Product: Blinatumomab (AMG 103) Clinical Study Report: MT Date: 19 April 2013 Page 2 of 9510

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1 Date: 19 April 2013 Page 2 of SYNOPSIS Name of Sponsor: Amgen Research (Munich), formerly Micromet AG/Micromet GmbH, Staffelseestrasse 2, Munich, Germany Name of Finished Product: Blinatumomab Name of Active Ingredient: A murine recombinant single-chain antibody derivative that combines in 1 molecule the binding specificity for both the pan-b cell antigen CD19 and the epsilon chain of the T-cell receptor/cd3 complex (AMG 103; MT103) Title of Study: An Open-Label, Multi-Center Phase 1 Study to Investigate the Tolerability and Safety of a Continuous Infusion of the Bispecific T-Cell Engager MT103 in Subjects With Relapsed Non-Hodgkin s Lymphoma (NHL) Investigator(s) and Study Center(s): This study was conducted at 9 centers in Germany. Centers and principal investigators are listed in Appendix 4. Publication(s): Bargou et al, 2008; Goebeler et al, 2010, 2011; Viardot et al, 2011, 2010, 2009; Nagorsen et al, 2009; Poster presentations at Annual Meeting of American Society of Hematology. 2009, 2010, Study Period: 22 June 2004 to 17 April 2012 Development Phase: 1 Objectives: The primary objective was to evaluate the safety and tolerability of continuous intravenous (CIV) infusions of blinatumomab at different dose levels in subjects with relapsed NHL. The secondary objectives were: To determine the pharmacokinetics of blinatumomab To evaluate the pharmacodynamics of blinatumomab (cytokine levels, T- and B-cell count) To assess the antitumor activity of blinatumomab (based on the objective remission of the disease) Methodology: This trial was designed as a dose escalation study to determine the safety, tolerability and maximal tolerable dose (MTD) of blinatumomab in subjects with relapsed NHL. Blinatumomab was administered as 4- or 8-week CIV infusion at 7 dose levels ranging from 0.5 to 90 µg/m²/d. After inclusion of the first 42 subjects treated with various steroid co-medications, recruitment was extended to allow enrolment of another 34 subjects (trial extension phase) at 60 µg/m 2 /d to further study mitigation of central nervous system (CNS) adverse events and to gain more experience in a broader patient population, in particular, subjects with diffuse large B-cell lymphoma (DLBCL). Intra-individual weekly dose escalation in a single- or double-step mode (5/(15)/60 µg/m 2 /d) was combined with various steroid co-medications or defined dexamethasone treatment. Number of Subjects Planned: approximately 80 Number of Subjects Enrolled: 76 Diagnosis and Main Criteria for Eligibility: Eligible subjects were men or women 18 years of age who had first or later (2 nd, 3 rd, etc.) relapse of histologically confirmed follicular lymphoma (FL) (grade I/II), marginal zone lymphoma, lymphoplasmocytic lymphoma, mantle cell lymphoma (MCL), or small lymphocytic lymphoma requiring therapy and not eligible for curative therapy. Inclusion criteria were amended during a later phase of the trial to include subjects with diffuse large B-cell lymphoma (DLBCL). Other eligibility criteria included measurable disease documented by computed tomography (CT) scan, Eastern Cooperative Oncology Group (ECOG) performance status 2, life expectancy at least 6 months, as well as adequate liver, renal, and bone marrow function. Subjects with known or suspected central nervous involvement, history of or current relevant CNS pathology, history of malignancy other than B-cell lymphoma within the last 5 years, active infection, or presence of human anti-murine antibodies (HAMA) were excluded..

