Blinatumomab in Adults With Relapsed/Refractory Philadelphia Positive B-precursor Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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The primary objective is to evaluate the rate of complete remission/complete remission with partial hematological recovery (CRh*) in adults with relapsed/refractory Philadelphia chromosome positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) who receive blinatumomab.

Detailed Description
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This is a single-arm Simon II stage design, multicenter study consisting of a screening period, an induction treatment period (2 cycles of blinatumomab), a consolidation treatment period (up to 3 additional cycles of blinatumomab for applicable participants), and a safety follow-up visit 30 days after treatment. Following the safety follow-up visit, participants will be followed for response duration and survival every 3 months for 18 months or death, whichever occurs first.

Official Title
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A Phase 2 Single Arm, Multicenter Trial to Evaluate the Efficacy of the BiTE Antibody Blinatumomab in Adult Subjects With Relapsed/Refractory Philadelphia Positive B-precursor Acute Lymphoblastic Leukemia (Alcantara Study)

Conditions
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Relapsed/Refractory Philadelphia Positive B-precursor ALL

Intervention / Treatment
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* Drug: Blinatumomab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients with Ph+ B-precursor ALL, with any of the following: Relapsed or refractory to at least one second generation tyrosine kinase inhibitor (TKI) (dasatinib, nilotinib, bosutinib, ponatinib) OR intolerant to second generation TKI and intolerant or refractory to imatinib mesylate Greater than 5% blasts in bone marrow Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Age ≥ 18 years of age, at the time of informed consent. Subject has provided informed consent or subject's legally acceptable representative has provided informed consent 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. Exclusion Criteria History of malignancy other than ALL within 5 years prior to start of protocol-required therapy, except for adequately treated selected cancers without evidence of disease History or presence of clinically relevant central nervous system (CNS) pathology as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis Active ALL in the CNS or testes Isolated extramedullary disease Current autoimmune disease or history of autoimmune disease with potential CNS involvement Allogeneic hematopoietic stem cell transplantation (HSCT) within 12 weeks before blinatumomab treatment Active acute or extensive chronic graft-versus-host disease (GvHD) which included the administration of immunosuppressive agents to prevent or treat GvHD within 2 weeks before blinatumomab treatment immediately previous cancer chemotherapy, radiotherapy, or immunotherapy; and eligibility for allogeneic HSCT at the time of enrollment.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinatumomab<br>Participants will receive blinatumomab by continuous intravenous (CIVI) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieve a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose will be 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 for all subsequent cycles of treatment. | Drug: Blinatumomab<br>* Blinatumomab is administered as a continuous intravenous infusion (CIV). A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks of blinatumomab followed by a 2-week treatment-free interval.<br>* Other names: AMG 103;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery (CR/CRh*) During the First Two Treatment Cycles | Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts. Complete remission was defined as meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl. Complete remission with partial hematological recovery (CRh*) was defined as meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow no evidence of disease partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. Participants without a post-baseline disease assessment were considered non-responders. | Approximately 12 weeks, as of the data cut-off date of 20 May 2015 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Minimal Residual Disease (MRD) Remission During the First 2 Cycles of Treatment | Bone marrow samples were evaluated for MRD remission by a central laboratory using bcr-abl fusion gene reverse transcription polymerase chain reaction (RT-PCR). An MRD response was defined as MRD < 10^-4 measured by PCR. Participants with no post-baseline MRD assessment were considered non-responders. | Approximately 12 weeks | 
| Duration of CR or CRh* Response | Duration of response was measured for participants in remission (CR/CRh*), and was measured from the time the participant first achieved remission until first documented relapse or death from disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of the last bone marrow assessment or the last survival follow-up visit to confirm remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their date of death. | Up to the data cut-off date of 20 May 2015; median observation time was 7.0 months | 
| Percentage of Participants With Complete Remission (CR) During the First Two Treatment Cycles | Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts. Complete remission was defined as meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl. Participants without a post-baseline disease assessment were considered non-responders. | Approximately 12 weeks, as of the data cut-off date of 20 May 2015 | 
| Percentage of Participants With Complete Remission With Partial Hematological Recovery (CRh*) During the First Two Treatment Cycles | Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts. Complete remission with partial hematological recovery (CRh*) was defined as meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. Participants without a post-baseline disease assessment were considered non-responders. | Approximately 12 weeks, as of the data cut-off date of 20 May 2015 | 
| Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi) During the First Two Treatment Cycles | Efficacy was evaluated via a central bone marrow aspiration and local peripheral blood counts. Complete remission was defined as meeting the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl. Complete remission with partial hematological recovery was defined as meeting the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. Complete remission with incomplete hematologic recovery was defined as meeting all of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; incomplete recovery of peripheral blood counts: platelets > 100,000/μl or ANC > 1000/μl. Participants without a post-baseline disease assessment were considered non-responders. | Approximately 12 weeks, as of the data cut-off date of 20 May 2015 | 
| Overall Survival | Overall survival was assessed from the date the participant received the first infusion of blinatumomab until death from any cause or the date of the last follow-up. Participants still alive at the data cut-off date were censored on the last documented visit date or the date of the last contact when the patient was last known to have been alive. | From first dose of blinatumomab until the data cut-off date; median observation time was 8.8 months. | 
| Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission | Participants who achieved remission (CR/CRh*) during the first 2 cycles of treatment and received an allogeneic HSCT. | Up to the data cut-of date of 20 May 2015; Maximum duration on study was 14.5 months. | 
| 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant | The analysis of 100-day mortality after allogeneic HSCT was assessed for participants who received an allogeneic HSCT while in remission (CR/CRh*) after 2 cycles of blinatumomab treatment and did not receive any additional antileukemic treatment. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT. 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. Participants 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. | From the date of allogeneic HSCT until the data cut-off date of 20 May 2015; median observation time was 3.2 months. | 
| Number of Participants With Adverse Events | Adverse events (AEs) were graded for severity according to the CTCAE version 4.0, where Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. Treatment-related adverse events (TRAEs) were those assessed by the investigator as possibly related to blinatumomab based on response to the question: Is there a reasonable possibility that the event may have been caused by blinatumomab or other protocol-specified therapies/procedures? | From the first dose of blinatumomab until 30 days after the last dose, up to the cut-off date of 20 May 2015; the median duration of treatment was 53.8 days. | 
| Number of Participants Who Developed Anti-blinatumomab Antibodies | Anti-blinatumomab binding antibodies were evaluated with a validated blinatumomab anti-drug antibody assay with the electrochemiluminescence detection technology. | Day 29 of each treatment period and 30 days after the last dose | 
| Steady State Concentration of Blinatumomab |  | Cycle 1, day 8, 6 to 8 hours after the dose step to 28 μg/day, and Cycle 2, day 1, 6 to 8 hours after blinatumomab infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed; Refractory; Philadelphia Positive; B-precursor; Acute Lymphoblastic Leukemia; ALL; Blinatumomab; Leukemia;