Background:

Relapse after conventional chemotherapy for newly diagnosed AML is responsible for the majority of treatment failure. Relapsed (R/R) disease is frequently refractory to salvage attempts with further chemotherapy. The effectiveness of stem cell transplant and associated graft vs. leukemia effect implies an important role for immune-based therapy in producing long lasting remissions. Existing approaches using immunotherapy have failed to establish a suitable surface target or treatment paradigm that is effective in myeloid malignancies. Hu8F4 is a humanized T-cell receptor-like monoclonal antibody that binds to the conformational epitope of PR1 bound to HLA-A2, which is highly, differentially expressed on the surface of AML compared to normal progenitors.

Methods:

This is a first-in-human, Phase I dose escalation trial of Hu8F4 in patients (pts) with myeloid malignancies. Pts with R/R AML, MDS, CMML, and myeloid blast phase of CML with adequate organ function and PS ≤ 2 were eligible. Pts were treated on 7 escalating dose levels, ranging from 0.01 mg/kg to 10 mg/kg IV on D1 & 15. Initial dose levels required 1 pt per dose (0.01, 0.03, 0.1, 0.3, 1), followed by 3 pts per dose (3, 10).

Results:

Fifteen pts with R/R AML have been enrolled, with a median age of 62 years (range, 23-77 years), including 7 females (47%). Pts had received a median of 4 prior therapies; 5 pts (33%) had a PS of 2. At enrollment, the median WBC was 2 (0.1 - 18.4), median BM blasts were 21% (0 - 76); 9 pts (60%) had complex karyotype and 4 (27%) had a TP53 mutation. All pts had > 98% surface expression of PR1 on the myeloid blasts. Hu8F4 C max ranged up to 160,000 ng/mL with t 1/2 of 48 hours and clearance of 2.61 hr*ng/mL at the highest dose. Weak anti-drug antibodies were observed after week 4 in 2 of 3 pts treated at 3 mg/kg. With a median follow up of 5 months (1.1 - 9.9), pts have received a median of 1 (1-4) cycle of therapy. No DLTs were observed at the 3 mg/kg cohort.; 4 additional pts who were on concomitant tacrolimus were enrolled at this level to assess safety with concurrent use, and no DLTs were observed. Three pts were enrolled at the 10 mg/kg level, and 1 experienced dose limiting thrombocytopenia, triggering expansion to 6 pts. Two pts had a decline in BM blasts and 4 had stable disease. There was rapid decline in peripheral blasts immediately after infusion of Hu8F4 on D1 and 15 with associated elevation in serum LDH in some pts and a rise in normal granulocytes, consistent with drug-mediated anti-leukemia effects. The pharmacokinetic parameters and transient blast reduction indicated a possible sink effect mediated by high levels of circulating blasts. SAEs documented on study were mostly disease-related and included infections, cytopenias, hemoptysis, pneumonia, and GI bleeding. Treatment related AEs were temporally related to the drug infusion, including hypotension (Grade 2: N=2), and rigors (Grade 2: N=10; Grade 1: N=1). Infusion reactions were observed at all dose levels, more common at 3 and 10 mg/kg, but were transient, and managed with steroids and antihistamines. All pts proceeded with their next dose without further issues. Neither cytokine release syndrome nor neurologic toxicities were observed. Correlative studies support antibody dependent cellular cytotoxicity and phagocytosis as important mechanisms of anti-AML activity, which was more effective at lower dose levels.

Conclusion:

Hu8F4, a first-in-class TCR mimic antibody, was well tolerated with expansion planned at more frequent dose intervals. On-target peripheral blast reduction temporally related to infusion suggests biological activity. Real-time pharmacokinetic data indicate a possible sink effect that may be overcome by a more frequent dosing strategy that is planned.

