Abstract CT101: Phase I study of the T-cell receptor-like antibody Hu8F4 in patients with advanced hematologic malignancies
Authors: Kadia Tapan M. , Kantarjian Hagop , Alatrash Gheath , Sergeeva Anna , He Hong , St. John Lisa , Koppikar Priya , Kerros Celine , Maiti Abhishek , Dinardo Courtney , Jabbour Elias , Vesrstovsek Serge , Pemmaraju Naveen , Jain Nitin , Issa Ghayas , Montalban-Bravo Guillermo , Shastri Aditi , Couriel Daniel , Pinsoy Rhona , Parshottam Sapna , Champlin Richard , Cortes Jorge , Molldrem Jeffrey 
Published: April 2023

Abstract
Background: Despite recent advances in the treatment of AML, most approaches are rarely curative and most patients (pts) succumb to relapsed disease. 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. Traditional 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: We conducted a first in human, phase I dose escalation trial of Hu8F4 in pts with myeloid malignances. 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: 10 pts with R/R AML have been enrolled, with a median age of 65 years (range, 23-77), including 6 females (60%). Pts had received a median of 4 (1-4) prior therapies; 5 pts (50%) had a PS of 2. At enrollment, the median WBC was 1.9 (0.1 - 18.4), median BM blasts were 32% (8 - 76); 9 (90%) pts had complex karyotype and 3 (30%) had a TP53 mutation. All pts had &gt; 98% surface expression of PR1 on the myeloid blasts. Hu8F4 Cmax ranged up to 160,000 ng/mL with t1/2 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 3.5 months (1.1 - 9.9), pts have received a median of 1 (1-4) cycle of therapy. Two pts had decline in BM blasts and 4 had stable disease. Routine peripheral blood testing revealed sharp 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 on-tumor 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 infusion included hypotension (Grade 2: N=2), rigors (Grade 2: N=2; Grade 1: N=1). All infusion reactions were observed at dose levels of 3 and 10 mg/kg, but were transient, and managed with steroids and antihistamines. All pts proceeded with their next dose without further issues. No cytokine release syndrome or neurologic toxicity was observed. Correlative studies support antibody dependent cellular cytotoxicity and phagocytosis as important mechanisms of anit-AML activity.
Conclusion: Hu8F4 was well tolerated with no dose-limiting toxicities observed at the maximum planned dose. On-target peripheral blast reduction temporally related to infusion suggests biological activity. Real-time pharmacokinetic data on study indicate a possible sink effect that may be overcome by a more frequent dosing strategy.
Citation Format: Tapan M. Kadia, Hagop Kantarjian, Gheath Alatrash, Anna Sergeeva, Hong He, Lisa St. John, Priya Koppikar, Celine Kerros, Abhishek Maiti, Courtney Dinardo, Elias Jabbour, Serge Vesrstovsek, Naveen Pemmaraju, Nitin Jain, Ghayas Issa, Guillermo Montalban-Bravo, Aditi Shastri, Daniel Couriel, Rhona Pinsoy, Sapna Parshottam, Richard Champlin, Jorge Cortes, Jeffrey Molldrem. Phase I study of the T-cell receptor-like antibody Hu8F4 in patients with advanced hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT101.