2 Date: 19 April 2013 Page 3 of 9510 Investigational Product, Dose and Mode of Administration, Manufacturing Batch Number:. Blinatumomab was the only investigational product for this open-label study; there was no blinding. Blinatumomab was administered as a CIV infusion over 4 or 8 weeks. Subjects were assigned to cohorts of at least 3 subjects each based on the rules of a trial design and the recommendations of a Data Review Committee (DRC). The starting dose was 0.5 µg/m 2 /d. In the first 3 cohorts, subjects were treated with a flat dose (ie, same starting dose and maintenance dose) throughout the treatment period. From cohort 4 onwards intra-individual dose escalations, eg, in a single- or double-step mode (5/(15)/60 µg/m 2 /d), were also investigated in some cohorts. The fill lot numbers of blinatumomab administered in this study are provided in (Appendix 18). Reference Therapy, Dose and Mode of Administration, Manufacturing Batch Number: Not applicable. Duration of Treatment: All subjects were to be treated for at least 4 weeks unless dose-limiting toxicities (DLT) or relevant disease progression occurred. Subjects with at least stable disease at week 4 were permitted to receive 4 weeks of additional treatment with blinatumomab for a total of up to 8 weeks as a first treatment cycle. Treatments of all subjects who experienced DLT were discontinued after completion of the follow-up visits. The end of study (EoS) visit was scheduled 4 weeks after end of blinatumomab infusion. After completion of the core study (defined as the first treatment cycle of up to 8 weeks of infusion followed by a 4-week follow-up period), subjects with clinical benefit (reference assessment validated a shrinkage of the measurable lesions) were offered an additional treatment approximately 3 months after infusion stop at the respective initial dose level delivered to the individual subject or a dose level already investigated and confirmed safe by the DRC. Study Endpoints: The primary endpoint was overall frequency of adverse events (clinical symptoms, laboratory abnormalities, serious adverse events [SAEs], and treatment-limiting adverse events). Secondary endpoints included the following: Serum concentrations of blinatumomab Peripheral lymphocytes: B- and T-cell counts Cytokine serum concentration Objective disease remission according to the NCI-sponsored International Workshop to standardize Response Criteria (also known as Cheson criteria). Statistical Methods: The statistical analysis was based on descriptive methods. Duration of response (DOR) was counted starting from the first assessment of either complete response (CR), unconfirmed CR (CRu), or partial response (PR) until progression of disease, initiation of a new anti-tumor therapy or death, whichever event occurred earlier. Subjects without any of these events were censored on the last available visit date. Kaplan-Meier estimates were used to estimate the median duration of response (and the 1st and 3rd quartiles); the estimation of the corresponding two-sided 95% confidence intervals was based on the sign test. Cytokine levels and lymphocyte counts were analyzed by descriptive statistics. Summary of Results: Subject Disposition: A total of 76 subjects were enrolled in this study and were treated with blinatumomab. In this study there were 20 separate cohorts. Six dose groups were defined based on the dose that was intended to be given to a subject as follows: Dose group 5 μg/m 2 /d: subjects from cohorts who received daily dosages up to 5 μg/m 2 /d of blinatumomab, ie, cohort 1, cohort 2, cohort 2 reduced, and cohort 3 Dose group 15 μg/m 2 /d: subjects from cohorts who received 15 μg/m 2 /d of blinatumomab, ie, cohort 4, cohort 4 flat, and cohort 4 ramp Dose group 30 μg/m 2 /d: subjects from cohorts who received 30 μg/m 2 /d of blinatumomab, ie, cohort 4.5 flat, and cohort 4.5 ramp

3 Date: 19 April 2013 Page 4 of 9510 Dose group 60 μg/m 2 /d flat: subjects from cohorts who received 60 μg/m 2 /d without a lower dose, ie, cohort 5 flat, cohort 5 flat new, and cohort 5 adapted Dose group 60 μg/m 2 /d step: cohorts for subjects who received 60 μg/m 2 /d after starting at lower doses for specified time frames ie, cohort 5 (15/60), cohort 5 (5/60), cohort 5 PPS (5/60), cohort 5 lowbt(5/15/60), cohort 5 highbt(5/15/60), cohort 5 DLBCL(5/15/60), and cohort 5 DLBCL(5/15/60)DEX Dose group 90 μg/m 2 /d: cohorts for subjects who received 90 μg/m 2 /d, ie, cohort 5.5 and cohort 5.5 (90/90). Twelve subjects were assigned to the 5μg/m²/d dose group; 13 subjects to the 15μg/m²/d dose group; 6 subjects to the 30μg/m²/d dose group; 9 subjects to the 