Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Properties of Rozibafusp Alfa, a Bispecific Inhibitor of BAFF and ICOSL: Analyses of Phase I Clinical Trials.

Rozibafusp alfa (AMG 570) is a first-in-class bispecific IgG2-peptide fusion designed to inhibit inducible T-cell costimulator ligand (ICOSL) and B-cell activating factor (BAFF). The pharmacokinetics (PK) and pharmacodynamics (PD) of rozibafusp alfa were investigated in two randomized, placebo-controlled clinical studies: a phase Ia single ascending-dose study (7-700 mg subcutaneously (s.c.)) in healthy subjects and a phase Ib multiple ascending-dose study (70-420 mg s.c. every 2 weeks (q2w)) in patients with rheumatoid arthritis. Rozibafusp alfa exhibited nonlinear PK and dose-related and reversible dual-target engagement. Maximal reduction of naïve B cells from baseline (> 40%), reflective of BAFF inhibition, was achieved with rozibafusp alfa exposure (area under the concentration-time curve from time 0 to time infinity (AUCinf ) and AUC within a dosing interval from day 0 to day 14 (AUCtau )) above 51 and 57 days•µg/mL for the single-dose (≥ 70 mg) and multiple-dose studies (≥ 70 mg q2w), respectively. ICOSL receptor occupancy on circulating B cells, a surrogate PD end point for ICOSL inhibition, was directly related to drug concentration. PK/PD analysis showed > 90% RO at rozibafusp alfa ≥ 22.2 µg/mL (≥ 420-mg single dose or ≥ 210 mg q2w multiple dose), with saturation occurring at higher drug concentrations. These results informed the design and dose selection of a phase IIb study assessing the safety and efficacy of rozibafusp alfa in patients with active systemic lupus erythematosus.

Impact of Sotorasib on the Pharmacokinetics and Pharmacodynamics of Metformin, a MATE1/2K Substrate, in Healthy Subjects.

BACKGROUND AND OBJECTIVE: The objectives of this study were to evaluate the effect of sotorasib on metformin pharmacokinetics and pharmacodynamics and the effect of metformin on sotorasib pharmacokinetics in healthy subjects. Sotorasib is an oral, small molecule inhibitor of the Kirsten rat sarcoma oncogene homolog (KRAS) G12C mutant protein (KRASG12C) protein approved by the U.S. Food and Drug Administration in 2021 for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) in adults who have received at least one prior systemic therapy METHODS: This was a phase I, single-center, open-label, three-period, fixed-sequence study. Subjects received single oral doses of metformin 850 mg, sotorasib 960 mg, and metformin 850 mg with sotorasib 960 mg. Urine and plasma were collected and assayed for metformin and sotorasib pharmacokinetics. Blood glucose was also measured for metformin pharmacodynamics. In addition, an in vitro study was conducted to determine whether sotorasib was an inhibitor of MATE1/2K or OCT2 transport. RESULTS: Geometric least-squares mean ratio of sotorasib area under the concentration-time curve from time 0 to infinity and peak plasma concentration were 0.910 and 0.812, respectively, when sotorasib was coadministered with metformin compared with administration of sotorasib alone. Geometric least-squares mean ratio of metformin area under the concentration-time curve from time 0 to infinity and peak plasma concentration were 0.99 and 1.00, respectively, when comparing metformin coadministered with sotorasib to metformin alone. Geometric mean estimates of serum glucose area under the concentration-time curve from time 0 to 2 h following metformin alone, sotorasib alone, and metformin with sotorasib were 179, 222, and 194, respectively. CONCLUSIONS: These results demonstrated that coadministration of metformin with sotorasib does not impact sotorasib exposure to a clinically significant extent. Coadministration of sotorasib with metformin does not affect metformin exposure or its antihyperglycemic effect, in contrast to the inhibitory effect observed in vitro. Doses of sotorasib 960 mg and metformin 850 mg were safe and well tolerated when coadministered to healthy subjects.

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3-5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.

Distribution, Metabolism, and Excretion of Gedatolisib in Healthy Male Volunteers After a Single Intravenous Infusion.

In this open-label study (NCT02142920), we investigated the distribution, pharmacokinetics, and metabolism of the pan-class-I isoform phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor gedatolisib (PF-05212384), following a single intravenous administration in healthy male subjects. A single, 89-mg, intravenous dose of gedatolisib was associated with a favorable safety profile in the 6 healthy subjects evaluated. Peak plasma concentrations for unchanged gedatolisib and total radioactivity were observed at the end of the 30-minute infusion. The only observed drug-related material in plasma was the parent drug, gedatolisib. Terminal half-life for plasma gedatolisib was ∼37 hours. Following the dose, 66%-73% of drug-related material was recovered in the feces. Metabolism of gedatolisib was trace; only 1 oxidative metabolite, M5, was identified in feces (<1% of total dose). Identification of gedatolisib in feces suggests that biliary and/or intestinal secretion of unchanged parent drug significantly contributes to gedatolisib clearance.

Modeling and simulations relating overall survival to tumor growth inhibition in renal cell carcinoma patients.

PURPOSE: To assess the link between tumor growth inhibition (TGI) and overall survival (OS) based on historical renal cell carcinoma (RCC) data. To illustrate how simulations can help to identify TGI thresholds based on target OS benefit [i.e., hazard ratio (HR) compared with standard of care] to support new drug development in RCC. METHODS: Tumor size (TS) data were modeled from 2552 patients with first-line or refractory RCC who received temsirolimus, interferon, sunitinib, sorafenib or axitinib in 10 Phase II or Phase III studies. Three model-based TGI metrics estimates [early tumor shrinkage (ETS) at week 8, 10 or 12, time to tumor growth (TTG) and growth rate] as well as baseline prognostic factors were tested in multivariate lognormal models of OS. Model performance was evaluated by posterior predictive check of the OS distributions and hazard ratio across treatments. RESULTS: TTG was the best TGI metric to predict OS. However, week 8 ETS had a satisfactory performance and was employed in order to maximize clinical utilization. The week 8 ETS to OS model was then used to simulate clinically relevant ETS thresholds for future Phase II studies with investigational treatments. CONCLUSIONS: The published OS model and resultant simulations can be leveraged to support Phase II design and predict expected OS and HR (based on early observed TGI data obtained in Phase II or Phase III studies), thereby informing important mRCC development decisions, e.g., Go/No Go and dose regimen selection.

First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer.

PURPOSE: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. RESULTS: Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life, 30-37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. CONCLUSIONS: These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies.

Effect of axitinib on the QT interval in healthy volunteers.

PURPOSE: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization. METHODS: The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration-QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily). RESULTS: Axitinib and ketoconazole had opposite effects on heart rate: Axitinib lowered it, ketoconazole raised it. The final analysis showed a flat relationship between QTc and axitinib concentration (slope -0.0314 ms·mL/ng) for axitinib alone. Mean highest placebo-matched change from baseline in QTc was -3.0 [90 % confidence interval (CI) -5.4, -0.6] ms. At supratherapeutic axitinib exposures achieved with potent cytochrome P450 3A4/5 inhibition by ketoconazole, the model predicted mean QTc change of 6.5 (90 % CI 4.4-8.5) ms. The slope population mean estimate was -0.331 (95 % CI -0.860, 0.198) ms·mL/µg for ketoconazole alone and 0.0725 (0.0445-0.1005) ms·mL/ng for axitinib in the presence of ketoconazole. The results were then compared with those obtained based on more widely used Fridericia's, Bazett's, and study-specific correction methods. CONCLUSIONS: Since axitinib plasma concentrations observed in this study exceeded the range of concentrations observed in patients with RCC at the highest approved clinical dose (10 mg twice daily), axitinib was not associated with clinically significant QTc prolongation in target populations.

Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity of the PI3K/mTOR inhibitor PF-04691502, administered orally once daily. METHODS: Escalating doses of PF-04691502 were administered to 23 patients with advanced solid tumors in sequential cohorts across the following dose levels: 2 mg, 4 mg, 8 mg, and 11 mg. 14 additional patients were enrolled in an expansion cohort at the MTD to ensure at least five matched pre- and post-treatment biopsies for biomarkers of PI3K activity. RESULTS: The MTD of PF-04691502 was 8 mg orally once daily. There were three dose-limiting toxicities: one grade 3 fatigue at 8 mg, one grade 3 rash at 11 mg, and one intolerable grade 2 fatigue at 11 mg. Among 37 patients enrolled, treatment-related adverse events included fatigue, decreased appetite, nausea, hyperglycemia, rash, and vomiting. Across all dose levels, average steady-state plasma PF-04691502 concentrations approximated or exceeded the target concentration of 16.2 ng/mL required for ≥75 % tumor growth inhibition in preclinical models. PF-04691502 resulted in increased mean fasting serum glucose, insulin, and c-peptide levels, and produced partial blockade of PI3K signalling in five paired tumor biopsies, as demonstrated by reductions in phosphorylated Akt, FKHR/FKHRL1, and STAT3. No objective anti-tumor responses were observed. CONCLUSIONS: Daily oral administration of PF-04691502 was tolerable at 8 mg orally once daily, with a safety profile similar to other PI3K/mTOR inhibitors. PF-04691502 demonstrated PI3K pathway inhibition by changing glucose homeostasis, and by decreasing phosphorylation of downstream molecules in tumor tissue.

