SEA-TGT is a human nonfucosylated monoclonal antibody (mAb) targeting the T cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) protein. TIGIT is an immunoregulatory receptor expressed on activated and memory T cells, Tregs, and NK cells. TIGIT binding to CD155 and CD112 on tumor cells drives an inhibitory signal resulting in decreased T cell functionality. TIGIT targeting has been reported to release these inhibitory signals, drive Treg depletion, augment CD8+ T cell generation, and promote anti-tumor responses. SGNTGT-001 (NCT04254107) is a phase 1 clinical trial that evaluated the safety and tolerability of SEA-TGT as monotherapy in solid tumors and lymphomas at doses ranging from 0.01 to 6 mg/kg. Because an MTD was not identified in dose escalation, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints were measured to assess biological activity and inform dose selection. The biological activity of SEA-TGT as monotherapy was compared across different dose levels using a clinical utility index (CUI), which mathematically integrated multiple clinically-meaningful PK and PD endpoints into a single readout. PD endpoints included NK and CD8+ T cell proliferation, maintenance of overall peripheral CD8+ T cell numbers, depletion of peripheral regulatory T cells, and peripheral target engagement. The PK endpoint was pharmacokinetic linearity. Surrogates of predicted tumor efficacy metrics included tumor target engagement and formation of the TIGIT:SEA-TGT:Fc receptor gamma (FcγRIIIa) trimer complexes in the tumor. An increase in the CUI score, representing an increase in biological activity, was observed during dose escalation, with an apparent plateau between the 0.3 and 6.0 mg/kg levels. Based on safety signals at 6 mg/kg and PK variability at lower doses, 1 and 3 mg/kg were of most interest for further evaluation. Both 1 and 3 mg/kg represented biologically active dose levels as they showed PK and PD activity that were within desirable ranges and had similarly high overall CUI scores relative to all doses evaluated. Dose selection for SEA-TGT was based on biological activity as assessed via PK/PD endpoints and integrated into a CUI model. Based on the totality of clinical data and the CUI results from monotherapy dose escalation from SGNTGT-001, the SEA-TGT dose of 1 mg/kg was determined to be the lowest biologically active dose with acceptable safety and tolerability. Citation Format: Gabriela Patilea-Vrana, John Harrold, Joseph A. Ware, Shaparak Lonning, Hun Lee, Lisa Brooks, Haley Neff-LaFord, William D. Hanley, Andres Forero-Torres. Using clinical utility index (CUI) to determine the optimal biological dose of a nonfucosylated anti-TIGIT antibody: A proposed alternative to maximum tolerated dose (MTD). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5668.

Supplementary Table 2. Details of patients who achieved a partial response by RECIST, GCIG CA125 or 18F-FDG-PET EORTC criteria.

Supplementary Table 1. Dose reductions and discontinuations in stage 2 Supplementary Table 2. Pharmacokinetic parameters of apitolisib Supplementary Table 3. Summary of radiological responses at the recommended phase 2 doses of 40mg and 30mg 28/28 day schedule for solid tumors and malignant pleural mesothelioma (MPM) patients, respectively. Supplementary Table 4. Characteristics of pleural mesothelioma patients treated with apitolisib Supplementary Figure 1: Apitolisib study schematic Supplementary Figure 2 (A) Waterfall of FDG-PET responses to apitolisib for subjects with higher (black bars) or lower (grey bars) steady-state AUC0-24h than the median exposure for the RP2D of 40 mg QD. (B) The corresponding change in pre-scan fasting blood glucose (FBG) for each patient relative to baseline values during PET procedure. Supplementary Figure 3 CT thorax and MRI pelvis images demonstrate confirmed partial response in E545K PIK3CA mutant clear cell ovarian carcinoma with lung and right common iliac lymphadenopathy on third line apitolisib.

