Trial in progress: A Phase I/II study to investigate the combination of LP-118, ponatinib, vincristine and dexamethasone (LPVd regimen) in relapsed/refractory T-ALL/lbl

Abstract Background and significance: T-lineage acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) accounts for 15% of pediatric and 25% of adult ALL cases. Precursor T-ALL and its more immature subset, early T precursor (ETP) ALL, have limited treatment options after first-line chemotherapy. Due to this unmet need, long-term survival for relapsed/refractory (R/R) T-ALL is <10%. During normal T-cell development in thymus, early precursor cells first rearrange T-cell receptor β chain (TCRβ), which pairs with an invariant surrogate pre-Tα chain to create pre-TCR signaling complex. Pre-TCR signaling promotes cell survival, proliferation and differentiation in a ligand-independent manner. We and others have shown that in T-ALL, oncogenic mutations frequently hijack this pathway, leading to constitutive activation of downstream signaling cascades. We discovered that the inhibition of pre-TCR (LCK) signaling leads to induction of apoptosis in T-ALL, and BCL-2/BCL-xL inhibitors which activate suicide pathways can synergize with LCK inhibitors (Saygin, Clin Cancer Res 2023). LP-118 is an oral dual BCL-2/BCL-xL inhibitor, with a modified structure and fine-tuned BCL-xL activity to minimize platelet toxicity. Based on our preclinical work showing the synergy between LP-118 and ponatinib (pre-TCR signaling inhibitor), we designed the phase 1/2 LPVd trial combining LP-118 and ponatinib (LCK inhibitor) with low-intensity chemotherapy backbone (Vd: vincristine, dexamethasone) in patients with R/R T-ALL/LBL (NCT06207123). The trial was activated at the University of Chicago in September 2024, and we plan to open it at four additional sites. Study design and methods: Adult patients (≥18 years) with R/R T-ALL/LBL, defined as bone marrow or blood involvement with ≥5% lymphoblasts, or measurable residual disease (MRD) with >10-4 level detected by multiparameter flow cytometry or NGS-based MRD, or patients with isolated extramedullary disease that is measurable by CT scan are eligible. Participants should otherwise have good performance status (ECOG 0-2), adequate organ function, and no active infections. In phase 1, a standard 3+3 design is implemented to test the combination of different dose levels of LP-118 with low-intensity chemotherapy (Vd) at dose levels 1 (100 mg), 2 (200 mg) and 3 (300 mg), followed by the addition of ponatinib 30 mg to different dose levels of LP-118 at levels 4 (100 mg), 5 (200 mg) and 6 (300 mg). Ponatinib dose reduction to 15 mg is allowed for participants who experience toxicity or achieve MRD-negative remission. The primary objective of the phase 1 portion is to identify the recommended phase 2 dose (RP2D) of this novel-novel combination therapy. The primary endpoint is dose limiting toxicity (DLT), defined as a grade ≥3 non-hematologic toxicity related to the study drugs, except for the following which will not be considered DLT: grade 3 fatigue, asthenia, fever, anorexia, constipation; grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total parenteral nutrition or hospitalization; infection, bleeding or other expected direct complication of cytopenias due to active underlying leukemia. The maximum tolerated dose is the dose such that <33% of patients (<2 of 6) experience DLT. At the time of this submission, 9 patients have been enrolled. After identifying the RP2D from the phase 1 portion, we will do a phase 2 dose expansion by enrolling 12 additional patients at this dose level to investigate the efficacy of LPVd. R/R T-ALL is a rare disease for which large phase III studies are rarely conducted. Primary endpoint of the phase 2 portion is complete remission (CR). The CR rate with re-induction chemotherapy in patients with R/R T-ALL is 10%. A previous phase 1b/2 study of venetoclax, navitoclax and chemotherapy in R/R T-ALL showed 50% CR rate. Therefore, we anticipate a CR rate of 30% in our study, which combines LP-118 with similar chemotherapy backbone. A total of 18 patients are needed to achieve 80% power under one-sided alpha= 0.10. We will include 6 patients from phase 1 portion in our efficacy analysis. Several correlative studies are planned to identify biomarkers of response and resistance, including BH3 profiling, molecular genetic profiling (DNA- and RNA-seq), and pre-TCR signaling activity in baseline vs relapse samples. This investigator-initiated trial is funded by the Leukemia Lymphoma Society Academic Clinical Trials grant.