drug.

Official Title
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A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)

Conditions
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Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Blinatumomab


Participation Criteria
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Eligibility Criteria
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Adult Subjects Key Inclusion Criteria: Age ≥ 18 years old at enrollment Subjects with Philadelphia-negative B-precursor ALL, with any of the following: Relapsed or refractory after first line therapy with first remission duration ≤ 12 months; or Relapsed or refractory after first salvage therapy; or Relapsed or refractory within 12 months of allogeneic hematopoietic stem cell transplant (alloHSCT) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2. Greater than 5% blasts in bone marrow Pediatric Subjects Key Inclusion Criteria: Age < 18 years old at enrollment Relapsed/refractory disease, defined as one of the following: second or later bone marrow relapse; any marrow relapse after alloHSCT; or Refractory to other treatments: For subjects in first relapse: failure to achieve a complete response (CR) following a full standard reinduction chemotherapy regimen For subjects who have not achieved a first remission: failure to achieve remission following a full standard induction regimen Greater than 5% blasts in bone marrow Karnofsky performance status ≥ 50% for subjects ≥ 16 years Lansky performance status ≥ 50% for subjects < 16 years Key Exclusion Criteria Subjects with Burkitt´s Leukemia according to World Health Organization (WHO) classification History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis; with the exception of well-controlled CNS leukemia Active ALL in the CNS or testes Current autoimmune disease or history of autoimmune disease with potential CNS involvement Autologous HSCT within 6 weeks prior to start of blinatumomab treatment AlloHSCT within 12 weeks prior to start of blinatumomab treatment Any active acute Graft-versus-Host Disease (GvHD) grade 2-4 according to Glucksberg criteria or active chronic GvHD requiring systemic treatment

