Date: 11 July 2014 Page 1. 2. SYNOPSIS Name of Sponsor: Amgen Research (Munich) GmbH Name of Finished Name of Active Ingredient: Blinatumomab, a murine recombinant single-chain antibody derivative that combines in 1 molecule the binding specificity for both the pan-b cell antigen cluster of differentiation (CD) 19 and the epsilon chain of the T cell receptor/cd3 complex (AMG 103; MT103) Title of Study: An Open-label, Multicenter, Phase 2 Study to Evaluate Efficacy and Safety of the Bi-specific T cell Engager (BiTE ) Antibody Blinatumomab in Adult Subjects with Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) Investigators and Study Centers: This study was conducted at 37 centers in Germany, Italy, Spain, France, the United Kingdom, and the United States. The coordinating investigator is. All centers and principal investigators are listed in Section 16.1.4. Publications: Topp MS, Goekbuget N, Stein AS, et al. Confirmatory open-label, single arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). J Clin Oncol 2014; 32(15 suppl):7005 [abstract]. Study Period: 06 December 2011 (first screening visit performed) to 10 October 2013 (subjects had the opportunity to be assessed for at least the first 2 cycles of treatment [all subjects enrolled under protocol version 3.0 or earlier for whom the primary efficacy endpoint was defined]). For this version of the clinical study report (CSR) (ie, primary analysis), data for subjects from the first 3 stages (N =189) are reported). Serious and fatal adverse events from 11 October 2013 to 30 March 2014 are reported for all subjects who received blinatumomab. Core study data for all subjects who enrolled in this study (protocol version 3.0 or earlier) will be reported in the secondary analysis CSR. Development Phase: 2 Objectives: Primary Objective: to evaluate the efficacy of blinatumomab in subjects with relapsed/refractory B-precursor ALL Secondary Objectives: to evaluate safety of blinatumomab in subjects with relapsed/refractory B-precursor ALL to evaluate pharmacokinetics (PK) and pharmacodynamics (PD) of blinatumomab Note: data from subjects in recruitment stage 4 will be reported in the secondary analysis CSR. Methodology: This study investigated the efficacy, safety, PK, PD, and central nervous system (CNS) symptoms of blinatumomab in subjects with relapsed/refractory B-precursor ALL. Subjects received blinatumomab as a continuous intravenous (CIV) infusion at a target dose of 28 g/day over 4 weeks followed by a treatment-free period of 2 weeks (corresponding to 1 treatment cycle). During the first cycle, the dose of blinatumomab was 9 g/day for 7 days, then 28 g/day for the remaining 3 weeks of this cycle and for subsequent cycles. Subjects who achieved complete remission (CR) or a complete remission with partial hematological recovery (CRh*) during the first 2 cycles could receive up to 3 additional cycles of blinatumomab. Subjects who relapsed during the follow-up period could receive up to an additional 3 cycles of treatment.
