MINT1526A is a monoclonal antibody that blocks the interaction of integrin alpha 5 beta 1 (α5β1) with its extracellular matrix ligands. This phase I study evaluated the safety and pharmacokinetics of MINT1526A with or without bevacizumab in patients with advanced solid tumors.

Cobimetinib is eliminated mainly through cytochrome P450 (CYP) 3A4-mediated hepatic metabolism in humans. A clinical drug–drug interaction (DDI) study with the potent CYP3A4 inhibitor itraconazole resulted in an approximately sevenfold increase in cobimetinib exposure. The DDI risk for cobimetinib with other CYP3A4 inhibitors and inducers needs to be assessed in order to provide dosing instructions.

The objective of this study was to evaluate the potential for a pharmacokinetic (PK) drug-drug interaction (DDI) between trastuzumab and carboplatin and to evaluate the potential effect of trastuzumab on the electrocardiogram QT interval. Here, we report the results of the PK DDI assessment and an interim safety analysis. Patients with metastatic or locally advanced, inoperable, human epidermal growth factor receptor 2-positive cancer received docetaxel and carboplatin on cycle 1, day 1 and then on day 1 of each subsequent 3-weekly treatment cycle. Trastuzumab was administered by intravenous infusion, with an accelerated loading dose on cycle 1, day 2 and cycle 1, day 8, and then a maintenance dose on day 1 of each subsequent 3-weekly treatment cycle. Blood was collected at various time points to assess free (unbound) plasma carboplatin and serum trastuzumab PK. The study enrolled 59 patients. Carboplatin concentrations in the presence and absence of trastuzumab were similar, as demonstrated by the geometric mean ratios for PK parameters, which were close to 1.0 (no effect). The observed trastuzumab concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, computed using the actual sampling time. In this interim safety analysis, 84.5% of patients had experienced adverse events of grade three or higher, the most common of which were hematologic and as expected. The results suggest that there is no clinically relevant PK DDI between carboplatin and trastuzumab. The safety profile of trastuzumab plus carboplatin and docetaxel was consistent with the known safety profile of this combination.

PURPOSE:To characterize cobimetinib pharmacokinetics and evaluate impact of clinically relevant covariates on cobimetinib pharmacokinetics.METHODS:Plasma samples (N = 4886) were collected from 487 patients with various solid tumors (mainly melanoma) in three clinical studies (MEK4592g, NO25395, GO28141). Cobimetinib was administered orally, once daily on either a 21-day-on/7-day-off, 14-day-on/14-day-off or 28-day-on schedule in a 28-day dosing cycle as single agent or in combination with vemurafenib. Cobimetinib doses ranged from 2.1 to 125 mg. NONMEM was used for pharmacokinetic analysis.RESULTS:A linear two-compartment model with first-order absorption, lag time and first-order elimination described cobimetinib pharmacokinetics. The typical estimates (inter-individual variability) of apparent clearance (CL/F), central volume of distribution (V2/F) and terminal half-life were 322 L/day (58 %), 511 L (49 %) and 2.2 days, respectively. Inter-occasion variability on relative bioavailability was estimated at 46 %. CL/F decreased with age. V2/F increased with body weight (BWT). However, the impact of age and BWT on cobimetinib steady-state exposure (peak and trough concentrations and AUC following the recommended daily dose of 60 mg 21-day-on/7-day-off) was limited (<25 % changes across the distribution of age and BWT). No significant difference in cobimetinib pharmacokinetics or steady-state exposure was observed between patient subgroups based on sex, renal function, ECOG score, hepatic function tests, race, region, cancer type, and co-administration of moderate and weak CYP3A inducers or inhibitors and vemurafenib.CONCLUSION:A population pharmacokinetic model was developed for cobimetinib in cancer patients. Covariates had minimal impact on steady-state exposure, suggesting no need for dose adjustments and supporting the recommended dose for all patients.

This study evaluated the potential effect of trastuzumab on the electrocardiogram (ECG) QT interval and assessed the potential pharmacokinetic interaction between trastuzumab and carboplatin. Here, we report the QT and safety results.