Supplementary Table S1. Patient Demographics and Disease Characteristics. Supplementary Table S2. Treatment-Related Adverse Events of Grade 3 or Higher Observed in either Cycle 1 or Cycle greater than or equal to 2. Supplementary Table S3. Adverse Events in greater than or equal to 10% of Patients Regardless of Attribution. Supplementary Table S4. Adverse Events of Grade 3 or Higher Regardless of Attribution. Supplementary Figure S1. Trellis plot of individual and fitted tumor volumes to day 21 following treatment with taselisib (GDC-0032). Supplementary Figure S2. PI3K pathway suppression was evaluated in KPL-4 tumor xenografts following a single oral dose of 1, 5 and 25 mg/kg taselisib or MCT (0.5% methylcellulose/0.2% Tween-80) vehicle at the time points indicated. Supplementary Figure S3. Schematic showing the decision-making related to selection of recommended dose for future studies. Supplementary Figure S4. Mean plasma concentration vs. time following single dose on day 1 (A) and multiple dose on day 15 (B). Supplementary Figure S5. Duration of treatment of patients treated via PIK3CA mutation status and dose level. Supplementary Figure S6. Antitumor activity observed with taselisib treatment. Supplementary Figure S7. Example of patient with partial response upon taselisib treatment and changes in circulating tumor DNA (ctDNA).

PDF file, 83KB, Representative Western blots of ERK1/2 and total ERK1/2 of tumor tissue homogenate collected from WM-266-4 xenograft studies.

Supplementary Figure 1. Changes in insulin and glucose levels with pictilisib.

Supplementary Figure 3. Details of a 49 year old patient with platinum-refractory metastatic ovarian cancer and 5 previous lines of chemotherapy treated with oral pictilisib at 100mg once-daily on days 1-21 every 28 days.

PDF file, 72KB, Summary of pharmacokinetic parameters estimated from fitting PK model from WM-266-4 xenograft studies (Figure 1A) to GDC-0973 concentration-time data from humans.

Titles and Captions for supplementary tables and figures.

PDF file, 57KB, Structure of GDC-0973.

Background: Oxaliplatin (OX)-containing regimens are frequently utilized to treat gastrointestinal (GI) cancers. OX is eliminated predominately via urinary excretion (GFR and active tubular secretion). The contribution of active transport via OCT2 and MATE1/2-K to OX clearance is not fully understood. Tyrosine kinase inhibitors (TKIs) are frequently found to interact with OCT2/MATE transporters; however, a gap in knowledge remains between their clinical potential to impact OX pharmacokinetics (PK) and in turn, impact renal function. Tucatinib (TUC) is a highly selective human epidermal growth factor receptor 2 (HER2)-directed TKI approved in multiple regions in combination with trastuzumab and capecitabine for adult patients with metastatic HER2+ breast cancer and is currently being investigated in other HER2+ tumors. TUC inhibits OCT2/MATE-mediated transport of metformin and creatinine in vitro and in vivo. In this study, we investigated the impact of TUC on OX plasma PK, OX renal clearance (Clr), and renal function. Methods: In vitro inhibition of OCT2/MATE-mediated transport of OX by TUC was assessed in OCT2, MATE1, or MATE2-K-expressing MDCK-II cells. SGNTUC-024 (NCT04430738) is a Ph1b/2 clinical study in patients with HER2+ GI cancers evaluating the impact of TUC on the safety and PK of OX. Patients received TUC 150 mg (Cohort 1A) or 300 mg (Cohort 1B) BID starting on C1D8 of a 2-week cycle in combination with modified FOLFOX6/7. Intensive PK was collected in plasma and urine for OX alone (C1D1) or with steady-state TUC (C2D1). Total plasma platinum (Pt, analyzed as a surrogate for OX and catabolites), plasma Pt ultrafiltrate (PUF, unbound), and urine Pt were quantitatively analyzed via ICP-MS. Serum Cystatin C (CysC) was measured as a pharmacodynamic (PD) renal function marker in Cohorts 1A and 1B. Results: TUC inhibited in vitro OX transport by MATE1 (IC50 = 0.0639 µM), MATE2-K (IC50 = 0.0382 µM), and OCT2 (IC50 = 0.491 µM). In 11 patients, total Pt and PUF AUC0-8h geometric mean ratio (GMR) and 90% confidence intervals (CI) between patients who received OX alone compared to in combination were 1.1 (0.98, 1.3) and 1.0 (0.78, 1.4) in Cohort 1A (n=4) and 1.1 (0.96, 1.2) and 1.0 (0.98, 1.1) in Cohort 1B (n=7), respectively. OX GM (%CV) renal clearance (Clr,0-8h in mL/min) and fraction excreted 24h post-dose (fe,0-24h) were similar with and without TUC in both Cohort 1A (C1D1 Clr0-8h = 277 (33), fe,0-24h = 22% (17); C2D1 Clr0-8h = 249 (78), fe,0-24h = 21% (15)) and Cohort 1B (C1D1 Clr0-8h = 189 (37), fe,0-24h = 17.7% (16); C2D1 Clr0-8h = 177 (40), fe,0-24h = 16.6% (35)). Reversible slight increases in CysC (normalized to baseline) on day 3 of each cycle, irrespective of tucatinib, were observed. Conclusions: This investigation of in vitro and in vivo determinants of OX PK demonstrates that TUC does not alter the renal clearance of oxaliplatin nor renal function when OX is administered in combination with TUC. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, Vineet Kumar, Michelle Ubowski, JoAl G. Mayor, Layth I. Abdulrasool, Clark M. Henderson, Joseph A. Ware, Christopher J. Endres. Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5060.