Date: 11 July 2014 Page 2 Number. of Subjects Planned: Approximately 220 (up to190 enrolled before protocol version 4.0 [29 in stage 1; 32 in stage 2; 129 in stage 3] and 30 subjects in the additional CNS evaluation cohort) Number of Subjects Enrolled for the Primary Analysis: 189 (29 in stage 1; 37 in stage 2; 123 in stage 3). Seventy-eight subjects were screen failures. Number of Subjects Analyzed: For efficacy and safety analyses, the data for 189 subjects (Primary Analysis Set; PAS) who received any infusion of blinatumomab were presented up to the cut-off date of 10 October 2013, when the last subjects enrolled were projected to complete cycle 2. PAS and Full Analysis Set (FAS) are identical for this CSR, but the FAS will include the extension cohort and be reported in the secondary CSR. Serious and fatal adverse events since the cut-off date (11 October 2013 through 30 March 2014) are presented for all subjects who received blinatumomab regardless of protocol version. Diagnosis and Main Criteria for Eligibility: Adult subjects with Philadelphia (Ph) chromosome-negative B-precursor ALL, whose disease was refractory or had relapsed with first remission duration of 12 months in first salvage, or relapsed or refractory after first salvage therapy, or relapsed within 12 months of allogeneic hematopoietic stem cell transplant (HSCT), and had 10% blasts in bone marrow. Important exclusion criteria were the presence of active disease in the CNS or testis, or a history or presence of clinically relevant CNS pathology (eg, as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson s disease, cerebellar disease, organic brain syndrome, psychosis). Investigational Product, Dose and Mode of Administration, Manufacturing Batch Number: Blinatumomab was administered as a CIV infusion. In the first cycle, the initial dose was 9 μg/day for 7 days, then 28 μg/day for the remaining 3 weeks. The target dose of 28 μg/day was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Dose reduction was possible in the case of adverse events. Two distinct manufacturing batches were used for this study: Manufacturing batch numbers are provided in Section 16.1.6. Reference Therapy, Dose and Mode of Administration, Manufacturing Batch Number: Not applicable. Duration of Treatment: Subjects may have received up to 5 treatment cycles at a target dose of 28 g/day. Subjects with hematological relapse during the follow-up period may have received up to 3 additional cycles of blinatumomab for a maximum of 8 cycles at the investigator s discretion. The duration of core study participation for each subject was up to 37 weeks: up to 3 weeks screening period; up to 30 weeks consisting of up to 5 consecutive cycles (each of which was up to 6 weeks of duration), and the end of core study visit 30 days after the end of the last cycle. After the last treatment cycle, efficacy follow-up visits occurred for up to 24 months from the date of the first infusion for subjects who had responded to treatment. Subjects moved into survival follow-up earlier than 24 months after treatment start if CR/CRh* was not achieved, if they suffered hematological relapse after CR/CRh*, or if they proceeded to other anti-leukemia therapy or received HSCT. Survival follow-up visits were performed every 6 months until death or 3 years from the time of first treatment, whichever occurred first. In the case of retreatment after hematological relapse during the follow-up period, information regarding hematological status was collected for a maximum of 3 years after the start of retreatment. The maximum duration of this study is approximately 5 or 7 years depending on whether subjects undergo retreatment. The assessment of the primary endpoint was approximately 3 months after enrollment of the last subject in the PAS. Study Endpoints: The primary endpoint was the CR/CRh* rate within 2 cycles of treatment with blinatumomab. A CR was defined as 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/L and absolute neutrophil
Date: 11 July 2014 Page 3 counts. [ANC] > 1,000/L). A CRh* was defined as 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/L and ANC > 500/L). Secondary endpoints included: time to hematological relapse (duration of response); proportion of subjects eligible for allogeneic HSCT who underwent the procedure after blinatumomab treatment; CR rate, CRh* and partial remission rates within 2 cycles of treatment with blinatumomab; relapse-free survival; event-free survival; overall survival; overall incidence and severity of adverse events; 100-day mortality after allogeneic HSCT; PK parameters: steady state serum concentration; cytokine concentrations; blast free hypoplastic or aplastic bone marrow within the first 2 cycles of treatment added from the Statistical Analysis Plan [SAP]); best treatment response rates (CR, CRh*, blast free hypoplastic or aplastic bone marrow, and partial remission rates) during the core study (added from the SAP). Exploratory and other endpoints included: overall survival - Landmark