A Phase 1b Study of Blinatumomab Including Subcutaneous Administration in Relapsed / Refractory (R/R) Indolent Non Hodgkin's Lymphoma (NHL)
Authors: Rossi Giuseppe , Prince Henry Miles , Tam Constantine S. , Ku Matthew , Thieblemont Catherine , Popplewell Leslie L. , Wermke Martin , Haioun Corinne , Wong Doo Nicole , Viardot Andreas , Ferreri Andrés J M , Ferrari Silvia , Wong Hansen L. , Kadu Priti , Zugmaier Gerhard , Zeng Yi , Rambaldi Alessandro 
Published: November 2021

Abstract
Background: Blinatumomab, a bispecific T-cell engager (BiTE ®) molecule that directs cytotoxic T-cells to lyse CD19-expressing B lineage cells, has been investigated in NHL (Goebeler JCO 2016, Viardot Blood 2016, Katz ASH 2019). Here, we evaluated subcutaneous (SC) blinatumomab, which may simplify administration, improve convenience, and potentially reduce adverse events (AEs).
Methods: Patients (pts; ≥18 y) had indolent NHL (follicular, marginal zone, lymphoplasmacytic, mantle cell, or small lymphocytic) that was primary refractory (1+ prior line), relapsed (within 1 y of first response), or that had responded to initial therapy for ≥1 y and relapsed after 2+ lines, including an anti-CD20 monoclonal antibody. Disease must not have been irradiated and was measurable (≥1.5 cm) on PET-CT or CT. Pts had a 3-wk continuous intravenous (cIV) run-in period followed by SC dosing in 5 cohorts, a further 2 wks of cIV dosing, and the option for a second cycle of cIV dosing (Figure). The primary objective was safety and tolerability of SC blinatumomab; secondary objectives included pharmacokinetics (PK), estimating the maximum tolerated dose (MTD), ie, the highest dose at which ≤1/6 pts had a dose-limiting toxicity (DLT), and efficacy (NCT 02961881).
Results: Pts (n=29) had a median (range) age of 64 (42-75) y, 55% were male, 90% Caucasian, with follicular I-IIIA (76%), marginal zone (10%), mantle cell (10%) and lymphoplasmacytic lymphoma (3%) subtypes; no pts had prior allo-hematopoietic stem cell transplant (HSCT), 38% had prior auto-HSCT. Of the 29 pts, 5 discontinued (D/C) blinatumomab due to AEs (n=3; 2 cIV, 1 SC), pt request (1), and disease progression (1); no pts D/C due to COVID-19 control measures; 26 pts completed the study; pts received a median (range) of 5 (3-10) doses. AEs leading to D/C in SC treatment included neurologic events of aphasia and seizure.
During SC dosing, 2 DLTs occurred (aphasia, n=1; seizure, n=1 ). MTD was not reached. Five pts had grade 3 (G3) AEs (thrombocytopenia, erosive esophagitis, asthenia, device-related infection, hyperglycemia, aphasia, seizure; pts may have had &gt;1 G3 AE); there were no G4 AEs or fatal AEs. AEs of interest included neurologic events (all, n=15; G3, n=2), infection (2; 1), and cytokine release syndrome (4; 0). One pt had grade 1 injection site erythema. Anti-blinatumomab antibodies have not been detected to date.
Preliminary PK results were consistent across the 5 SC cohorts and 3 different dosing regimens. Following the first dose, maximum concentrations (C max) were reached after ~5-12 hours and exposures (C max and area under concentration-time curve [AUC] from 0-12 hours) increased in a dose-related manner. At steady state, exposures (AUC over the dosing interval) increased in a dose-related manner for dosing intervals of once every 12, 24, and 48 hours across cohorts. Blinatumomab bioavailability and apparent terminal elimination half-life were favorable for extending the dosing interval to once every other day and potentially longer intervals. The steady-state concentrations during both cIV infusion periods were consistent with those previously reported in NHL pts.
In all pts, the overall response rate (ORR, representative of cIV, 5 wks and SC, 1wk) per Cheson criteria was 69% (evaluable, n=23: complete response [CR], 21%; partial response [PR], 48%; cycle 1 [C1], n=22: ORR, 62%; CR, 14%; PR,48%; cycle 2 [C2], n=17: 45%; 17%; 28%; respectively); per Lugano criteria, the ORR was 52% (n=21: CR, 24%; PR, 28%; C1, n=18: 45%; 17%; 28%; C2, n=12: 31%; 21%; 10%); for follicular lymphoma, ORR was 77% per Cheson (n=19: CR, 23%; PR, 55%) and 55% per Lugano (n=15: CR, 23%; PR, 32%)..
Conclusions: In pts with R/R indolent NHL, SC blinatumomab had a favorable safety profile, with the caveat that pts who could not tolerate cIV blinatumomab did not advance to SC dosing. Efficacy was comparable with that seen for cIV dosing in prior blinatumomab NHL studies. In contrast to prior blinatumomab trials, no dose dependency in efficacy or toxicity was observed because SC dosing was administered for only 1 wk, after 3 wks of cIV; pts not tolerating cIV did not receive SC dosing. Safety/tolerability of blinatumomab SC administration over the whole cycle is currently being evaluated in a phase 1 trial of pts with R/R acute lymphoblastic leukemia (NCT 04521231). SC blinatumomab PK, including bioavailability and half-life, showed promising features, warranting further investigation.
Figure 1 Figure 1.

Disclosures
Rossi: Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Prince: Takeda: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria. Tam: Janssen: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Loxo: Consultancy; Roche: Consultancy, Honoraria; Novartis: Honoraria; Pharmacyclics: Honoraria. Ku: Roche: Consultancy; Genor Biopharma: Consultancy; Antegene: Consultancy. Thieblemont: Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Popplewell: Pfizer: Other: Travel; Hoffman La Roche: Other: Food; Novartis: Other: Travel. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding. Haioun: Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen-Cilag: Consultancy; Celgene: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Servier/Pfizer: Honoraria; Gilead Sciences: Consultancy, Honoraria; Takeda: Consultancy; Miltenyi Biotec: Consultancy. Viardot: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; University Hospital of Ulm: Current Employment. Ferreri: Pfizer: Research Funding; x Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Genmab: Research Funding; BMS: Research Funding; Hutchison Medipharma: Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; Adienne: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ospedale San Raffaele srl: Patents & Royalties; Beigene: Research Funding. Wong: Amgen: Current Employment; Amgen: Current equity holder in publicly-traded company. Kadu: IQVIA: Current Employment. Zugmaier: Amgen: Current Employment; Micromet/Amgen: Patents & Royalties: Patents 20190300609 and 20130323247 licensed; receives royalties of family members of international applications published as WO2010/052014; WO2010/052013; WO2011/051307; WO2012/055961; WO 2012/062596; WO2014/122251; and WO2015/181683; Amgen: Current equity holder in publicly-traded company. Zeng: Amgen: Current Employment, Current equity holder in publicly-traded company. Rambaldi: Celgene: Other: Travel, Accommodations, Expenses; Jazz Pharmaceuticals: Consultancy; Astellas Pharma: Consultancy; Novartis: Consultancy; Omeros: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

OffLabel Disclosure:
Blinatumomab is approved in the United States for administration as a continuous intravenous infusion. It has not been approved for subcutaneous administration.