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25 A Phase 1 First-in-Human Study of AMG 330, an Anti-CD33 Bispecific T-Cell Engager (BiTE®) Antibody Construct, in Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)

Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Immunotherapy and New Agents
Hematology Disease Topics & Pathways:
Adult, antibodies, Biological, Diseases, AML, Therapies, Biological Processes, Study Population, Clinically relevant, Myeloid Malignancies, immune mechanism
Saturday, December 1, 2018: 7:30 AM
Seaport Ballroom F (Manchester Grand Hyatt San Diego)

Farhad Ravandi, MBBS1, Anthony S. Stein, MD2, Hagop M. Kantarjian, MD3, Roland B. Walter, MD, PhD, MS4, Peter Paschka, MD5, Mojca Jongen-Lavrencic, MD, PhD6, Gert J. Ossenkoppele, MD, PhD7, Zhao Yang8*, Bhakti Mehta9* and Marion Subklewe, MD10*

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA
3Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX
4Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
5Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
6Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
7University Medical Center, Amsterdam, Netherlands
8Amgen, Inc., Thousand Oaks, CA
9Amgen Inc., Thousand Oaks, CA
10Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital, LMU Munich, Munich, Germany

Background: Current treatment options for R/R AML are highly inadequate. CD33 is expressed in >99% of AML cases. BiTE®s have been effective in R/R Acute Lymphoblastic Leukemia. AMG 330 is a BiTE® that binds CD33 and CD3 on T cells, facilitating T-cell destruction of CD33+ cells. The objectives of this ongoing study are to evaluate the safety, pharmacokinetics, and pharmacodynamics of AMG 330 in R/R AML and to estimate the maximum tolerated dose.

Methods: This was a phase 1 dose escalation study evaluating AMG 330 as a continuous IV infusion in patients with R/R AML, with single-patient cohorts for the first 3 doses and subsequently 3-6 patients per cohort (NCT#02520427). Response was per revised IWG criteria with the addition of complete response (CR) with partial hematologic recovery. After completing the first cycle without dose‑limiting toxicity (DLT), up to 5 additional cycles could be given for benefit. After the 30 μg/day (d) cohort, risk mitigation measures for cytokine release syndrome (CRS) were put in place, including step‑dosing and pretreatment with a single dose of corticosteroids. The modified treatment regimen consisted of an initial run-in dose of 10 μg/d × 4d followed by the target dose. A 2-step regimen was then tested, ie 10 μg/d, 60 μg/d, and then the target dose, for a treatment duration of 14d or 28d, followed by 1-4 weeks off treatment.

Results: As of June 14, 2018, 35 patients had enrolled in 12 dose cohorts with a target dose range of 0.5-480 μg/d in this ongoing study. Over half (20/35, 57%) of patients were male and the median age was 58 (range: 18-80) years; 14/35 (40%) have previously received a stem cell transplant. Median AML disease duration at baseline was 1.3 (range: 0.3-9.6) years, median proportion of blasts at baseline was 37% (range: 3%-95%), and the median # of prior treatments was 4 (range: 1-15). Median baseline ANC was 0.2 (range: 0-8.6) × 109/L.

Patients received a median of 1 (range: 1-6) cycle with AMG 330; 31/35 (89%) patients discontinued treatment for disease progression (n=24), adverse events (AEs; n=5, 2 treatment-related), and patient request (n=2). One patient completed the maximum of 6 cycles allowed and 3 patients are still receiving study drug. Serious AEs (SAEs) were seen in 23/35 (66%) patients (treatment-related in 15 patients); SAEs seen in >1 patient included CRS (n=11), febrile neutropenia (n=6), pneumonia (n=4), leukopenia (n=3), thrombocytopenia (n=2), and subdural hematoma (n=2); 1 patient died on study due to AML progression (not treatment-related). One patient each in the 10 μg/d and 30 μg/d cohorts (no lead‑in) experienced severe CRS; CRS signs and symptoms resolved in 1d with corticosteroids, vasopressors, and IV fluids, and interruption of AMG 330. There were DLTs of grade 2 CRS and grade 4 ventricular fibrillation with a target dose of 480 μg/d; the target dose was then decreased to 240 μg/d.

Two patients had a CR at a target dose of 240 μg/d (lead-in of 10 μg/d→60 μg/d); 1 patient each at target doses of 120 μg/d and 240 μg/d had a CRi and 1 patient who received 1.5 μg/d had a morphologic leukemia-free state (MLFS, <5% blasts, no hematologic recovery). One patient with a CR had bone marrow blasts decrease from ~5%-10% (estimated due to patchy disease) to 2.5% by d29 by flow cytometry, with no morphologic evidence of residual AML and normo- to hypercellular marrow and recovery of peripheral blood counts. The second CR patient had blasts decrease from 40% to 3% with recovery of peripheral blood counts by d42 after receiving one cycle of AMG 330. Correlative data will be presented.

Conclusions: Preliminary data of AMG 330 dosed up to 480 μg/d provide encouraging early evidence of tolerability and anti-leukemic activity in heavily pre-treated patients with R/R AML. Expected CRS was mitigated through step-up dosing, corticosteroid pretreatment, IV fluids, tocilizumab, and drug interruption if needed; most patients had short periods of CRS which responded well to treatment. A 2-step approach will be used in the future to quickly achieve the target dose and optimize clinical response. Regarding pharmacodynamics, to date, 2 CRs and 2 CRis have been observed at target doses of 120 and 240 μg/d. As nearly all patients were substantially cytopenic at baseline, it is challenging to evaluate the impact of AMG 330 on cytopenias. Of note, both CR patients had a complete recovery of blood counts after one cycle of treatment. These promising data validate the use of the BiTE® platform to target CD33.

Disclosures: Ravandi: Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Xencor: Research Funding; Jazz: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau. Stein: Celgene: Speakers Bureau; Amgen: Speakers Bureau. Kantarjian: Pfizer: Honoraria, Research Funding; Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria. Walter: Amphivena Therapeutics: Consultancy, Equity Ownership, Other: Clinical trial support, Research Funding; Aptevo Therapeutic: Consultancy, Other: Clinical trial support, Research Funding; Covagen AG: Consultancy, Other: Clinical trial support, Research Funding; Seattle Genetics, Inc.: Consultancy, Other: Clinical trial support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer: Consultancy; Amgen Inc.: Other: Clinical trial support, Research Funding; Actinium Pharmaceuticals, Inc.: Other: Clinical trial support, Research Funding. Paschka: Amgen: Other: Travel support; Jazz: Speakers Bureau; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Astex: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel support. Ossenkoppele: Celgene: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Karyopharm: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genmab: Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding. Yang: Amgen Inc.: Employment, Equity Ownership. Mehta: Amgen Inc.: Employment, Equity Ownership. Subklewe: Roche: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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*signifies non-member of ASH