Supplementary Figure 4. Association between severity of treatment-related rash and steady-state exposure (day 15 AUC0-24) to pictilisib. (Gr=Grade).

PDF file, 66KB, Plot of observed versus predicted GDC-0973 plasma concentrations following fitting of PK model (Figure 1A) to mean GDC-0973 plasma concentration-time data from patients in cohort 1.

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.

Supplementary Table 1. Additional pharmacokinetic parameters of pictilisib

Examine relationships between the systemic exposure of acalabrutinib, a highly selective, next‐generation Bruton tyrosine kinase inhibitor, and its active metabolite (ACP‐5862) vs. efficacy and safety responses in patients with B‐cell malignancies who received acalabrutinib as monotherapy or in combination with obinutuzumab.

Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved to treat adults with chronic lymphocytic leukemia, small lymphocytic lymphoma, or previously treated mantle cell lymphoma. As the bioavailability of the acalabrutinib capsule (AC) depends on gastric pH for solubility and is impaired by acid-suppressing therapies, coadministration with proton-pump inhibitors (PPIs) is not recommended. Three studies in healthy subjects (N = 30, N = 66, N = 20) evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability of acalabrutinib maleate tablet (AT) formulated with pH-independent release. Subjects were administered AT or AC (orally, fasted state), AT in a fed state, or AT in the presence of a PPI, and AT or AC via nasogastric (NG) route. Acalabrutinib exposures (geometric mean [% coefficient of variation, CV]) were comparable for AT versus AC (AUC(inf) 567.8 ng h/mL [36.9] vs 572.2 ng h/mL [38.2], C-max 537.2 ng/mL [42.6] vs 535.7 ng/mL [58.4], respectively); similar results were observed for acalabrutinib's active metabolite (ACP-5862) and for AT-NG versus AC-NG. The geometric mean C-max for acalabrutinib was lower when AT was administered in the fed versus the fasted state (C-max 255.6 ng/mL [%CV, 46.5] vs 504.9 ng/mL [49.9]); AUCs were similar. For AT + PPI, geometric mean C-max was lower (371.9 ng/mL [%CV, 81.4] vs 504.9 ng/mL [49.9]) and AUC(inf) was higher (AUC(inf) 694.1 ng h/mL [39.7] vs 559.5 ng h/mL [34.6]) than AT alone. AT and AC were similar in BTK occupancy. Most adverse events were mild with no new safety concerns. Acalabrutinib formulations were comparable and AT could be coadministered with PPIs, food, or via NG tube without affecting the PKs or PDs.