60μg/m²/d flat dose group; 32 subjects to the 60μg/m²/d step dose group; and 4 subjects to the 90μg/m²/d dose group. Baseline Demographics: Sex: 57 subjects (75%) were men. Age: The mean (standard deviation [SD]) age was 60.3 (12.4) years (range: years). Ethnicity/Race: All subjects were Caucasian. Efficacy Results: All 76 subjects were evaluable for response assessment. Peripheral B-cell depletion was demonstrated in all subjects at a dose of 5 μg/m²/d. No objective responses were seen at doses < 15 μg/m²/d. At dose levels 15 and 30 µg/m²/d, 4 objective responses (2 CRs and 2 PRs) were observed among 19 subjects (21%). At 60 μg/m²/d, the objective response rate (ORR) was 69% (24 of 35 subjects). Dose escalation was continued up to 90 μg/m²/d, but this dose level was not tolerated. In light of a higher ORR at 60 μg/m²/d), this dose was selected as the target dose for efficacy. In subjects with FL with target dose 60 g/m 2 /d, ORR was 80% (12 of 15 subjects), with 6 responses each being CR/CRu and PR. Subjects with MCL had an ORR of 71% (5 of 7 subjects) with 3 responses being CR/CRu and 2 responses being PR. In subjects with DLBCL, ORR was 55% (6 of 11 subjects) with 4 responses being CR/CRu and 2 responses being PR. Follow-up data as of May 2, 2012 for responding subjects treated at a dose level of 60 μg/m 2 /d showed a median DOR of 404 days (95% confidence interval ranging from 205 days to 1129 days) with 8 subjects in ongoing remission. Thirteen subjects had long term remissions of more than 1 year, among these there were 2 subjects with refractory DLBCL. Median DOR for subjects with DLBCL was 147 days, for MCL 489 days and for FL 518 days. Pharmacokinetics Results: Will be added. Pharmacodynamics Results: Blinatumomab caused depletion of circulating B cells that was complete and sustained at dose levels of 5 µg/m 2 /d and above. At the dose range of 5 ug/m 2 /d to 90 ug/m 2 /d, B-cell recovery was observed in only 5 subjects at EoS in the follow-up period (4 subjects at 15 μg/m²/d and 1 subject at 60 μg/m²/d). In the remaining subjects the levels were not detectable. From a total of 14 subjects treated with additional cycles, 5 of them had nondetectable B-cell counts before the start of the additional cycle. T-cell kinetics showed a characteristic redistribution after start of infusion and any dose step, ie, a fast disappearance of circulating T cells within the first 6 hours and a subsequent reappearance during the following 2 to 7 days depending on initial B-cell counts. T-cell redistribution correlated well with up-regulation of activation marker CD69 on T cells and with increased T-cell adhesiveness as demonstrated by binding of soluble intercellular adhesion molecule-1 (ICAM-1) to intermediate affinity LFA-1 (integrin) on T cells. Also, release of Ang2, a marker for endothelial cell activation, into serum during T-cell redistribution was demonstrated in selected subjects, further indicating direct T cell/endothelial cell contact during redistribution. Although not directly engaged by bispecific T-cell engager (BiTE) molecules, natural killer (NK) cells exhibited similar redistribution kinetics as T cells did. Monocytes displayed similar redistribution kinetics as both T and NK cells did. Although marked changes were detected in serum concentrations of angiopoietin-1 (Ang 1), angiopoietin-2 (Ang 2), and S100β, no striking differences emerged between subjects with or without CNS events. No correlation between the occurrence of CNS events and serum levels of the PD markers monocyte chemoattractant protein (MCP)-1, interleukin (IL)-1β, and vascular endothelial growth factor (VEGF) was observed, and they do not qualify as serum biomarkers for the occurrence of CNS

4 Date: 19 April 2013 Page 5 of 9510 events. No correlation between granzyme B (GranB) serum levels and drug response was seen. in subjects with relapsed NHL. A total of 1091 serum samples were analyzed for their content of cytokines. In most subjects, cytokine levels of IL-2, IL-6, and IL-10 increased sharply immediately after start of blinatumomab infusion and returned to baseline levels within 1 to 2 days. A similar observation was noted for TNF-α and IFN-γ in some subjects. Cytokine elevation was mainly in cycle 1 and highly variable among individuals. Safety Results: Dose escalation phase and MTD Forty-two subjects were treated during the dose escalation phase. Subjects received CIV blinatumomab infusion for 4 or 8 weeks starting at 0.5 µg/m 2 /d (1.5, 5, 15, 30, 60, 90). In total,10 of 76 subjects experienced 24 events of DLT and discontinued treatment. DLTs occurred at highest intended dose levels of 15 g/m 