Clinical dose rationale of tislelizumab in patients with solid or hematological advanced tumors.

Tislelizumab, an anti-programmed cell death protein 1 monoclonal antibody, has demonstrated improved survival benefits over standard of care for multiple cancer indications. We present the clinical rationale and data supporting tislelizumab dose recommendation in patients with advanced tumors. The phase I, first-in-human, dose-finding BGB-A317-001 study (data cutoff [DCO]: August 2017) examined the following tislelizumab dosing regimens: 0.5-10 mg/kg every 2 weeks (q2w), 2-5 mg/kg q2w or q3w, and 200 mg q3w. Similar objective response rates (ORRs) were reported in the 2 and 5 mg/kg q2w or q3w cohorts. Safety outcomes (grade ≥3 adverse events [AEs], AEs leading to dose modification/discontinuation, immune-mediated AEs, and infusion-related reactions) were generally comparable across the dosing range examined. These results, alongside the convenience of a fixed q3w dose, formed the basis of choosing 200 mg q3w as the recommended dosing regimen for further clinical use. Pooled exposure-response (E-R) analyses by logistic regression using data from study BGB-A317-001 (DCO: August 2020) and three additional phase I/II studies (DCOs: 2018-2020) showed no statistically significant correlation between tislelizumab pharmacokinetic exposure and ORR across multiple solid tumor types or classical Hodgkin's lymphoma, nor was exposure associated with any of the safety end points evaluated over the dose range tested. Hence, tislelizumab showed a relatively flat E-R relationship. Overall, the totality of data, including efficacy, safety, and E-R analyses, together with the relative convenience of a fixed q3w dose, provided clinical rationale for the recommended dosing regimen of tislelizumab 200 mg q3w for multiple cancer indications.

A Phase 1, Open-Label, Fixed-Sequence, Drug-Drug Interaction Study of Zanubrutinib with Rifabutin in Healthy Volunteers.

Zanubrutinib is a second-generation Bruton tyrosine kinase inhibitor that is primarily metabolized by CYP3A enzymes. Previous drug-drug interaction (DDI) studies have demonstrated that co-administration of zanubrutinib with rifampin, a strong CYP3A inducer, reduces zanubrutinib plasma concentrations, potentially impacting activity. The impact of the co-administration of zanubrutinib with less potent CYP3A inducers is unclear. This phase 1, open-label, fixed-sequence DDI study evaluated the pharmacokinetics, safety, and tolerability of zanubrutinib when co-administered with steady-state rifabutin, a known CYP3A inducer less potent than rifampin, in 13 healthy male volunteers (NCT04470908). Co-administration of zanubrutinib with rifabutin resulted in a less than 2-fold reduction of zanubrutinib exposures. Overall, zanubrutinib was well tolerated. The results of this study provide useful information for the evaluation of the DDI between rifabutin and zanubrutinib. In conjunction with safety and efficacy data from other clinical studies, these results will be taken into consideration to determine the appropriate dose recommendation of zanubrutinib when co-administered with CYP3A inducers.

Absorption, Metabolism, and Excretion of Taselisib (GDC-0032), a Potent ß-Sparing PI3K Inhibitor in Rats, Dogs, and Humans.

Taselisib (also known as GDC-0032) is a potent and selective phosphoinositide 3-kinase (PI3K) inhibitor that displays greater selectivity for mutant PI3Kα than wild-type PI3Kα To better understand the absorption, distribution, metabolism, and excretion properties of taselisib, mass balance studies were conducted following single oral doses of [14C]taselisib in rats, dogs, and humans. Absolute bioavailability (ABA) of taselisib in humans was determined by oral administration of taselisib at the therapeutic dose followed by intravenous dosing of [14C]taselisib as a microtracer. The ABA in humans was 57.4%. Absorption of taselisib was rapid in rats and dogs and moderately slow in humans. The recovery of radioactivity in excreta was high (>96%) in the three species where feces was the major route of excretion. Taselisib was the major circulating component in the three species with no metabolite accounting for >10% of the total drug-derived material. The fraction absorbed of taselisib was 35.9% in rats and 71.4% in dogs. In rats, absorbed drug underwent moderate to extensive metabolism and biliary excretion of taselisib was minor. In dog, biliary excretion and metabolism were major clearance pathways. In humans, 84.2% of the dose was recovered as the parent drug in excreta indicating that metabolism played a minor role in the drug's clearance. Major metabolism pathways were oxidation and amide hydrolysis in the three species while methylation was another prominent metabolism pathway in dogs. The site of methylation was identified on the triazole moiety. In vitro experiments characterized that the N-methylation was dog-specific and likely mediated by a thiol methyltransferase. SIGNIFICANCE STATEMENT: This study provides a comprehensive description of the absorption, distribution, and metabolism and pharmacokinetic properties of taselisib in preclinical species and humans. This study demonstrated the importance of oral bioavailability results for understanding taselisib's clearance pathways. The study also describes the identification and characterization of a unique dog-specific N-methylation metabolite of taselisib and the enzyme mediating N-methylation in vitro.

Model-based population pharmacokinetic analysis of tislelizumab in patients with advanced tumors.

