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A Phase 1b Study of Blinatumomab Including Subcutaneous Administration in Relapsed / Refractory (R/R) Indolent Non Hodgkin's Lymphoma (NHL)
Blood ; 138:2436, 2021.
Article in English | EMBASE | ID: covidwho-1582209
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 >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 dosi g 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. [Formula presented] 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. OffLabelDisclosure Blinatumomab is approved in the United States for administration as a continuous intravenous infusion. It has not been approved for subcutaneous administration.
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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Blood Year: 2021 Document Type: Article

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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Blood Year: 2021 Document Type: Article