analyses (day 36 and day 77) (added from the SAP); rate of minimal residual disease (MRD) response within 2 cycles of treatment; rate of MRD complete response within 2 cycles of treatment; time to CR/CRh* and CR (added from the [SAP]); and quantification and characterization of peripheral blood lymphocyte subsets. Statistical Methods: The primary analysis was based on the PAS (subjects from the first 3 stages of the study who received any infusion of blinatumomab [all subjects enrolled under protocol version 3.0 or earlier for whom the primary efficacy endpoint was defined]). The FAS was defined as all subjects who received any infusion of blinatumomab. Safety analyses were based on the FAS at the time of the data cut-off date (10 October 2013) for this CSR. The safety analyses may be considered interim analyses based on the FAS. Serious and fatal adverse events are also reported since the cut-off date (from 11 October 2013 through 30 March 2014). For this CSR, the efficacy analyses based on the EFS and PPS were performed as sensitivity analyses. Subgroup analyses were also performed. For this primary analysis CSR, the FAS was equivalent to the PAS. All documented parameters were evaluated. Individual data were listed. Data were summarized using suitable descriptive statistics. Data were analyzed overall and differentiated (eg, by age, blast count at baseline and further disease-related risk factors). Two-sided 95% confidence intervals (CI) were calculated for response rates. Time-to-event data were analyzed by Kaplan-Meier methods. Subjects in the PAS without any evaluable response assessment within the first 2 cycles of treatment with blinatumomab (eg, early drop outs) were included in the analysis of the primary efficacy endpoint as nonresponders. For the primary analysis at the end of stage 3 (after response assessments from the first 2 cycles of treatment were available for all PAS subjects) the following hypothesis was tested using the exact binomial test on a 2.5% significance level (1-sided hypothesis): H0: π 30% versus H1: π > 30%. Summary of Results: Subject Disposition: One hundred eighty-nine subjects were enrolled and received at least 1 infusion of blinatumomab, and were included in the PAS/FAS. At the time of the data cut-off date, 5.3% (10/189) of subjects had completed 5 cycles of treatment and treatment was ongoing for 1.1% (2/189) of subjects; 38.1% (72/189) of subjects were still in the study, while 61.9% (117/189) of subjects had ended the study.
Date: 11 July 2014 Page 4 Baseline. Demographics and Subject Characteristics: Sex: Men: 63% (119/189); Women: 37% (70/189) Age: The median age was 39.0 years (range 18 to 79 years); 18 to < 35 years: 47.6 % (90/189); 35 to < 55 years: 24.3% (46/189); 55 to < 65 years: 14.8% (28/189); 65 years: 13.2% (25/189) Ethnicity/Race: White: 85.8% (145/189); Asian: 3.6% (6/189); Black/African American: 4.1% (7/189); American Indian/Alaska native: 0.6% (1/189); native Hawaiian/other Pacific Islander: 0.6% (1/189); other 5.3% (9/189); not recorded: 20 (race was not recorded for subjects enrolled in France) Prior Salvage Therapy: None: 20.1% (38/189); 1 prior salvage therapy: 40.7% (77/189); 2 prior salvage therapies: 22.2% (42/189); > 2 prior salvage therapies: 16.9% (32/189) Prior Allogeneic HSCT: Yes: 33.9% (64/189); No: 66.1% (125/189) Efficacy Results: The primary efficacy endpoint of this study was the CR/CRh* rate within the first 2 cycles of treatment with blinatumomab. The rate of CR/CRh* within the first 2 treatment cycles was 42.9 % (81/189; 95% CI: 35.7% to 50.2%). The CR/CRh* rate was significantly greater than 30%. For the PAS, the CR rate was 33.3% (63/189) and the CRh* rate was 9.5% (18/189) for the first 2 cycles of treatment; 9% (17/189) of subjects had blast free hypoplastic or aplastic bone marrow and 2.6% (5/189) of subjects had partial remission. One additional subject achieved CR after cycle 2. Three subjects achieved CRh* within the first 2 cycles of treatment, then converted to CR during subsequent cycles, making the overall CR rate during the core study 35.4% (67/189; 95% CI: 28.6% to 42.7%). The median relapse-free survival was 5.9 months (95% CI: 4.8 to 8.3 months) for subjects who achieved remission (CR/CRh*) during the core study. The median time to hematological relapse was 6.7 months (95% CI: 5.1 months to not estimable [n.e.]) for subjects who achieved remission during the core study. The median overall survival was 6.1 months (95% CI: 4.2 to 7.5 months). All subjects who achieved CR/CRh* were considered eligible for allogeneic HSCT for analysis purposes. Among these subjects, 39.5% (32/81; 95% CI: 28.8% to 51%) received an allogeneic HSCT without any other subsequent anti-leukemic medication (excluding conditioning regimens). Of these 32 subjects, 28 subjects had been in CR during the first 2 cycles of treatment, and 4 had been in CRh*. This corresponds to an HCST rate of 44.4% and 22.2% for subjects who achieved CR and CRh* during the first 2 treatment cycles, respectively. There