Early clinical development of a novel IL-7R antibody for treating children with relapsed T-cell leukemia

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Project Summary Treatment of patients with relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL) remains a major unmet medical need, with a five-year survival of only 21-39% in children and 20% in adults. Outcomes in B-Cell ALL (B-ALL) have improved, with several recently approved second-line therapies. In contrast, in the much smaller T-ALL population (~20% of ALL), nelarabine was the last new agent approved by FDA, in 2005, and few new therapies are in development. Fannin Partners, with its subsidiary, Allterum Therapeutics, is developing 4A10, a chimeric monoclonal antibody targeting the IL-7a receptor (CD127) developed by Dr. Scott Durum at the National Cancer Institute. The IL7R, critical to lymphocyte development, also plays an important role in the development and maintenance of T-ALL, including in relapsed disease. 4A10 binds the IL7R receptor, with an IgG1 Fc region that mediates antibody- dependent cell-mediated cytotoxicity (ADCC) in addition to inhibiting IL-7 signaling. 4A10 has demonstrated robust anti-cancer activity against IL7R-expressing T-ALL in-vitro and in-vivo, including prolonged survival of mice with patient-derived T-ALL xenografts. Support from a Cancer Prevention and Research Institute of Texas (CPRIT) grant and seed financing, enabled our manufacturing scale-up and toxicological work, and we are now working towards submission of an IND. Further grant funding will enable us to conduct a first-in-human Phase 1 clinical trial to assess the safety and activity of 4A10 in T-ALL patients and assess pharmacodynamic and tumor biomarkers and correlate with 4A10 activity and tolerability in T-ALL patients. These specific aims will allow us (1) determine safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of 4A10 as monotherapy, (2) Determine the pharmacokinetic profile of 4A10 as monotherapy, (3) Assess the activity of 4A10 as monotherapy, (4) Explore potential pharmacodynamic markers of biologic and clinical activity and safety, (5) Explore correlation of tumor IL- 7R expression with clinical activity, and (6) Explore correlation of cancer genetics with biologic and clinical activity and tolerability to 4A10. Completion of these aims will enable us to advance to a pivotal trial in patients with relapsed T-ALL, as well as other studies in additional ALL subpopulations and other IL7R-expressing cancers. It is very well known that CD127 is a highly polymorphic gene and undergoes shedding from the membrane or alternative splicing which is detectable in patient samples. Soluble CD127 plasma concentrations have been reported to remain stable over time in a normal individual, and upregulation of soluble CD127 may indicate metastatic disease progression in patients. The long-term goal of this diversity supplement project is to be able to use soluble CD127 as a noninvasive biomarker which could be easily detected from a simple blood test. We can harness this information to clinically individualize 4A10 therapy for high soluble CD127 patients, who we expect will benefit more from 4A10 treatment.