Kadia:Astellas Pharma Global Development: Research Funding; Novartis: Consultancy; Hikma Pharmaceuticals: Speakers Bureau; Genentech: Consultancy, Research Funding; Delta-Fly Pharma, Inc.: Research Funding; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Ascentage Pharma Group: Research Funding; Amgen, Inc.: Research Funding; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Iterion: Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Regeneron Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Celgene: Research Funding; Liberum: Consultancy; GenFleet Therapeutics: Research Funding; Cure: Speakers Bureau; SELLAS Life Sciences Group: Research Funding; Cyclacel: Research Funding; AstraZeneca: Research Funding; Cellenkos Inc.: Research Funding; Genzyme: Honoraria; Pulmotect, Inc.: Consultancy, Research Funding; Janssen Research and Development: Research Funding; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Sanofi-Aventis: Consultancy; Agios: Consultancy; Servier: Consultancy; Pinotb-Bio: Consultancy; BMS: Consultancy, Research Funding; Astex: Honoraria. Kantarjian:KAHR Medical: Honoraria; Shenzhen Target Rx: Honoraria; Precision Biosciences: Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; Abbvie (Inst): Research Funding; Ascentage Pharma Group: Honoraria; Ipsen: Honoraria; Pfizer: Honoraria; Taiho Pharmaceutical: Honoraria; Bristol-Myers Squibb (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Novartis: Honoraria; Immunogen (Inst): Honoraria, Research Funding; Daiichih-Sankyo (Inst): Honoraria, Research Funding; Astellas Pharma: Honoraria; AstraZeneca/MedImmune: Honoraria; Novartis (Inst): Research Funding; Amgen (Inst): Research Funding. Maiti:Celgene: Research Funding; Lin BioScience: Research Funding. DiNardo:ImmuniOnc: Honoraria; Notable Labs: Honoraria; Servier: Honoraria; Fogham: Honoraria; AbbVie/Genentech: Honoraria; Novartis: Honoraria; Schrödinger: Consultancy; Takeda: Honoraria; Astellas: Honoraria; BMS: Honoraria. Jabbour:Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Pemmaraju:Medscape: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmunoGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Curio Science: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magdalen Medical Publishing: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Harborside Press: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; Imedex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pacylex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; CareDx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karger Publishers: Other: Licenses; OncLive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; United States Department of Defense (DOD): Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aplastic Anemia & MDS International Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PeerView Institute for Medical Education: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intellisphere: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CancerNet: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Protagonist Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ClearView Healthcare Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Other: Uncompensated; Physician Education Resource (PER): Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASH Committee on Communications: Other: Leadership; Neopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Patient Power: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASCO Cancer.Net Editorial Board: Other: Leadership; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cimeio Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aptitude Health: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jain:BMS: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; CareDX: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Newave: Research Funding; Takeda: Research Funding; Beigene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Genentech: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Dialectic Therapeutics: Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pfizer: Research Funding; Aprea Therapeutics: Research Funding; Mingsight: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TransThera Sciences: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; ADC Therapeutics: Research Funding; Novalgen: Research Funding; Servier: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Fate Therapeutics: Research Funding; Incyte: Research Funding; Ipsen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MEI Pharma: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Pharmacyclics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Medisix: Research Funding; Loxo Oncology: Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Issa:Syndax: Research Funding; Celgene: Research Funding; Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; NuProbe: Consultancy; Merck: Research Funding. Garcia-Manero:AbbVie: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Other: Medical writing support, Research Funding. Montalban-Bravo:Rigel: Research Funding; Takeda: Research Funding. Shastri:Gilead Sciences: Honoraria; Rigel Pharmaceuticals: Honoraria; Kymera Therapeutics: Honoraria, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria. Couriel:Incyte: Consultancy; SeaGen: Consultancy. Champlin:Arog: Consultancy; Actinium Pharmaceuticals: Consultancy; Omeros: Consultancy; Cell Source: Research Funding; Takeda Corporation: Patents & Royalties; Orca Bio: Consultancy; Johnson & Johnson/Janssen: Consultancy; Kadmon: Consultancy. Cortes:Takeda: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Forma Therapuetic: Consultancy; Pfizer: Consultancy, Research Funding; Biopath Holdings: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Research Funding; Gilead: Consultancy.

2023
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