were a total of 52 subjects without prior HSCT who achieved CR/CRh* within the first 2 treatment cycles. Of these 52 subjects, 27 subjects (51.9%; 27/52) went to transplant in a blinatumomab induced remission. The 100-day post-hsct mortality rate (relative to transplant date) for the 32 subjects who underwent HSCT in blinatumomab remission was 11.3% (95% CI: 0% to 23.4%). For subjects in remission (CR/CRh*) with a MRD assessment during the first 2 cycles (N = 73), the MRD response rate was 82.2% (60/73), and the complete MRD response rate was 69.9% (51/73). For subjects who achieved CR within the first 2 treatment cycles, the MRD response rate was 86.2% (50/58) and the complete MRD response rate was 74.1% (43/58). For subjects who achieved CRh* within the first 2 treatment cycles, the MRD response rate was 66.7% (10/15) and the complete MRD response was 53.3% (8/15). Among the 10 subjects who achieved blast-free hypoplastic marrow and had an MRD assessment, 5 (50%) had MRD response and 2 (20%) had complete MRD response. Subgroup analyses revealed that among the prespecified analyses, the factors most strongly associated with response and survival were percent blasts in the bone marrow and number of platelets at baseline. Subjects generally had a more favorable response or more durable remission when baseline blasts were < 50% and when baseline platelets were > 100 x 109/L.
Date: 11 July 2014 Page 5 Pharmacodynamics:. Serum Cytokines The cytokine levels increased immediately after start of blinatumomab dosing in respective cycles with a peak level observed within 24 hours of treatment start, then declined quickly to below detection limit within 48 hours. Cytokine elevations were also observed, but to a reduced extent, with the dose step from 9 µg/day to 28 µg/day in cycle 1, and were lower in subsequent cycles. Lymphocyte Subpopulations (Exploratory) In most subjects, peripheral B cell counts dropped to 10 cells/μl during the first treatment cycle and remained low to undetectable throughout treatment. Peripheral B cell depletion was not achieved in some of the nonresponding subjects. Peripheral T cell counts remained stable during treatment with blinatumomab in most subjects. The kinetics of T-cell subtypes appeared to be similar in both responders and nonresponders. Lower proportions of CD19+ B lymphocytes and higher proportions of CD3+ lymphocytes, as well as lower proportions of lymphocytes and higher proportions of granulocytes in the leukocyte compartment of peripheral blood at screening were significantly associated with the achievement of CR/CRh*. Pharmacokinetics: Following CIV infusion at 9 µg/day and 28 µg/day, mean steady state serum concentrations (Css) of blinatumomab increased approximately dose proportionally. Mean Css were similar between the 2 formulations CTM4 and CTM5 in both the first and second treatment cycles; the ratio (CTM5/CTM4) of least squares geometric mean was 0.91 and 1.13, respectively. There were no clinical meaningful relationships between the clearance (CL) and baseline body weight, body surface areas (BSA), or creatinine clearance. Safety Results: For the FAS, 189 subjects (100%; 189/189) received at least 1 infusion of blinatumomab (119 subjects received CTM4 only, 55 subjects received CTM5 only, and 15 subjects received both CTM4 and CTM5); 51.9% (98/189) of subjects initiated a second cycle of blinatumomab treatment during the core study. Excluding retreatment cycles, most subjects received treatment for 28 days in each cycle. The median absolute cumulative dose received over the whole infusion period was 654.971 g (range: 10.80 g to 4070.05 g). For the PAS/FAS, the median number of cycles started was 2.0 (range: 1 to 5 cycles) and the median number of cycles completed was 1.0 (range: 0 to 5 cycles). The safety data in this CSR are reported as follows: up to the cut-off data of 10 October 2013: all safety data for the first 189 subjects (FAS) from 11 October 2013 to 30 March 2014 reported from the Amgen Global Safety Database: additional safety data collected for the first 189 subjects; safety data (serious and fatal adverse events) collected for all subjects who received blinatumomab (included additional CNS evaluation cohort) There was no meaningful difference in the incidence of treatment-emergent adverse events between subjects treated with. For the FAS, a total of 188 (99.5%) subjects experienced at least 1 treatment-emergent adverse event. The highest incidences (> 25%) of treatment-emergent adverse events by preferred term were pyrexia (59.8%; 113/189), headache (34.4%; 65/189), febrile neutropenia (28%; 53/189), and peripheral oedema (25.9%; 49/189). The highest incidence of treatment-emergent related adverse events (preferred term) was pyrexia (42.9%; 81/189), followed by febrile neutropenia (17.5%; 33/189), headache (14.8%; 28/189), and tremor (14.3%; 27/189). The highest incidence of grade 3 treatment-emergent adverse event (preferred term) was febrile neutropenia (24.3% [46/189] grade 3; 1.1% [2/189] grade 4).