Tislelizumab, a humanized immunoglobulin G4 monoclonal antibody, is a programmed cell death protein 1 (PD-1) inhibitor designed to minimize Fc gamma receptor binding on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The pharmacokinetic (PK) profile of tislelizumab was analyzed with population PK modeling using 14,473 observed serum concentration data points from 2596 cancer patients who received intravenous (i.v.) tislelizumab at 0.5-10 mg/kg every 2 weeks or every 3 weeks (q3w), or a 200 mg i.v. flat dose q3w in 12 clinical studies. Tislelizumab exhibited linear PK across the dose range tested. Baseline body weight, albumin, tumor size, tumor type, and presence of antidrug antibodies were identified as significant covariates on central clearance, whereas baseline body weight, sex, and age significantly affected central volume of distribution. Sensitivity analysis showed that these covariates did not have clinically relevant effects on tislelizumab PK. Other covariates evaluated, including race (Asian vs. White), lactate dehydrogenase, estimated glomerular filtration rate, renal function categories, hepatic function measures and categories, Eastern Cooperative Oncology Group performance status, therapy (monotherapy vs. combination therapy), and line of therapy did not show a statistically significant impact on tislelizumab PK. These results support the use of tislelizumab 200 mg i.v. q3w without dose adjustment in a variety of patient subpopulations.

A phase 1, open-label, randomized drug-drug interaction study of zanubrutinib with moderate or strong CYP3A inhibitors in patients with B-cell malignancies.

BTK inhibitor exposure increases significantly when coadministered with CYP3A inhibitors, which may lead to dose-related toxicities. This study explored the pharmacokinetics, efficacy, and safety of zanubrutinib when coadministered with moderate or strong CYP3A inhibitors in 26 patients with relapsed or refractory B-cell malignancies. Coadministration of zanubrutinib (80 mg BID) with moderate CYP3A inhibitors fluconazole and diltiazem or zanubrutinib (80 mg QD) with strong CYP3A inhibitor voriconazole resulted in comparable exposures to zanubrutinib (320 mg QD) with AUC0-24h geometric least squares mean ratios approaching 1 (0.94, 0.81, and 0.83, for fluconazole, diltiazem, and voriconazole, respectively). The most common treatment-emergent adverse events were contusion (26.9%), back pain (19.2%), constipation and neutropenia (15.4% each), and rash, diarrhea, and fall (11.5% each). This study supports current United States Prescribing Information dose recommendations for the coadministration of reduced-dose zanubrutinib with moderate or strong CYP3A inhibitors and confirms the favorable efficacy and safety profile of zanubrutinib.

In vitro investigations into the roles of CYP450 enzymes and drug transporters in the drug interactions of zanubrutinib, a covalent Bruton's tyrosine kinase inhibitor.

Zanubrutinib is a highly selective, potent, orally available, targeted covalent inhibitor (TCI) of Bruton's tyrosine kinase (BTK). This work investigated the in vitro drug metabolism and transport of zanubrutinib, and its potential for clinical drug-drug interactions (DDIs). Phenotyping studies indicated cytochrome P450 (CYP) 3A are the major CYP isoform responsible for zanubrutinib metabolism, which was confirmed by a clinical DDI study with itraconazole and rifampin. Zanubrutinib showed mild reversible inhibition with half maximal inhibitory concentration (IC50 ) of 4.03, 5.69, and 7.80 µM for CYP2C8, CYP2C9, and CYP2C19, respectively. Data in human hepatocytes disclosed induction potential for CYP3A4, CYP2B6, and CYP2C enzymes. Transport assays demonstrated that zanubrutinib is not a substrate of human breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1/1B3, organic cation transporter (OCT)2, or organic anion transporter (OAT)1/3 but is a potential substrate of the efflux transporter P-glycoprotein (P-gp). Additionally, zanubrutinib is neither an inhibitor of P-gp at concentrations up to 10.0 µM nor an inhibitor of BCRP, OATP1B1, OATP1B3, OAT1, and OAT3 at concentrations up to 5.0 µM. The in vitro results with CYPs and transporters were correlated with the available clinical DDIs using basic models and mechanistic static models. Zanubrutinib is not likely to be involved in transporter-mediated DDIs. CYP3A inhibitors and inducers may impact systemic exposure of zanubrutinib. Dose adjustments may be warranted depending on the potency of CYP3A modulators.

Targeting TIGIT for Immunotherapy of Cancer: Update on Clinical Development.

Immune checkpoint blockers have dramatically improved the chances of survival in patients with metastatic cancer, but only a subset of the patients respond to treatment. Search for novel targets that can improve the responder rates and overcome the limitations of adverse events commonly seen with combination therapies, like PD-1 plus CTLA-4 blockade and PD-1/PD-L1 plus chemotherapy, led to the development of monoclonal antibodies blocking T-cell immunoglobulin and ITIM domain (TIGIT), a inhibitory checkpoint receptor expressed on activated T cells and NK cells. The strategy showed potential in pre-clinical and early clinical studies, and 5 molecules are now in advanced stages of evaluation (phase II and above). This review aims to provide an overview of clinical development of anti-TIGIT antibodies and describes the factors considered and thought process during early clinical development. Critical aspects that can decide the fate of clinical programs, such as origin of the antibody, Ig isotype, FCγR binding, and the dose as well as dosing schedule, are discussed along with the summary of available efficacy and safety data from clinical studies and the challenges in the development of anti-TIGIT antibodies, such as identifying patients who can benefit from therapy and getting payer coverage.

Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma.

This report summarizes a totality-of-evidence approach supporting recommendation of a 320-mg total daily dose, either as 160-mg twice daily (BID) or 320-mg once daily (QD) for zanubrutinib in patients with mantle cell lymphoma. Data were derived from a phase 2 study in patients receiving 160-mg BID and a phase 1/2 study with similar response rates observed with 160-mg BID or 320-mg QD. Given the limited number of patients in the QD dose group, population pharmacokinetics and exposure-response analyses were employed to bridge the two regimens. The analyses showed that similar plasma exposure and BTK inhibition were achieved, and differences in trough concentration and maximum plasma concentration between the two regimens are unlikely to have a meaningful impact on efficacy and safety endpoints. The totality of data, including pharmacokinetic, pharmacodynamic, safety, efficacy, and exposure-response analyses, provided support for the recommended 320-mg total daily dose for the approved indication.

Human Mass Balance and Metabolite Profiling of [14 C]-Pamiparib, a Poly (ADP-Ribose) Polymerase Inhibitor, in Patients With Advanced Cancer.

Pamiparib, a selective poly (ADP-ribose) polymerase 1/2 inhibitor, demonstrated tolerability and antitumor activity in patients with solid tumors at 60 mg orally twice daily. This phase 1 open-label study (NCT03991494; BGB-290-106) investigated the absorption, metabolism, and excretion (AME) of 60 mg [14 C]-pamiparib in 4 patients with solid tumors. The mass balance in excreta, blood, and plasma radioactivity and plasma pamiparib concentration were determined along with metabolite profiles in plasma, urine, and feces. Unchanged pamiparib accounted for the most plasma radioactivity (67.2% ± 10.2%). Pamiparib was rapidly absorbed with a median time to maximum plasma concentration (Cmax ) of 2.00 hours (range, 1.00-3.05 hours). After reaching Cmax , pamiparib declined in a biphasic manner, with a geometric mean terminal half-life (t1/2 ) of 28.7 hours. Mean cumulative [14 C]-pamiparib excretion was 84.7% ± 3.5%. Pamiparib was mainly cleared through metabolism, primarily via N-oxidation and oxidation of the pyrrolidine ring. A dehydrogenated oxidative product (M3) was the most abundant metabolite in biosamples. A mean of 2.11% and 1.11% of [14 C]-pamiparib was excreted as unchanged pamiparib in feces and urine, respectively, indicating near-complete absorption and low renal clearance of parent drug. Cytochrome P450 (CYP) phenotyping demonstrated CYP2C8 and CYP3A involvement in pamiparib metabolism. These findings provide an understanding of pamiparib AME mechanisms and potential drug-drug interaction liability.

The pharmacokinetics of pamiparib in the presence of a strong CYP3A inhibitor (itraconazole) and strong CYP3A inducer (rifampin) in patients with solid tumors: an open-label, parallel-group phase 1 study.

PURPOSE: Pamiparib is an investigational, selective, oral poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that has demonstrated PARP-DNA complex trapping and CNS penetration in preclinical models, as well as preliminary anti-tumor activity in early-phase clinical studies. We investigated whether the single-dose pharmacokinetic (PK) profile of pamiparib is altered by coadministration of a strong CYP3A inducer (rifampin) or a strong CYP3A inhibitor (itraconazole) in patients with solid tumors. METHODS: In this open-label, phase 1 study, adults with advanced solid tumors received either oral pamiparib 60 mg (days 1 and 10) and once-daily oral rifampin 600 mg (days 3-11) or oral pamiparib 20 mg (days 1 and 7) and once-daily oral itraconazole 200 mg (days 3-8). Primary endpoints included pamiparib maximum observed concentration (Cmax), and area under the plasma concentration-time curve from zero to last quantifiable concentration (AUC0-tlast) and infinity (AUC0-inf). Secondary endpoints included safety and tolerability. RESULTS: Rifampin coadministration did not affect pamiparib Cmax (geometric least-squares [GLS] mean ratio 0.94; 90% confidence interval 0.83-1.06), but reduced its AUC0-tlast (0.62 [0.54-0.70]) and AUC0-inf (0.57 [0.48-0.69]). Itraconazole coadministration did not affect pamiparib Cmax (1.05 [0.95-1.15]), AUC0-tlast (0.99 [0.91-1.09]), or AUC0-inf (0.99 [0.90-1.09]). There were no serious treatment-related adverse events. CONCLUSIONS: Pamiparib plasma exposure was reduced 38-43% with rifampin coadministration but was unaffected by itraconazole coadministration. Pamiparib dose modifications are not considered necessary when coadministered with CYP3A inhibitors. Clinical safety and efficacy data will be used with these results to recommend dose modifications when pamiparib is coadministered with CYP3A inducers.