Inhibition of MAP/ERK kinase (MEK) is a promising strategy to control the growth of tumors that are dependent on aberrant signaling in the MEK pathway. Cobimetinib (GDC-0973) (S)-[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone) inhibits proliferation of a variety of human tumor cell lines by inhibiting MEK1 and MEK2. A specific high performance liquid chromatography-mass spectrometric assay was developed and validated for the determination of cobimetinib in human plasma. The overall mean recovery using protein precipitation extraction with acetonitrile was found to be 54.1%. The calibration curve was ranged from 0.20 to 100 ng/mL. The LLOQ was sensitive enough to detect terminal phase concentrations of the drug. The intra- and inter-assay precision (%CV) was within 10.3% and 9.5% for cobimetinib. The assay accuracy (%RE) was within ±13.7% of the nominal concentration values for cobimetinib with the normal analytical QCs. The developed assay was successfully used to analyze the human plasma samples (for pharmacokinetic analysis) from clinical trials.

Onartuzumab is a unique, humanized, monovalent (one-armed) monoclonal antibody (mAb) against the MET receptor. The intravenous (IV) pharmacokinetics (PK) of onartuzumab were investigated in a phase I study and a phase II study in recurrent non-small cell lung cancer (NSCLC) patients. The potential for drug-drug interaction (DDI) was assessed during co-administration of IV onartuzumab with oral erlotinib, by measuring the PK of both drugs. The concentration-time profiles of onartuzumab were adequately described using a two-compartment model with linear clearance (CL) at doses between 4 and 30mg/kg. The estimates for CL, central compartment volume (V-1), and median terminal half-life were 0.439L/day, 2.77L, and 13.4 days, respectively. Statistically significant covariates included creatinine clearance (CrCL) on clearance, weight and gender on V-1, and weight on peripheral compartment volume (V-2), but the clinical relevance of these covariates needs to be further evaluated. The current analysis did not indicate obvious DDI between onartuzumab and erlotinib. MET diagnostic status did not impact the exposure of either agent. Despite the slightly faster clearance compared with typical bivalent mAbs, the PK of onartuzumab support dosing regimens of 15mg/kg every 3 weeks or doses equivalent to achieve the target minimum tumoristatic concentration in patients.

PRO95780, a human monoclonal antibody (mAb) against death receptor 5 (DR5/TRAIL-R2/TNFRSF10B), was developed for the treatment for cancer. Our objective was to characterize pharmacokinetics (PK) in mice, rats, and cynomolgus monkeys and concentration–effect relationships of PRO95780 in xenograft mouse models of human cancers; this would guide the selection of dose and regimen for clinical trials.

PURPOSE. To characterize ranibizumab pharmacokinetics in patients with AMD.METHODS. A population approach of nonlinear mixed-effect pharmacokinetic modeling based on concentration-time data from 2993 serum samples from 674 AMD patients enrolled in 5 phase 1 to 3 clinical trials of single or multiple intravitreal (ITV) doses of ranibizumab (0.3-2.0 mg/eye) administered biweekly or monthly for up to 24 months.RESULTS. A total of 696 concentration-time records from 229 subjects with one or more measurable total serum ranibizumab concentrations were analyzed. The systemic concentration-time data for ranibizumab were best described by a one-compartment model with first-order absorption into and first-order elimination from the systemic circulation. Vitreous elimination half-life (t(1/2)) was calculated to be 9 days and the intrinsic systemic elimination t(1/2) was calculated to be approximately 2 hours. Following ITV administration, ranibizumab egresses slowly into the systemic circulation, resulting in an apparent serum t(1/2) of 9 days. Systemic-to-vitreous exposure ratio was estimated to be 1: 90,000. With monthly and quarterly ITV regimens, the serum concentrations of ranibizumab at steady-state for both the 0.3 and 0.5 mg/eye dose levels were estimated to be below the range needed to inhibit VEGF-A-induced endothelial cell proliferation in vitro by 50% at all times.CONCLUSIONS. Systemic exposure to ranibizumab after ITV injection was very low due to elimination on reaching systemic circulation from the vitreous. Population pharmacokinetic analysis of data from a representative sample of AMD patients did not identify clinically significant sources or correlates of variability in ranibizumab exposure. (ClinicalTrials.gov numbers, NCT00056836, NCT00056823.) (Invest Ophthalmol Vis Sci. 2013;54:1616-1624) DOI:10.1167/iovs.12-10260

