A phase I pharmacokinetic (PK) trial of XAA296A (Discodermolide) administered every 3 wks to adult patients with advanced solid malignancies

Abstract

2025 Background: XAA296A is a natural product isolated from the marine sponge Discoderma dissoluta. It stabilizes microtubules more potently than paclitaxel and has activity against paclitaxel-refractory xenografts. Methods: In this phase I trial, XAA296A was administered IV as a fixed infusion rate of 0.77mg/ml/min once every 3 weeks. Results: 26 pts (17 M, 9 F) have been treated at the following dose levels (mg/m2): 0.6 (3 pts); 1.2 (3 pts); 2.4 (4 pts); 4.8 (4 pts); 9.6 (4 pts); 14.4 (6 pts) and 19.2 (2 pts). The median age = 59.5 (19–79). All patients had KPS ≥70%. 9/ 26 received prior taxane therapy. No drug related DLTs have occurred to date. G1 pain and burning at site of injection was noticed at initial dose levels but resolved with central administration of XAA296A. One patient had G4 anemia during third cycle. Number of patients with G2/3 adverse events with suspected relationship to XAA296A (all cycles): Anemia (5,1), Nausea (6, 0), Vomiting (3, 1), Fatigue (5, 1), Diarrhea (4, 0), Mucositis (2, 0), Stomatitis (1,0), Pruritus (1,0), ↑Alk phos (1,0), ↑ Creatinine (1,0), Myalgias (1,0). No neuropathy or neutropenia has been observed. One patient with appendix carcinoma had stable disease for 4 cycles. PK of XAA296A was evaluated in 24 pts after the 1st and 2nd dose using noncompartmental approach. Concentrations were determined by an LC/MS/MS method. XAA296A concentrations showed Cmax at the end of infusion, thereafter declining rapidly in a multiphasic manner. By 24 h post-dose, blood concentrations had decreased to <10% of Cmax, but then showed nonlinear PK, evidenced by a convexity of the terminal phase on a semi-log scale. This was observed in the majority of concentration-time profiles, suggesting prolonged recycling of drug between tissue and the systemic circulation. AUClast, Cmax, and MRTlast ranged from 103–15211 ng*h/ml, 29–482 ng/ml, and 32–162 h, respectively. Conclusions: XAA296A is a novel microtubule stabilizer which has minimal toxicities in this phase I trial. In addition, it demonstrates nonlinear PK characterized by a second broad peak at the terminal phase. Dose accrual is continuing to define the phase II dose. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp.