Pevonedistat (MLN4924), a First‐in‐Class NEDD8‐activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111220/1/bjh13323.pd

Optimal Design for Estimating Parameters of the 4-Parameter Hill Model

Many drug concentration-effect relationships are described by nonlinear sigmoid models. The 4-parameter Hill model, which belongs to this class, is commonly used. An experimental design is essential to accurately estimate the parameters of the model. In this report we investigate properties of D-optimal designs. D-optimal designs minimize the volume of the confidence region for the parameter estimates or, equivalently, minimize the determinant of the variance-covariance matrix of the estimated parameters. It is assumed that the variance of the random error is proportional to some power of the response. To generate D-optimal designs one needs to assume the values of the parameters. Even when these preliminary guesses about the parameter values are appreciably different from the true values of the parameters, the D-optimal designs produce satisfactory results. This property of D-optimal designs is called robustness. It can be quantified by using D-efficiency. A five-point design consisting of four D-optimal points and an extra fifth point is introduced with the goals to increase robustness and to better characterize the middle part of the Hill curve. Four-point D-optimal designs are then compared to five-point designs and to log-spread designs, both theoretically and practically with laboratory experiments

Effect of CYP3A inhibitors on the pharmacokinetics of pevonedistat in patients with advanced solid tumours

Aims This phase I study evaluated the effects of the moderate cytochrome P450 (CYP) 3A inhibitor fluconazole and the strong CYP3A/P‐glycoprotein (P‐gp) inhibitor itraconazole on the pharmacokinetics of the investigational neural precursor cell expressed, developmentally downregulated 8 (NEDD8)‐activating enzyme inhibitor pevonedistat in patients with advanced solid tumours. Methods Patients received single doses of intravenous pevonedistat 8 mg m−2, alone and with fluconazole (loading: 400 mg; maintenance: 200 mg once daily), or pevonedistat 8, 15 or 20 mg m−2, alone and with itraconazole 200 mg once daily. Serial blood samples for pevonedistat pharmacokinetics were obtained pre‐ and post‐infusion on days 1 (alone) and 8 (with fluconazole/itraconazole). After completing the pharmacokinetic portion, patients remaining on study received pevonedistat with docetaxel or carboplatin and paclitaxel. Results The ratios of geometric mean area under the concentration–time curves (n; 90% confidence interval) of pevonedistat in the presence vs. absence of fluconazole or itraconazole were 1.11 (12; 1.03–1.19) and 1.14 (33; 1.07–1.23), respectively. Fifty patients (98%) experienced at least one adverse event (AE), with maximum severity of grade 1–2 in 28 patients (55%) and of grade ≥3 in 22 patients (43%). The most common drug‐related AEs were vomiting (12%), diarrhoea (10%) and nausea (8%). No new safety findings were observed for pevonedistat. Conclusions Fluconazole or itraconazole had insignificant effects on pevonedistat pharmacokinetics, indicating minor contributions of CYP3A/P‐gp to pevonedistat clearance. The safety profile of single doses of pevonedistat plus steady‐state fluconazole or itraconazole was consistent with prior clinical experience, with no new safety signals observed

Abstract B26: Phase 1b trial of investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in combination with docetaxel, paclitaxel/carboplatin, or gemcitabine in patients (pts) with solid tumors