Cobimetinib is a potent and highly selective inhibitor of MEK1/2. Since cobimetinib exhibited absorption variability in cancer patients, a series of single-dose studies in healthy subjects were conducted to determine absolute bioavailability and elucidate potential effects of formulation, food, and elevated gastric pH on cobimetinib bioavailability. Three crossover trials were performed with a 20 mg cobimetinib oral dose: absolute bioavailability using a 2 mg intravenous infusion (n = 13), relative bioavailability of tablets versus capsules and food effect (n = 20), and drug interaction with a proton pump inhibitor (20 mg of rabeprazole daily for 5 days prior to cobimetinib administration; n = 20). Absolute bioavailability of cobimetinib was 46.2% (24.2, CV %), likely due to metabolism rather than incomplete absorption. The mean systemic clearance of cobimetinib was low (11.7 L/h [28.2, CV %]). Administration of cobimetinib tablets with a high-fat meal delayed drug absorption (prolonged tmax) but had no statistically significant effect on cobimetinib exposure (Cmax and AUC0-∞). Tablet and capsule formulations of cobimetinib showed comparable exposures. Cobimetinib exhibited delayed absorption (tmax) in the presence of rabeprazole, with no statistically significant effects on drug exposure (Cmax and AUC0-∞) in the fasted state. In conclusion, cobimetinib oral absorption was not affected by change in formulation, food, or elevated gastric pH.

Background: Deregulation of the RAS/RAF/MEK/ERK signaling pathway has been implicated in diverse human tumors. GDC-0623 is an orally bioavailable inhibitor of MEK1/2 which has shown antitumor activity in preclinical models (Hatzivassiliou et al. 2013).Methods: An open-label Phase I dose-escalation study using a 3 + 3 design was initiated in patients with advanced solid tumors to evaluate the safety and pharmacokinetic (PK) characteristics of GDC-0623. Patients were administered oral GDC-0623 as a QD or BID regimen on a 21-day on/7-day off dosing schedule in the fasted state (minimum 2 hour fast). In addition, two cohorts were enrolled to examine the effect of food (4 pts) and acidic beverage (3 pts) on GDC-0623 PK. Serial plasma samples for GDC-0623 PK analysis were collected over 24 hours following first dose and after 15 days of continuous dosing.Results: On the QD regimen, 45 pts enrolled in eight successive cohorts (7-160 mg). Dose-limiting toxicities (DLTs) were Grade 4 (G4) creatine phosphokinase (CPK) elevation (90 mg), transient G3 visual disturbance and the serious adverse event (SAE) of G3 dehydration both occurring in the same patient (120 mg), and G3 thrombocytopenia and G3 hyponatremia (160 mg). The maximum tolerated dose was 120 mg (QD cohort). Eight patients enrolled in a single cohort dosing at 45 mg BID. One patient had a DLT of G2 retinal pigment epithelial detachment. Further BID cohorts were not enrolled since the AE profiles between on 90 mg QD and 45 mg BID were comparable. The most frequent adverse events (AE) attributed by the investigator to be GDC-0623-related were rash, visual disturbance - including impaired or blurred vision - which was often associated with sub-retinal fluid, diarrhea, nausea and vomiting, fatigue, elevated CPK, peripheral edema, decreased appetite, headache and dizziness.Preliminarily, GDC-0623 showed dose-proportional PK over the dose range administered. GDC-0623 was rapidly absorbed and distributed, with a terminal half-life of 4-6 hours. Due to its short half-life, GDC-0623 had no accumulation at steady-state following daily oral dosing. Effect of food or acidic beverage on GDC-0623 PK was inconclusive given the inter-patient and intra-patient variability in GDC-0623 PK and very small sample size. One confirmed partial response was observed in a patient with KRAS wild type squamous cell vaginal carcinoma at the QD MTD. Six patients had stable disease ≥ 5 months.Conclusion: GDC-0623 is well-tolerated and showed dose-proportional and time-independent PK. Classic MEK-related AEs, including rash, gastrointestinal symptoms and visual disturbance occurred with similar frequency for QD and BID dosing regimens at the same total daily dose, suggesting comparable intensity of MEK target effect. Updated data will be presented.Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B75.Citation Format: Anthony El-Khoueiry, Carla Kurkjian, Thomas Semrad, Luna Musib, Mary Gates, Steve Eppler, Ilsung Chang, Iris Chan, Isabelle Rooney, Johanna Bendell. A first in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0623 in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B75.

