PRELIMINARY RESULTS OF ASTX660, A NOVEL NON‐PEPTIDOMIMETIC cIAP1/2 AND XIAP ANTAGONIST, IN RELAPSED/REFRACTORY PERIPHERAL T‐CELL LYMPHOMA AND CUTANEOUS T CELL LYMPHOMA

Abstract

NCT01492088) and adult studies (NCT00412282) were performed to quantify sources of variability, including body size effects, on ADC and monomethyl auristatin E (MMAE) PK in paediatric pts with classical Hodgkin lymphoma (cHL). Methods: POPPK base-models were based on previously reported models. A full model was developed including all statistically-relevant prespecified covariate effects; a final model was chosen by retaining only the significant covariate effects (p<0.001). Model parameters were estimated using NONMEM (v7.3). The final model was used to simulate mg/kg or body surface area (BSA)-based dosing scenarios in paediatric pts to inform selection of posology that provides exposures matching those achieved in adults with weight-based (mg/kg) dosing.Results: Data were collected from 84 pts with a median age of 25.7 years (range 7-87, 34 of whom [40.5%] were aged <18 years), median weight of 67 kg (range 21-154), and median BSA of 1.8 m 2 (range 0.86-2.8). ADC PK was described by a linear 3-compartment model with zero-order input and first-order elimination. In covariate analyses, BSA was the best predictor of body size effects on ADC PK, and was a strong predictor of clearance (CL), V 1 , and V 3 ; anti-drug 526 ABSTRACT remarkable response to single-agent therapy with ALRN-6924, a stapled dual MDM4/MDM2-inhibiting peptide, suggests particularly impressive efficacy of this novel targeted therapy for MDM4-amplified cases, and implies clinically detectable cytogenetic MDM4 amplifications as a possible biomarker to guide future use and patient selection.ABSTRACT 527

Antagonism of inhibitors of apoptosis proteins reveals a novel, immune response-based therapeutic approach for T-cell lymphoma

“…Interestingly, the regressions observed in this syngeneic model mirrored the singleagent effects noted in the clinic, with some PTCL patients experiencing long-term complete responses (on treatment of more than 1 year). 13 Taken together, these data demonstrate a clear immunomodulatory role for tolinapant as a single agent and complement recent studies suggesting a role of tolinapant in immune cell modulation in combination settings. 31,40 Our studies unveil the complex nature of tolinapant's mechanism of action, simultaneously acting in a multimodal fashion on several components of the antitumor immune response.…”

“…25 Interestingly, the IAP antagonist tolinapant, which is currently being evaluated in a phase 2 study, has demonstrated preliminary evidence of single-agent activity in relapsed/refractory PTCL and cutaneous T-cell lymphoma. 13,14 To investigate the mechanism of action behind the single-agent activity observed in the clinic with tolinapant in TCL, we have used a comprehensive translational approach via integration of in vitro and in vivo preclinical models along with human patient data from an ongoing clinical trial (NCT02503423).…”

“…In the ongoing phase 2 ASTX660-01 study, tolinapant has demonstrated preliminary evidence of single-agent clinical activity in relapsed/refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma patients. 13,14 In this study, we aim to further our understanding of tolinapant's mechanism of action in TCL using a combination of preclinical models and patient-derived biopsies. Together with its well-characterized pro-apoptotic effect, we describe a novel role for tolinapant as an immunomodulatory molecule capable of promoting an antitumor immune response in TCL.…”

“…In the ongoing phase 2 ASTX660-01 study, tolinapant has demonstrated preliminary evidence of single-agent clinical activity in relapsed/refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma patients. 13,14 …”

Emerging Therapeutic Landscape of Peripheral T-Cell Lymphomas Based on Advances in Biology: Current Status and Future Directions

“…The most common AEs of any grade were subclinical lipase and amylase elevation. These results demonstrate the clinical activity of ASTX660 in T-cell lymphomas, and expansion of the phase 2 cohort is ongoing [116].…”