Date: 11 July 2014 Page 6 At. the time of the data cut-off date, 16.4% (31/189) of subjects had died as a result of an adverse event regardless of relationship to study drug; 14.8% (28/189) of subjects died due to treatment-emergent adverse events. Nine of the 28 subjects experienced infections that led to death. The events leading to death which were considered related to blinatumomab were Escherichia sepsis, sepsis, and Candida infection. No adverse events leading to death were reported for subjects on blinatumomab who were in remission. Between 11 October 2013 and 30 March 2014, fatal adverse events were reported in 15 subjects; infections were reported in 8 of these subjects. At the time of the data cut-off date, the subject incidence of treatment-emergent serious adverse events was 64% (121/189). The highest incidences of treatment-emergent serious adverse events regardless of relationship were febrile neutropenia (8.5%; 16/189) and pyrexia (5.8%; 11/189). The incidence of grade 3 treatment-emergent serious adverse events regardless of relationship was 55.6% (105/189). Pneumonia was the most frequently reported grade 3 treatment-emergent serious adverse event regardless of relationship. Treatment-emergent serious adverse events related to blinatumomab were reported in 36.5% (69/189) of subjects. The highest incidences of treatment-emergent related serious adverse events (preferred terms) were febrile neutropenia (3.2%; 6/189), encephalopathy, overdose, and tremor (2.6%; 5/189 for each), and confusional state, neutropenia, pneumonia, and pyrexia (2.1%; 4/189 for each). Fifty-five subjects (55/189; 29.1%) experienced grade 3 treatment-emergent related serious adverse events. The highest incidence of grade 3 related treatment-emergent serious adverse event was febrile neutropenia (3.2%; 6/189). During the treatment period, 29.6% (56/189) of subjects experienced at least 1 treatment-emergent related serious adverse event of any grade that resolved compared with 4.8% (9/189) of subjects who experienced at least 1 treatment-emergent related serious adverse events of any grade that did not resolve; the outcome was unknown for 0.5% (1/189) of subjects. Between 11 October 2013 and 30 March 2014, serious adverse events were reported in 34 subjects; infections were reported in 16 subjects. Important identified risks for the blinatumomab program include neurologic events, cytokine release syndrome, tumor lysis syndrome (TLS), infections, overdose, elevated liver enzymes, neutropenia/febrile neutropenia, decreased immunoglobulins, capillary leak syndrome, and infusion reactions. Up to the cut-off date, treatment-emergent neurologic events were reported in 51.9% (98/189) of subjects. The subject incidence of treatment-emergent grade 3 neurologic events was 12.7% (24/189). Of the 24 subjects who were reported as having grade 3 events, events resolved for 19 subjects, 1 subject that was downgraded from grade 4 to grade 1, 1 subject had an event that was unresolved, and 3 subjects died due to causes other than neurologic events. From 11 October 2013 through 30 March 2014, 6 subjects had serious neurologic disorders, and 1 event was fatal (encephalopathy). Up to the cut-off date, treatment-emergent cytokine release syndrome events (preferred terms cytokine release syndrome and cytokine storm) were reported in 12.7% (24/189) of subjects. The subject incidence of grade 3 treatment-emergent cytokine release syndrome events was 1.6% (3/189). No life-threatening or fatal (grade 4 or 5) treatment-emergent cytokine release syndrome events were reported. All grade 3 events resolved. Between 11 October 2013 and 30 March 2014, no cytokine release syndrome events were reported. Up to the cut-off date, treatment-emergent TLS events were reported in 4.2% (8/189) of subjects. Three subjects (1.6%; 3/189) experienced grade 3 treatment-emergent TLS events. Two subjects (1.1%; 2/189) recovered from their TLS events and 1 subject died due to causes other than a TLS event. Between 11 October 2013 and 30 March 2014, a serious, non-fatal TLS event was reported for 1 subject.