2 /d (2 subjects), 60 g/m 2 /d (5 subjects), and 90 g/m 2 /d (3 subjects). The majority of DLT events (16 of 24 events) were due to CNS events; DLTs also occurred in the system organ classes (SOCs) investigations (3 events), metabolism and nutrition disorders (2 events), and blood and lymphatic system disorders (3 events); all but 1 event (lymphopenia) were fully reversible after discontinuation of study treatment. With 3 out of 4 subjects experiencing DLTs (1 grade 3 event of convulsion and 2 grade 3 events of encephalopathy) at 90 μg/m 2 /d, 60 μg/m 2 /d was established as maximum tolerated dose (MTD) in this study, although no intermediate dose higher than 60 μg/m 2 /d but less than 90 μg/m 2 /d has been tested. In a retrospective analysis, it was revealed that subjects with B-NHL having a high initial B:T cell ratio in their peripheral blood (> 1:10) were potentially at lower risk for developing a CNS event. Trial extension phase In order to avoid DLT and treatment discontinuations due to CNS events and to treat subjects with DLBCL, the protocol was amended and an additional 34 subjects, including 14 subjects with DLBCL, were enrolled on dose level 60 µg/m 2 /24h to evaluate a stepwise dose approach in combination with steroid premedication. Of the 14 subjects with DLBCL, 7 subjects completed the study; 1 subject was lost to follow-up; 1 subject discontinued treatment due to pneumoperitoneum; and 5 subjects discontinued treatment due to CNS adverse events. It was observed that applying dexamethasone 12 hours (rather than only 1 hour) prior to treatment in combination with double step dose escalation in 5 subjects, no treatment discontinuations due to CNS adverse events were observed. Therefore, the combination of stepwise dose approach (5/15/60) with early dexamethasone prophylaxis was recommended for further development in DLBCL. Safety findings All 76 subjects had at least 1 treatment-emergent adverse event (TEAE), and the majority of events were grade 1-2; 75 subjects (98.7%) had at least 1 adverse event that was reported by the investigator as related to blinatumomab. Blinatumomab treatment was interrupted due to a TEAE in 14 (18.4%) subjects and was discontinued permanently due to TEAE in 30 (39.5%) subjects. The most frequent adverse events overall leading to permanent discontinuation of blinatumomab were encephalopathy (7.9%), aphasia (5.3%), and dyspnea (5.3%). Fifty-nine subjects (77.6%) experienced at least 1 serious adverse event (SAE) on study; the most frequent (incidence 5%) SAEs were lymphopenia in 55% of subjects; leukopenia, neutropenia, and pyrexia in 9% of subjects each; and encephalopathy in 8% of subjects. All serious adverse events were judged grade 3 in severity. Serious adverse events were judged by the investigator to be related to blinatumomab in 71.1% of subjects; the most frequent (5%) related SAEs were lymphopenia (51.3% of subjects), and leukopenia, neutropenia, encephalopathy, and pyrexia (7.9% of subjects each). Three subjects (3.9%) (1 each in the 5μg/m²/d, 15μg/m²/d, and 60μg/m²/d step dose groups) experienced fatal TEAEs (dyspnea due to disease progression, bacterial sepsis, and pneumocystis jirovecii infection). The sepsis and pneumonia were considered to be possibly related to treatment. The most commonly reported clinical adverse events were lymphopenia (80%) pyrexia (76%), fatigue (46%), headache (42%), weight increase (42%), and weight decrease (32%). Laboratory adverse events were mostly transient including hematological adverse events. The most frequently affected SOCs (those in which 50% of subjects experienced at least 1 adverse

5 Date: 19 April 2013 Page 6 of 9510 event) were as follows: blood and lymphatic system disorders (70 subjects [92.1%]); general. disorders and administration site conditions (70 [92.1%]); investigations (70 [92.1%]); metabolism and nutrition disorders (61 [80.3%]); nervous system disorders (50 [65.8%]); and gastrointestinal disorders (48 subjects [63.2%]). An important identified risk associated with blinatumomab treatment is CNS events, eg, encephalopathy, speech disorders (aphasia, dysarthria, and speech disorder), tremor, apraxia, and disorientation. Neurological and psychiatric events (excluding headache) were reported as TEAEs in 43 (56.6%) subjects; 18.4% events were judged by the investigator as related to blinatumomab treatment. Events grade 3 or higher in severity occurred in 14 (18.4%) subjects; none of these were judged related to treatment. Fourteen subjects (18.4%) reported serious treatment-emergent CNS events; none were considered related to treatment. Fifteen subjects (19.7%) had events