Aims Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, is approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukaemia. Many critically ill patients are unable to swallow and need oral medications to be delivered via a nasogastric (NG) tube. Furthermore, critically ill patients are typically administered proton-pump inhibitors (PPIs) to prevent stress ulcers. Concomitant administration with PPIs reduces acalabrutinib exposure and is not currently recommended. To evaluate acalabrutinib in subjects co-administered with PPIs who require NG delivery, a phase 1, open-label, randomized, crossover, single-dose study was conducted in healthy subjects. Methods The study assessed the relative bioavailability of an acalabrutinib suspension-in regular, degassed Coca-Cola-administered via NG tube (Acala-NG) versus the pharmacokinetics (PK) of an acalabrutinib capsule administered orally with water. In addition, the PPI effect was evaluated by comparing the PK following Acala-NG in the presence or absence of rabeprazole. Results Exposure of acalabrutinib and its active metabolite (ACP-5862) were comparable following administration of Acala-NG versus the oral capsule (Geo mean ratio, % ref [90% confidence interval, CI]: acalabrutinib AUC(inf): 103 [93-113]; C-max: 144 [120-173]). In addition, exposure was similar following administration of Acala-NG with and without a PPI (Geo mean ratio, % ref [90% CI]: acalabrutinib AUC(inf): 105 [79-138]; C-max: 95 [66-137]). No safety or tolerability concerns were observed, and all adverse events were mild and resolved without treatment. Conclusions Acala-NG with or without a PPI is safe and well-tolerated without impeding bioavailability.

This analysis aimed to describe the pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP‐5862. A total of 8935 acalabrutinib samples from 712 subjects and 2394 ACP‐5862 samples from 304 subjects from 12 clinical studies in patients with B‐cell malignancies and healthy subjects were analysed by nonlinear mixed‐effects modelling. Acalabrutinib PK was characterized by a 2‐compartment model with first‐order elimination. The large variability in absorption was adequately described by transit compartment chain and first‐order absorption, with between‐occasion variability on the mean transit time and relative bioavailability. The PK of ACP‐5862 was characterized by a 2‐compartment model with first‐order elimination, and the formation rate was defined as the acalabrutinib clearance multiplied by the fraction metabolized. Health status, Eastern Cooperative Oncology Group performance status, and coadministration of proton‐pump inhibitors were significant covariates. However, none of the investigated covariates led to clinically meaningful changes in exposure, supporting a flat dosing of acalabrutinib.

Aims Clinical drug interaction studies with itraconazole and rifampicin have demonstrated that acalabrutinib is a sensitive substrate of CYP3A. A physiologically based pharmacokinetic (PBPK) model was developed based on the data of these studies. One of the active CYP3A metabolites, ACP-5862, was identified but never studied in a drug interaction scenario. This study aims to evaluate both parent and metabolite exposure change with coadministration of moderate CYP3A inhibitors and its impact on safety and efficacy. Methods In an open label, randomized, 2-period study, we investigated the effect of coadministration of fluconazole or isavuconazole on the pharmacokinetics of acalabrutinib. Bruton tyrosine kinase receptor occupancy and safety were compared between different treatments. Experimental data were compared to PBPK simulation results. Results Least square means of acalabrutinib maximum plasma concentration and area under the curve increased 1.37 (1.14-1.64) and 1.60 (1.45-1.77)-fold in the presence of isavuconazole and 1.48 (1.10-1.98) and 2.16 (1.94-2.40)-fold in the presence of fluconazole, respectively. For ACP-5862, these values are 0.72 (0.63-0.82) and 0.91 (0.86-0.97) fold for isavuconazole and 0.65 (0.49-0.87) and 0.95 (0.91-0.99) fold for fluconazole coadministration. The PBPK model was able to recover acalabrutinib and ACP-5862 PK profiles in the study. Bruton tyrosine kinase receptor occupancy change was minimal in the presence of isavuconazole. There were no deaths, serious adverse events (AEs), or subject discontinuation due to AEs in this study. Only mild (Grade 1) AEs were reported during the study, by 17% of the study population. Conclusion Our results demonstrate the impact of fluconazole and isavuconazole on the pharmacokinetics of acalabrutinib and ACP-5862, and suggest that no dose adjustment is needed for concomitant administration with moderate CYP3A inhibitors. the current PBPK model can be used to propose dose adjustment for drug interactions via CYP3A.