Rituximab is a chimeric murine/human-engineered immunoglobulin (Ig) G1 anti-CD20 monoclonal antibody, selectively depleting CD20-expressing cells in peripheral blood and lymphoid tissues. As part of the rituximab registration-enabling program for rheumatoid arthritis, cynomolgus monkey embryo-fetal development and pre- and postnatal developmental toxicity studies were performed. In both studies, female cynomolgus monkeys were administered rituximab iv at doses of 0/0, 15/20, 37.5/50, and 75/100 mg/kg (loading dose/study dose) from gestation day (GD) 20 to 50 for the embryo-fetal development study and GD 20 to postpartum (pp) day 28 for the pre- and postnatal study. In the embryo-fetal development study, although maternal dosing ended during the first trimester at GD 50, placental transfer of rituximab to fetuses was demonstrated at GD 100. Consequently, fetuses demonstrated B-cell depletion in lymphoid tissues at GD 100. Repletion of B cells was demonstrated in infants in a follow-up pre- and postnatal study following fetal and neonatal exposure. In the pre- and postnatal study, despite B-cell depletion, there was no significant functional consequence on the infant's ability to mount T-cell-dependent antibody responses following vaccination or antigenic challenge. Overall, rituximab was well tolerated at maximum feasible doses up to 100 mg/kg in pregnant cynomolgus monkeys and their infants after exposure from the period of organogenesis throughout pregnancy, parturition, and postnatal development. Importantly, the preclinical data have been concordant with the clinical data in children for cases where rituximab was administered during pregnancy.

Abstract Background: GDC 0973 is a potent, selective, orally administered MEK1/2 inhibitor. It has shown antitumor activity in preclinical models. A first-in-human, phase 1 dose escalation study in cancer patients was conducted using a 3+3 design with two dosing schedules, followed by an expansion at the MTD for each dosing schedule. The pharmacokinetic objective was to evaluate GDC-0973 PK in patients on both dosing schedules. Methods: GDC-0973 was administered orally, once daily on a 21 day on/7 day off (21/7) or on a 14 day on/14 day off (14/14) dosing schedule. Plasma samples for PK analysis were collected on Day 1 and Day 21 (for 21/7) or Day 14 (14/14) of Cycle 1, and during the dosing holiday to determine half-life of GDC-0973. Urine samples were collected on Day 1 and on Day 21 (21/7) or Day 14 (14/14) over a 24-hour period for exploratory analysis. Plasma samples were analyzed using a validated LC/MS/MS method. GDC-0973 pharmacokinetic data was analyzed using a non-compartmental approach with the program WinNonlin. Results: GDC-0973 pharmacokinetics was evaluated at doses administered in the 21/7 schedule (0.05, 0.1 and 0.2 mg/kg in a liquid solution and 10, 20, 40, 60, and 80 mg as capsules) and the 14/14 schedule (60, 80, 100 and 125 mg as capsules). Pharmacokinetic data was available in 41 patients on the 21/7 and 11 patients on the 14/14 schedule. GDC-0973 Cmax was observed at 1-4 hours post-dose, and was similar across the entire dose range. Cmax and AUC increased dose proportionally in the dose range up to 100 mg. The mean apparent oral clearance ranged from 4.30 to 11.7 L/h in the 0.05 mg/kg-100 mg dose range. The mean elimination half-life ranged from 31.6 to 53.5 hours in all dose levels in both schedules. Following daily oral dosing, the mean accumulation ratio was 2.0 to 4.0, which is consistent with its half-life and dosing interval, indicating that the PK was constant over time. Given the mean half-life of ∼40 hours, steady-state exposures are expected to be achieved in 8-10 days. Preliminary data suggest that approximately 1-8% of intact drug is excreted in urine; hence, renal excretion is a minor pathway for elimination. Exploratory analysis showed no clear association between exposure and demographic factors (age, weight, sex) or concomitant medications. PK was consistent between patients in the 21/7 and 14/14 dose escalation stages, as well as the expansion stages when compared at the same doses. Doses of 40 mg or higher in patients achieved steady-state concentrations consistent with antitumor activity observed in xenograft models. Conclusion: GDC-0973 preliminary PK analysis shows a moderate rate of absorption; with generally dose-proportional increases in Cmax and AUC. Updated data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1304. doi:10.1158/1538-7445.AM2011-1304