that led to permanent interruption of blinatumomab treatment. The most common treatment-related CNS events (excluding headache) were tremor (18.4%), dizziness (14.5%), and aphasia (11.8%). Two (2.6%) subjects experienced convulsions. Eleven subjects who had CNS events also died; however, the deaths were not necessarily from the CNS events, and no grade 5 events were deemed CNS in nature or coded to a CNS event. Grade 4 or 5 CNS adverse events were not observed. A dose-response relationship for CNS events is assumed as discontinuation of treatment due to CNS adverse events was 75% on dose level 90 µg/m 2 /d (3 out of 4 subjects exposed; grade 3 convulsion in 1 subject, and grade 3 encephalopathy in 2 subjects). Most CNS events started within the first 2 days relative to the first infusion of each treatment cycle as well as the first infusion of each dose step. With the exception of 1 case of pleocytosis (60 μg/m 2 /d dose group) and 1 case of emotional distress (15 μg/m 2 /d dose group), all CNS events were fully reversible within hours to days. Electrocardiogram analyses did not reveal a risk for cardiac events associated with blinatumomab treatment. Conclusions: In Study MT , a phase 1 study in adult subjects with relapsed NHL, 76 subjects were enrolled and treated with blinatumomab at doses ranging from 0.5 μg/m²/d to 90 μg/m²/d for periods between 1 and 56 days in the initial treatment period of subjects. In this study, the majority of DLTs (16 of 24 events) were due to CNS events; DLTs also occurred in the SOCs investigations, metabolism and nutrition disorders, and blood and lymphatic system disorders. With 3 out of 4 subjects experiencing DLTs at 90 μg/m 2 /d, 60 μg/m 2 /d was established as MTD in this study, although no intermediate dose higher than 60 μg/m 2 /d but less than 90 μg/m 2 /d has been tested. All 76 subjects had at least 1 treatment-emergent adverse event (TEAE); all but 1 subject had at least 1 adverse event that was reported by the investigator as related to blinatumomab treatment. Blinatumomab treatment was interrupted due to a TEAE in 18.4% of subjects and was discontinued permanently due to a TEAE in 39.5% of subjects. Fifty-nine subjects (77.6%) experienced at least 1 SAE; the most common were lymphopenia, leukopenia, neutropenia, pyrexia, and encephalopathy; all serious adverse events were judged grade 3 in severity. SAEs were judged by the investigator to be related to blinatumomab in 71.1% of subjects. Three subjects (3.9%) (1 each in the 5μg/m²/d, 15μg/m²/d, and 60μg/m²/d step dose groups) experienced fatal TEAEs (dyspnea due to disease progression, bacterial sepsis, and pneumocystis jirovecii infection). The sepsis and pneumonia were considered to be possibly related to treatment. The most frequently affected SOCs were blood and lymphatic system disorders, general disorders and administration site conditions, investigations, metabolism and nutrition disorders, nervous system disorders, and gastrointestinal disorders. The most frequent adverse events observed (ie, affecting at least 50% of subjects overall) were lymphopenia and pyrexia. An important identified risk associated with blinatumomab treatment is CNS events. Neurological and psychiatric events (excluding headache) were reported as TEAEs in 56.6% of subjects, and judged by the investigator as related to blinatumomab treatment in 18.4% of subjects. The most common treatment-related CNS events (excluding headache) were tremor, dizziness, and aphasia. Events grade 3 or higher in severity occurred in 18.4% of subjects; none of these were judged related to treatment. Fourteen subjects (18.4%) reported serious treatment-emergent

6 Date: 19 April 2013 Page 7 of 9510 CNS events; none were considered related to treatment. Fifteen subjects (19.7%) had events that. led to permanent interruption of blinatumomab treatment. The rate of treatment discontinuation treatment due to CNS adverse events was the highest (75%; 3 out of 4 patients exposed) on dose level 90 µg/m 2 /d. Grade 4 or 5 CNS adverse events were not observed. Most CNS events started within the first 2 days relative to the first infusion of each treatment cycle as well as the first infusion of each dose step. With the exception of 1 case of pleocytosis (60 μg/m 2 /d dose group) and 1 case of emotional distress (15 μg/m 2 /d dose group), all CNS events were fully reversible within hours to days. In subjects with relapsed NHL receiving a target dose of blinatumomab 60 μg/m 2 /d, a 69% ORR was observed. In subjects with relapsed DLBCL receiving a target dose of blinatumomab 60 μg/m 2 /d, a 55% response rate was observed in evaluable subjects.