Phase I trial of the HSP90 inhibitor PF-04929113 (SNX5422) in adult patients with recurrent, refractory hematologic malignancies.

BACKGROUND: Heat shock protein (HSP)90 regulates the function of proteins responsible for cell growth and survival, is overexpressed in many cancers and is an attractive therapeutic target. We undertook a phase 1 trial of PF-04929113 (SNX-5422), a novel oral HSP90 inhibitor, to estimate the maximum tolerated dose and describe the pharmacokinetic and toxicity profiles. PATIENTS AND METHODS: Patients with relapsed, refractory, hematologic malignancies and adequate organ function were eligible. PF-04929113 was administered orally every other day for 21 days of a 28-day cycle. Twenty-five patients were treated, with dose escalation ranging from 5.32 mg/m(2) to 74 mg/m(2) using a 3 plus 3 trial design. RESULTS: All 25 patients enrolled were evaluable for toxicity. Most common toxicities included prolonged QTc interval, diarrhea, pruritus, thrombocytopenia, fatigue, and nausea. Grade 3/4 treatment-related adverse events were experienced by 7/25 patients (28%); thrombocytopenia was the most common (n = 3 grade 3; n = 2 grade 4). Partial response was experienced by a patient with transformed lymphoma, and prolonged stabilization of disease was observed in a patient with multiple myeloma. CONCLUSION: Alternate-day oral dosing of PF-04929113 at 74 mg/m(2) for 21/28 days was generally well tolerated with reversible toxicity. The responses observed in myeloma and lymphoma patients are encouraging.

Standard Error of Empirical Bayes Estimate in NONMEM® VI.

The pharmacokinetics/pharmacodynamics analysis software NONMEM® output provides model parameter estimates and associated standard errors. However, the standard error of empirical Bayes estimates of inter-subject variability is not available. A simple and direct method for estimating standard error of the empirical Bayes estimates of inter-subject variability using the NONMEM® VI internal matrix POSTV is developed and applied to several pharmacokinetic models using intensively or sparsely sampled data for demonstration and to evaluate performance. The computed standard error is in general similar to the results from other post-processing methods and the degree of difference, if any, depends on the employed estimation options.

A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas.

PURPOSE: To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas. METHODS: This was a single-institution, phase I, dose-escalation study of PF-04929113 administered twice weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic analysis of PF-04928473 (SNX-2112) and its prodrug PF-04929113, and assessment of response. RESULTS: Thirty-three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m(2) administered orally twice a week. One DLT (nonseptic arthritis) was noted. No grade 4 drug-related adverse events were seen; grade 3 adverse events included diarrhea (9%), nonseptic arthritis (3%), aspartate aminotransferase elevation (3%), and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. Pharmacokinetic data revealed rapid absorption, hepatic, and extrahepatic clearance, extensive tissue binding, and almost linear pharmacokinetics of the active drug PF-04928473. Pharmacodynamic studies confirmed inhibition of Hsp90 and a linear correlation between pharmacokinetic parameters and Hsp70 induction. CONCLUSIONS: PF-04929113 administered orally twice a week is well tolerated and inhibits its intended target Hsp90. No objective responses were seen, but long-lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study, the development of PF-04929113 has been discontinued because of ocular toxicity seen in animal models and in a separate phase I study.

Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors.

The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines.

Determination of PF-04928473 in human plasma using liquid chromatography with tandem mass spectrometry.