Abstract Introduction: Pevonedistat is a first-in-class NAE inhibitor. This open-label, multi-arm, dose-escalation study (NCT01862328) is the first study of pevonedistat plus standard-of-care (SoC) chemotherapy in pts with solid tumors. Methods: Objectives were to establish the MTD and safety/tolerability of pevonedistat (at &amp;lt;100 mg/m2) with 3 SoC therapies. Pts ≥18 yrs who could benefit from 1 of the SoC therapies received pevonedistat IV on d 1, 3, and 5 every 21 d, with docetaxel 75 mg/m2 IV (Arm 1) or paclitaxel 175 mg/m2 + carboplatin AUC5 (Arm 2) on d 1 (lead-in cohort: pevonedistat 15 mg/m2 + carboplatin AUC6), or pevonedistat + gemcitabine 1000 mg/m2 IV on d 1, 8, and 15 every 28 d (Arm 3). Pts were treated for up to 12 cycles (and could then continue single-agent pevonedistat) or until disease progression/unacceptable toxicity. Pevonedistat dose was escalated from 15 (Arm 1+2; 1 dose level below lowest single-agent dose tested) or 25 mg/m2 (Arm 3) using an adaptive Bayesian continual reassessment method. Once established, ∼6 additional pts were to be treated at each MTD. Results: As of 3 Jun 2015, 64 pts (median age 60.5 yrs; 47% male) had been enrolled: 22 to Arm 1, 26 to Arm 2 (6 in lead-in cohort), and 10 to Arm 3. Common tumor types were NSCLC (n = 16), breast, head and neck (each n = 6), and ovarian (n = 4) cancers. In Arm 1, MTD was pevonedistat 25 mg/m2 + docetaxel 75 mg/m2; 4 pts had dose-limiting toxicities (DLTs) of G3 AST/ALT elevations during dose escalation (n = 2) and expansion (n = 2), all at 25 mg/m2. In Arm 2, MTD was pevonedistat 20 mg/m2 + paclitaxel 175 mg/m2 + carboplatin AUC5; in the lead-in cohort 1 pt had a DLT of G3 AST/ALT elevation. Due to toxicity carboplatin AUC5 was used for dose escalation, DLTs included G3 febrile neutropenia (n = 1; 15 mg/m2), G3 AST/ALT elevation (n = 2; 20 mg/m2, n = 2; 25mg/m2), and G4 thrombocytopenia (n = 1; 20 mg/m2, C5D8). One DLT of G3 AST elevation occurred during MTD expansion. In Arm 3, MTD was not determined; the combination was deemed intolerable and discontinued. DLTs were G4/5 febrile neutropenia (n = 2) and G3 AST/ALT elevation (n = 1) at 25 mg/m2. Adverse events (AEs) were similar across arms; common drug-related AEs were fatigue (41%), nausea (34%), peripheral neuropathies (PN) (27%), and asymptomatic, reversible AST/ALT elevations (27/25%). 58% had &amp;gt;1 drug-related ≥G3 AE; most frequent were asymptomatic AST/ALT elevations (17/16%) and neutropenias (19%). Pevonedistat PK were unaffected by SoC therapies (n = 22/17/10 pts in Arms 1/2/3). Eleven objective responses were observed (3/22 pts Arm 1, 8/32 pts Arm 2; including pts previously exposed to carboplatin/cisplatin and paclitaxel). One pt with endometrial carcinoma achieved a complete response. Partial responses were observed in head and neck (n = 5), cholangiocarcinoma (n = 2), bladder, NSCLC, sarcoma, and breast cancer (each n = 1). Responses were durable for up to 12 cycles. Conclusion: Pevonedistat plus docetaxel or paclitaxel/carboplatin appeared well tolerated with MTDs of 25 and 20 mg/m2, respectively, and common drug-related AEs of fatigue, nausea, PN, and AST/ALT elevations. Preliminary data suggest antitumor activity with paclitaxel/carboplatin in pts with heavily pretreated solid tumors, notably endometrial carcinoma, head and neck cancer, cholangiocarcinoma, and NSCLC. Citation Format: A. Craig Lockhart, Todd M. Bauer, R. Donald Harvey, Carrie B. Lee, Charu Aggarwal, Roger B. Cohen, Farhad Sedarati, Ling Wang, Hélène M. Faessel, Bruce J. Dezube, Sergio Santillana, Afshin Dowlati. Phase 1b trial of investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in combination with docetaxel, paclitaxel/carboplatin, or gemcitabine in patients (pts) with solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B26.</jats:p

Advanced characterization unravels the structure and reactivity of wood-based chars

International audienceThis study aims at understanding the structural changes occurring in the carbonaceous matrix of wood-based chars during their thermal conversion. Although chars are routinely characterized by porosity measurements or scanning electron microscopy, the composition and structure of the carbonaceous matrix is often not investigated. Here, advanced characterization using X-ray synchrotron microtomography, transmission electron microscopy, Raman spectroscopy and X-ray diffraction provided a precise description of the char properties, allowing for an accurate discussion of their catalytic properties. Two chars were produced by slow pyrolysis of wood waste (400 and 700 °C) and a third one was fabricated by activation under steam at 850 °C of the char obtained at 700 °C. The results show that the pyrolysis temperature and the activation performed did not affect the macrostructure of the chars and that the pores were interconnected at the macroscopic scale. However, at 700 °C, the micro- and nanostructures were modified: short-range organized graphene fringes were observed. The activated char showed a homogeneous microstructure similar to that of its precursor. Besides, the ratio of graphene-like structures, the local organization of graphene sheets, and the imperfections in graphene-like sheets were clearly improved by the post-treatment. To our knowledge, this is the first time that such an approach, combining various tools, is applied for the study of pyrolysis chars