Ages Eligible for Study
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Minimum Age: 0 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinatumomab 9-28 µg/day Phase 1b Adult Population<br>Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter. | Drug: Blinatumomab<br>* Continuous intravenous infusion over four weeks per treatment cycle<br>* Other names: Blincyto®;|
| Experimental: Blinatumomab 5-15 µg/m^2/day Phase 1b Pediatric Population<br>Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. For pediatric participants the initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter. | Drug: Blinatumomab<br>* Continuous intravenous infusion over four weeks per treatment cycle<br>* Other names: Blincyto®;|
| Experimental: Blinatumomab 9-28 µg/day Phase 2 Adult Population<br>Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter. | Drug: Blinatumomab<br>* Continuous intravenous infusion over four weeks per treatment cycle<br>* Other names: Blincyto®;|
| Experimental: Blinatumomab 9-28 µg/day Adult Expansion Population<br>Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter. | Drug: Blinatumomab<br>* Continuous intravenous infusion over four weeks per treatment cycle<br>* Other names: Blincyto®;|
| Experimental: Blinatumomab 5-15 µg/m^2/day Pediatric Expansion Population<br>Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. For pediatric participants the initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter. | Drug: Blinatumomab<br>* Continuous intravenous infusion over four weeks per treatment cycle<br>* Other names: Blincyto®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants With Dose-limiting Toxicities | Dose-limiting toxicities (DLTs) were defined as any Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade ≥ 3 adverse event related to blinatumomab, excluding specific CTCAE grade ≥ 3 adverse events considered consistent with the current known safety profile of blinatumomab, CTCAE grade ≥ 3 fever or infection, and laboratory parameters of CTCAE grade ≥ 3 not considered clinically relevant and/or responding to routine medical management. | Days 1 to 14 | 
| Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment | Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl. | Within the first 2 cycles of treatment, 12 weeks | 
| Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. | From the start of the first infusion to 30 days after the end of the last infusion; median (min, max) treatment duration was 55.6 (25, 140) and 28.0 (8, 56) days in the adult and pediatric expansion cohorts, respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b Adults: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment | Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl | Within the first 2 cycles of treatment, 12 weeks | 
| Phase 1b Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment | M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease. | The first 2 cycles of treatment, 12 weeks | 
| Phase 1b and Phase 2: Duration of Response | Duration of response was calculated from the date of bone marrow aspiration when response (CR/CRh*) was detected for the first time during the first 2 cycles of treatment until the earlier of the following events: the date of bone marrow aspiration at which hematological relapse or progressive disease (PD) was first detected, the date of diagnosis on which the hematological or extra medullary relapse was documented, the date of death if patient died due to PD the date of end of induction phase if primary reason for treatment termination was hematological or extramedullary relapse. For a responder who did not report an event and was alive during the study, the end date of duration (censoring) was based on the date of the last available bone marrow aspiration prior to the data cutoff date for the analysis. Participants with response who did not report an event and who died due to reasons other than PD, were censored on the date of death, with death treated as a competing risk. | Median (minimum [min], maximum [max]) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2. | 
| Phase 1b and Phase 2: Relapse-free Survival | Relapse-free survival (RFS) was defined for participants who achieved a response (CR/CRh*) during the first 2 cycles of treatment. RFS was calculated from the date of bone marrow aspiration when response was detected for the first time to the date of bone marrow aspiration at which hematological relapse was first detected or the date of diagnosis on which the hematological or extra medullary relapse was documented or the date of death due to any cause, whichever was earlier. Participants who did not experience hematological relapse and did not die were censored on the date of the last available bone marrow aspiration prior to the data cutoff date for the analysis. | Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2. | 
| Phase 1b and Phase 2: Overall Survival | Overall survival (OS) was calculated from the start date of blinatumomab infusion in the first treatment cycle. All deaths were counted as events on the date of death. Participants still alive were censored on the last documented visit date or the date of the last phone contact when the participant was last known to have been alive. For participants who withdrew their informed consent, only information until the date of withdrawal was used in the analysis. | Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2. | 
| Phase 2: Best Overall Response Within 2 Cycles of Treatment | Best response was defined as one of the following: CR: ≤ 5% blasts in the bone marrow (BM); No evidence of disease; Full recovery of peripheral blood counts: Platelets > 100,000/µl, and absolute neutrophil count (ANC) > 1,000/µl CRh*: ≤ 5% blasts in BM; No evidence of disease; Partial recovery of peripheral blood counts: Platelets > 50,000/µl, and ANC > 500/µl CRi: CR with incomplete count recovery without CRh* Blast free hypoplastic or aplastic BM: ≤ 5 % blasts in BM; No evidence of disease; Insufficient recovery of peripheral blood counts: platelets ≤ 50,000/µl and/or ANC ≤ 500/µl Partial Remission: BM blasts > 5 to < 25% with at least a 50% reduction from baseline Hematological Relapse: > 5% blasts in BM or blasts in peripheral blood after documented CR/CRh* during the study PD: An increase from baseline of ≥ 25% of BM blasts or an absolute increase of ≥ 5,000 cells/µL in the number of circulating leukemia cells. | Within the first 2 cycles of treatment, 12 weeks | 
| Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission | Participants who were eligible for allogeneic HSCT were those who achieved remission (complete response or complete response with partial recovery of peripheral blood counts) after 2 cycles of blinatumomab treatment, and no further anti-leukemic medication was given before HSCT. | Median (min, max) follow-up time was 26.7 (3.0, 28.5) months. | 
| Phase 2: 100-Day Mortality After Allogeneic HSCT | The analysis of 100-day mortality after allogeneic HSCT was assessed for all participants who received an allogeneic HSCT while in any CR following treatment with blinatumomab. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT. Participants still alive alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. The 100-day mortality rate after allogeneic HSCT was defined as the percentage of participants having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. | 100 days, from the date of allogeneic HSCT; median (min, max) follow-up time was 26.7 (3.0, 28.5) | 
| Phase 1b and Phase 2: Number of Participants With TEAEs | TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. | From the start of the first infusion to 30 days after the end of the last infusion; median (min, max) treatment duration was 108 (56, 140), 56.0 (5, 84), and 56.0 (11, 115) days in adult phase 1b, adult phase 2 and pediatric phase 1b cohort respectively. | 
| Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State | The steady-state concentration (Css) of serum blinatumomab was summarized as the average of the observed concentrations collected after 5 half-lives or after 24 hours from the start of continuous IV infusion. Cycle 1, day 2 values represent steady-state concentration after CIV with the initial dose of blinatumomab (9 µg/day for adults and 5 µg/m²/day for pediatric patients). All other time points were measured after the dose step to 28 µg/day (adults) / 15 µg/m²/day (pediatric participants). | After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult). | 
| Phase 1b and Phase 2: Systemic Clearance of Blinatumomab | Systemic clearance (CL) was calculated as CL = R0/Css, where R0 is the infusion rate (µg/hour or µg/m²/hour). | After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult). | 
| Phase 1b and Phase 2: Terminal Half-life of Blinatumomab |  | Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion | 
| Phase 1b and Phase 2: Volume of Distribution of Blinatumomab |  | Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion | 
| Phase 1b and Phase 2: Number of Participants Who Developed Anti-Blinatumomab Antibodies | Antibodies to blinatumomab were detected using an electrochemiluminescence (ECL)-based assay. | Day 1 before first dose; cycles 1 and 2 day 29, 6 hours after end of infusion; 30 days after last dose. | 
| Phase 1b and Phase 2: Interleukin-2 Concentration | The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL). | Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start | 
| Phase 1b and Phase 2: Interleukin-6 Concentration | The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL). | Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start | 
| Phase 1b and Phase 2: Interleukin-10 Concentration | The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL). | Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start | 
| Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration | The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL). | Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start | 
| Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration | The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL). | Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start | 
| Expansion Cohort Adult: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment | Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl. | Within the first 2 cycles of treatment, 12 weeks | 
| Expansion Cohort Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment | M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease. | Within the first 2 cycles of treatment, 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amgen