A simple, rapid and sensitive liquid chromatography/tandem mass spectrometric (LC/MS/MS) analytical method was developed for quantification of Hsp90 inhibitor PF-04928473 in human plasma, following administration of its prodrug, PF-04929113. Sample processing involved protein precipitation by addition of 0.4 mL of methanol containing internal standard (PF-04972487) to 50 µL volume of plasma sample. Chromatographic separation of PF-04928473 and PF-04972487 was achieved on a Phenomenex®) Luna C18(2) (2.0 mm x 50 mm, 5 µm) column using a gradient elution method with mobile phase solvents: methanol containing 0.1% formic acid and 0.1% formic acid at a flow rate of 0.25 mL/min. Detection was performed in electrospray positive ionization mode, monitoring the ion transitions from m/z 465.1→350.1 (PF-04928473) and m/z 447.0→329.1 (PF-04972487). The retention times for PF-04928473 and PF-04972487 were 1.86 and 2.85 min, respectively. Calibration curves were generated in the range of 2-2000 ng/mL. The accuracy and precision ranged from 94.1 to 99.0% and 86.7 to 97.6%, respectively, which were calculated using quality control samples of three different concentrations analyzed in quintuplicate on four different days.

Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis.

PURPOSE: In this pharmacokinetic/pharmacodynamic meta-analysis, we investigated relationships between clinical endpoints and sunitinib exposure in patients with advanced solid tumors, including patients with gastrointestinal stromal tumor (GIST) and metastatic renal cell carcinoma (mRCC). METHODS: Pharmacodynamic data were available for 639 patients of whom 443 had pharmacokinetic data. Sunitinib doses ranged from 25 to 150 mg QD or QOD. Models to express endpoint values and/or changes from baseline by the highest-correlating exposure measures were developed in S-PLUS or NONMEM using fixed- and mixed-effects modeling. RESULTS: Tentative relationships were identified between (1) steady-state AUC of total drug (sunitinib + its active metabolite SU12662) and time to tumor progression (TTP), overall survival (OS), with AUC significantly associated with longer TTP and OS in patients with GIST and mRCC, and incidence, but not severity, of fatigue; (2) steady-state AUC of sunitinib and response probability, with AUC significantly associated with objective response in patients with mRCC and stable disease in patients with both mRCC and GIST (with no such correlations in patients with solid tumors); (3) dose and tumor size reductions; (4) total drug concentration and diastolic blood pressure (DBP), with a typical patient on sunitinib 50 mg QD (the recommended dose) predicted to experience a maximum DBP increase of 8 mmHg; and (5) cumulative AUC of total drug and absolute neutrophil count (ANC), with ANC reductions occurring predominantly after one treatment cycle. CONCLUSIONS: The results of this meta-analysis indicate that increased exposure to sunitinib is associated with improved clinical outcomes (longer TTP, longer OS, greater chance of antitumor response), as well as some increased risk of adverse effects. A sunitinib 50-mg starting dose seems reasonable, providing clinical benefit with acceptably low risk of adverse events.

A population pharmacokinetic meta-analysis of sunitinib malate (SU11248) and its primary metabolite (SU12662) in healthy volunteers and oncology patients.

PURPOSE: Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumor. Following administration, sunitinib is metabolized by cytochrome P450 3A4 to an active metabolite (SU12662). The objective of this analysis was to assess sunitinib and SU12662 pharmacokinetics and to identify covariates that might explain variability in exposure following oral administration. EXPERIMENTAL DESIGN: Data from 590 subjects (73 volunteers and 517 patients) in 14 studies were analyzed. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and gender, race, age, weight, creatinine clearance, Eastern Cooperative Oncology Group score, and tumor type. Simulations were done to determine the predicted effect of these covariates on exposure. RESULTS: Separate models were developed for sunitinib and SU12662 (each a two-compartment model with first-order absorption and elimination). Sunitinib parameters were estimated as CL/F, 51.8 L/h and Vd/F(central), 2,030 liters. SU12662 parameters were estimated as CL/F, 29.6 L/h and Vd/F(central), 3,080 liters. Tumor type (except acute myeloid leukemia), Asian race, gender, body weight, and elevated Eastern Cooperative Oncology Group score described a portion of the variability in CL/F for sunitinib and metabolite; gender and body weight explained some of the variability in Vd/F(central) for sunitinib and metabolite. Among patients, the predicted changes in sunitinib and metabolite AUC and C(max) as a result of the individual covariates ranged up to 17%. CONCLUSION: The magnitude of the predicted changes in exposure with the covariates studied minimizes the necessity for dose adjustment in any of these subpopulations.