FIGHT-102: A phase 1 study of pemigatinib in Japanese patients with advanced malignancies.

BACKGROUND: FIGHT-102 was a phase 1, dose-escalation, dose-expansion study of pemigatinib in Japanese patients with advanced solid tumors. Here, we report safety, tolerability, and preliminary efficacy of pemigatinib from FIGHT-102. METHODS: Patients (≥20 years old) self-administered oral pemigatinib 9, 13.5, or 18 mg QD on intermittent dosing (Part 1) or 13.5 mg QD intermittent or continuous dosing (Part 2). A dosing cycle was 21 days (2 weeks on/1 week off or 21 continuous days). Primary endpoint was safety. Secondary endpoints were pharmacokinetics, pharmacodynamics, and preliminary efficacy. RESULTS: Forty-four patients (Part 1, n = 14; Part 2, n = 30) were enrolled; most common tumors, cholangiocarcinoma, n = 8; esophageal, n = 6; 26 patients had confirmed FGF/FGFR alterations (Part 1, n = 3; Part 2, n = 23); 70.5% had ≥3 prior systemic therapies. Maximum tolerated dose was not identified. The recommended phase 2 dosage was determined to be 13.5 mg QD. Most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (81.8%), dysgeusia (45.5%), stomatitis (43.2%), and alopecia (38.6%); most frequent Grade ≥3 TEAEs were anemia and decreased appetite (9.1% each). In Part 1, no patient achieved partial response (PR) or complete response, and 7 (50.0%) patients had stable disease (SD). In Part 2, 5 (16.7%) patients achieved PR (one each with cholangiocarcinoma, gall bladder cancer, breast cancer, urothelial tract/bladder cancer, and sweat gland carcinoma) and 6 (20%) had SD. Median duration of response was 9.56 months (95% CI: 4.17, 14.95). CONCLUSIONS: Pemigatinib demonstrated manageable adverse events, consistent pharmacokinetics and pharmacodynamics profiles, and preliminary efficacy in Japanese patients with advanced solid tumors.

Constrained Nonlinear and Mixed Effects Integral Differential Equation Models for Dynamic Cell Polarity Signaling.

Polar cell growth is a process that couples the establishment of cell polarity with growth and is extremely important in the growth, development, and reproduction of eukaryotic organisms, such as pollen tube growth during plant fertilization and neuronal axon growth in animals. Pollen tube growth requires dynamic but polarized distribution and activation of a signaling protein named ROP1 to the plasma membrane via three processes: positive feedback and negative feedback regulation of ROP1 activation and its lateral diffusion along the plasma membrane. In this paper, we introduce a mechanistic integro-differential equation (IDE) along with constrained semiparametric regression to quantitatively describe the interplay among these three processes that lead to the polar distribution of active ROP1 at a steady state. Moreover, we introduce a population variability by a constrained nonlinear mixed model. Our analysis of ROP1 activity distributions from multiple pollen tubes revealed that the equilibrium between the positive and negative feedbacks for pollen tubes with similar shapes are remarkably stable, permitting us to infer an inherent quantitative relationship between the positive and negative feedback loops that defines the tip growth of pollen tubes and the polarity of tip growth.

Spatiotemporal dynamics of a reaction-diffusion model of pollen tube tip growth.

A reaction-diffusion model is proposed to describe the mechanisms underlying the spatial distributions of ROP1 and calcium on the pollen tube tip. The model assumes that the plasma membrane ROP1 activates itself through positive feedback loop, while the cytosolic calcium ions inhibit ROP1 via a negative feedback loop. Furthermore it is proposed that lateral movement of molecules on the plasma membrane are depicted by diffusion. It is shown that bistable or oscillatory dynamics could exist even in the non-spatial model, and stationary and oscillatory spatiotemporal patterns are found in the full spatial model which resemble the experimental data of pollen tube tip growth.