Date: 11 July 2014 Page 7. Up to the cut-off date, treatment-emergent infections were reported in 63% (119/189) of subjects. The subject incidence of treatment-emergent grade 3 infection events was 35.4% (67/189). Of the 67 subjects who experienced grade 3 infection events, events resolved for 36 subjects. Infection events were unresolved for 14 subjects. Infection events were fatal for 17 subjects (see deaths above). Between 11 October 2013 and 30 March 2014, serious infections were reported in 16 subjects, and infection was fatal in 8 subjects. Up to the cut-off date, treatment-emergent overdose events were reported in 3.2% (6/189) of subjects. All overdose events had been recorded as serious and related to blinatumomab treatment as per the protocol, regardless of the occurrence of symptoms associated with overdose; however, no events were grade 3. All overdose events were transient in nature (ie, resolved). Between 11 October 2013 and 30 March 2014, a serious event of overdose was reported for 1 subject. Up to the cut-off date, treatment-emergent elevated liver enzyme events were reported in 27.5% (52/189) of subjects. The subject incidence of grade 3 treatment-emergent elevated liver enzyme events was 15.3% (29/189); no grade 5 events were reported. Of the 29 subjects who experienced grade 3 elevated liver enzyme events, events resolved for 14 subjects (14/29; 48.3%), while events were either ongoing or unresolved for 6 subjects (6/29; 20.7%). Nine subjects died due to causes other than elevated liver enzyme events. No cases were identified as meeting the criteria of Hy s Law. Between 11 October 2013 and 30 March 2014, no elevated liver enzyme events were reported. Up to the cut-off date, treatment-emergent neutropenia events were reported in 42.9% (81/189) of subjects. The subject incidence of grade 3 treatment-emergent neutropenia events was 39.7% (75/189). No grade 5 events were reported. Of the 75 subjects who experienced grade 3 neutropenia events, events resolved for 54 subjects (54/75; 72%) and events were unresolved for 9 subjects (9/75; 12%). Ten subjects died due to causes other than neutropenia events. Between 11 October 2013 and 30 March 2014, serious febrile neutropenia was reported for 4 subjects and serious neutropenia was reported for 2 subjects. Up to the cut-off date, treatment-emergent decreased immunoglobulin events were reported in 11.1% (21/189) of subjects. Two subjects (1.1%; 2/189) experienced grade 3 treatment-emergent decreased immunoglobulins events; there were no grade 4 or grade 5 events. Neither event resolved during the study period. Between 11 October 2013 and 30 March 2014, no decreased immunoglobulin events were reported. Up to the cut-off date, treatment-emergent capillary leak syndrome was reported in 1 subject.the event was grade 4, serious, and related to blinatumomab treatment. The event resolved during the treatment period. Between 11 October 2013 and 30 March 2014, no capillary leak syndrome events were reported. Up to the cut-off date of 10 October 2013, treatment-emergent infusion reaction events were identified for 28.6% (54/189) of subjects. Seven subjects (3.7%; 7/189) experienced infusion reaction events that were considered grade 3; all events resolved. Between 11 October 2013 and 30 March 2014, serious pyrexia was reported for 7 subjects. Important potential safety risks include thromboembolic events (which include disseminated intravascular coagulation [DIC] and venous thrombosis), leukoencephalopathy, and lymphopenia. Up to the cut-off date, treatment-emergent DIC events were reported in 2.1% (4/189) of subjects. One subject had grade 3 treatment-emergent DIC which did not resolve during the study period; no grade 4 or grade 5 events were reported. Between 11 October 2013 and 30 March 2014, no DIC events were reported.
Date: 11 July 2014 Page 8. Up to the cut-off date, treatment-emergent venous thrombosis and thromboembolic events were reported in 10.6% (20/189) of subjects. The subject incidence of grade 3 treatment-emergent venous thrombosis and thromboembolic events was 3.7% (7/189). Of the 7 subjects who had venous thrombosis and thromboembolic events, events resolved for 3 subjects. Three subjects had events did not resolve. One subject experienced a treatment-emergent event that was fatal; the event (preferred term of embolism) was considered unrelated to blinatumomab. Between 11 October 2013 and 30 March 2014, no venous thrombosis and thromboembolic events were reported. Up to the cut-off date, treatment-emergent serious, grade 3 leukoencephalopathy was reported in 1 subject, which had not resolved during the treatment period. Between 11 October 2013 and 30 March 2014, no leukoencephalopathy events were reported. Up to the cut-off date, treatment-emergent lymphopenia events (preferred terms lymphopenia and lymphocyte count decreased) were reported in 1.1% (2/189) and 1.6% (3/189) of subjects, respectively. Of 4 subjects that experienced grade 3 lymphopenia events, events resolved for 3 subjects (75%; 3/4), while the event was unresolved 1 subject (25%; 1/4). Between 11 October 2013 and 30 March 2014, no lymphopenia events were reported. Treatment-emergent adverse events leading to treatment interruption regardless of relationship to blinatumomab were reported in 33.3% (63/189) of subjects. Treatment-emergent adverse events regardless of relationship to blinatumomab leading to permanent treatment discontinuation were reported for 18% (34/189) of subjects. Conclusions: This study enrolled a population with heavily pretreated and/or aggressive relapsed/refractory ALL. The primary endpoint of the study was a CR/CRh* rate of 42.9% (CR 33.3%, CRh* 9.5%) of subjects achieving CR/CRh within 2 cycles of blinatumomab therapy. The primary endpoint was supported by the key secondary endpoints: relapse-free survival was 5.9 months and nearly 40 % of subjects who achieved CR/CRh* proceeded to transplant. An important exploratory endpoint demonstrated an 82% MRD response rate among subjects achieving CR/CRh* and having an evaluable MRD sample. Remission rates were consistent across a wide range of demographic and baseline characteristic subgroups including the observation that subjects older than 65 years of age achieved the same response rate as subjects ranging in age from 18 to 35 years. Bone marrow blast percentage at baseline was the strongest predictor of response. Subjects with > 50% blasts at baseline achieved a 29.2% response rate whereas subjects with < 50% blasts had a 72.9% response rate. All fatal adverse events occurred in subjects with active leukemia; none occurred among patients on blinatumomab and in remission. No fatal or life-threatening cytokine release events were reported. There were no fatal neurologic events. Neurologic events were rarely life-threatening (2.1% grade 4) and mostly reversible. There was no loss of efficacy among subjects who interrupted but then resumed therapy. Mean steady state concentration values for blinatumomab increased approximately dose proportionally following the continuous intravenous infusion and were similar between the 2 formulations (CTM4 and CTM5). The safety profile was consistent with other blinatumomab studies. There was no obvious difference in safety between the 2 formulations. This study showed an acceptable safety profile and a high remission rate in adult patients with heavily pre-treated and/or aggressive relapsed/refractory B-precursor ALL at the target dose of 28 g/day.