A phase I study of the T-cell receptor-like antibody Hu8F4 in pts with advanced myeloid neoplasms Free

Background: Allogeneic (allo) stem cell transplantation (SCT) has been associated with improvement in long term outcomes in patients with myeloid malignancies. The effectiveness of allo SCT and its associated graft vs. leukemia effect suggests a critical role for immune-based approaches in inducing long lasting remissions. Conventional approaches using immunotherapy have failed to establish a suitable surface antigen 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 an MHC Class I molecule (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 ≥ 18 yrs 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). 4 additional pts were treated at 3mg/kg to evaluate safety in combination with tacrolimus.

Results: 15 pts with R/R AML have been enrolled, with a median age of 62 years (range, 23-77), including 7 females (47%). Pts on study identified as White (11, 73%), Black (2, 13%), Hispanic (1, 7%), or Asian (1, 7%). Pts had received a median of 3 (2-6) prior therapies. At enrollment, the median WBC was 1.9 (0.1 - 18.4), median BM and peripheral blasts were 21% (1 - 76) and 11% (0-85), respectively; 12 (80%) pts had adverse cytogenetics (cyto); 5 (33%) had complex cyto, 2 (13%) had inv(16), and 2 (13%) had other intermediate risk cyto. The most common mutations were: TP53 (7, 47%), DNMT3A (5, 33%), TET2 (5, 33%), RAS (4, 27%), and ASXL1 (4, 27%). All pts had > 98% surface expression of PR1 on the myeloid blasts. From the first 10 pts with pK data available, 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 30.3 months, pts have received a median of 1 (1-4) cycle of therapy. Two pts had decline in BM blasts and 4 had stable disease. Starting at 0.03 mg/kg, routine peripheral blood testing demonstrated a 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, suggestive of direct antileukemic effect. Pk testing post infusion revealed a decline in detectable Hu8F4 following blast clearance. The pK parameters and transient blast reduction indicated a possible sink effect mediated by circulating blasts. The median OS was 4 months (95%CI: 1.61-6.35) overall. The median OS by the two highest dose levels were: 3 mg/kg (n=7): 3.4 months (95%CI: 3.21-3.57) and 10 mg/kg (n=3): 7.1 months (95%CI: 2.13-12.02). Median OS in pts treated post SCT (n=7) was 5.2 months (95%CI: 0.56-9.85).

SAEs documented on study were mostly disease-related and included lung infections (6), neutropenic fever (3), sepsis (2), bleeding (2), and GI toxicity (2, bleeding, typhlitis). Treatment related AEs were temporally related to the infusion and included hypotension (Grade 2: n=2), rigors (Grade 2: n=5; 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 remaining doses without reaction. No neurologic toxicity or cytokine release syndrome was observed. No new or worsening GvHD in post SCT pts was observed. Correlative studies suggest antibody dependent cellular cytotoxicity and phagocytosis as important mechanisms of antileukemic activity.

Conclusion: The novel T-cell receptor-like antibody, Hu8F4 was well tolerated with no dose-limiting toxicities observed at the maximum planned dose. While there were no objective responses, rapid peripheral blast reduction temporally related to each infusion suggested antileukemic activity. Real-time pK data on study indicate a possible sink effect mediated by high circulating disease burden that may be overcome by a more frequent dosing strategy.