A phase 1b/2 study targeting apoptotic and signaling pathways in T-acute lymphoblastic leukemia
Wendy Stock
MDUniversity of Chicago
Project Term: July 1, 2023 - June 30, 2026
T-acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia with limited treatment options after first-line chemotherapy. Our preclinical work in animal models of T-ALL demonstrated the activity of a novel-novel combination treatment strategy, which includes LP-118 (activator of suicide pathways within leukemic cells) and tyrosine kinase inhibitors (inhibiting growth-promoting LCK and ACK1 signaling pathways). Leveraging the mechanistic insights gained from our laboratory work, we propose a phase Ib/II study investigating the feasibility and efficacy of the combined LP-118, ponatinib, and salvage chemotherapy in patients with relapsed T-ALL. This precision medicine approach addresses an unmet need in a fatal disease which lacks effective therapies.
A major challenge with this disease is that leukemia cells resist death by abnormal expression of survival signals. Recently, drugs that work by activating death pathways of leukemia cells have led to improvements in survival for patients with other forms of leukemia. We conducted an early phase clinical trial in patients with relapsed ALL which showed promising response rates when these drugs that trigger leukemia cell death were combined with standard chemotherapy. An example for this new class of drugs includes LP-118, which is a novel compound with a favorable side-effect profile that activates the death pathways within T-ALL cells. We tested LP-118 in mouse models of T-ALL and showed that it was effective in controlling leukemia without major organ toxicity to the animals. When we investigated why some leukemia cells become resistant to LP-118, we discovered that resistant cells activated their growth-promoting signaling pathways and suppress the activated death pathways. When these growth-promoting signaling pathways were blocked with specific drugs (like dasatinib), the cells became much more sensitive to LP-118, resulting in cell death. Based on these important preclinical observations, we hypothesize that the combination of LP-118 with signaling pathway inhibitors like dasatinib (or a cousin drug called ponatinib) can improve outcomes of patients with relapsed T-ALL.
In this proposal, we hope to investigate the feasibility of a novel – novel combination therapy in patients with relapsed T-ALL. First, we will assess the safety of LP-118, ponatinib and salvage chemotherapy combination in a phase I study to determine the safest combination doses for each drug. Then, we will enroll more patients in phase II dose expansion to evaluate the efficacy of this regimen by determining how many patients achieve remission following treatment. Finally, we will study the bone marrow samples obtained from trial participants in order to identify molecular genetic markers of treatment response and resistance. We will complete patient enrollment in 24 months, and the total duration of the study is expected to be 36 months. With its novel-novel combination design, our study leverages pre-clinical insights into improved treatment combination to address an unmet need in relapsed T-ALL.