Abstract COMPLETE RESULTS FROM A PHASE Ia DOSE-ESCALATION AND DOSE-EXPANSION STUDY OF SINGLE-AGENT MetMAb, A MONOVALENT ANTAGONIST ANTIBODY TO THE RECEPTOR MET, ADMINISTERED INTRAVENOUSLY IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS Background: The receptor tyrosine kinase Met and/or its ligand, the hepatocyte growth factor (HGF), are frequently over-expressed in cancers and their levels are closely related to cancer progression and prognosis. Aberrant activation of HGF/Met pathway can enhance invasion, proliferation, and survival. MetMAb was uniquely engineered as a recombinant, humanized, monovalent (one-armed) monoclonal antibody to act as an antagonist of HGF-induced Met signaling. Materials and Methods: This was a 3+3 open label, Phase Ia, dose escalation study in patients with advanced solid malignancies and consisted of two stages: a dose escalation stage, which tested 1, 4, 10, 20 and 30 mg/kg doses of MetMAb, and an expansion stage, which tested a recommended phase 2 dose (RP2D) of 15 mg/kg of MetMAb. Patients received MetMAb IV every 21 days. Pre- and post- dose serum was collected for evaluation of pharmacodynamic (PD) biomarkers that could be affected by inhibition of Met signaling. In addition, archival tissue was obtained for exploratory diagnostic assessments. Results: We present here the complete results from the Phase Ia study, in which 34 patients were treated with MetMAb as a single-agent – 21 patients in the dose-escalation phase and 13 patients in the expansion stage. MetMAb was generally well tolerated at all dose-cohorts up to the maximum administered dose (MAD) of 30 mg/kg. No Gr4 drug-related toxicities were observed. One Gr3 and dose-limiting toxicity (DLT) of pyrexia was observed at 4 mg/kg; other Gr3 drug-related toxicities included: abdominal pain, increased aspartate aminotransferase, hyponatremia and peripheral edema. In the dose expansion stage, the most frequent drug-related toxicities included fatigue (39%) and peripheral edema (54%). An objective complete response was observed in one patient with gastric carcinoma after 4 cycles of treatment (and patient continues to exhibit no evidence of disease); analysis of the patient's archived tumor showed findings characteristic of an HGF/cMet autocrine tumor. At the RP2D, MetMAb has a half-life and clearance approximating 11 days and 7 (±2.0) mL/day/kg, respectively. Conclusions: This Phase Ia study represents a first in human trial of a monovalent antibody. MetMAb, when administered as a single-agent, is generally safe and well tolerated. The combination of MetMAb plus bevacizumab is being investigated, and a Phase II study testing MetMAb in combination with erlotinib in NSCLC is currently ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2774.

To characterize the population pharmacokinetics of bevacizumab and the influence of demographic factors, disease severity, and concomitantly used chemotherapy agents on it’s pharmacokinetic behavior.

Objective: Our objective was to assess the pharmacokinetics of erlotinib in a large patient population with solid tumors, identify covariates, and explore relationships between exposure and safety outcomes (rash and diarrhea) in patients with non-small cell lung cancer receiving single-agent erlotinib.Methods. The population pharmacokinetic analysis was performed by use of NONMEM based on 4068 concentration samples from 1047 patients receiving erlotinib as a single agent or in combination with chemotherapy. By use of a 1-compartment model with first-order absorption, the influence of demographic and clinical characteristics on clearance and volume was examined. Spearman rank correlation analyses were performed to test for correlations between maximum grades of rash and diarrhea and erlotinib exposure in non-small cell lung cancer patients treated with single-agent erlotinib.Results. On the basis of the final model developed from patients treated with erlotinib as a single agent, the oral clearance was 3.95 L/h, the oral volume of distribution was 233 L, and the absorption rate was 0.95 h(-1). The median erlotinib half-life based on this patient population was 36.2 hours. Total biffimbin, alpha(1)-acid glycoprotein, and smoking status were the most important factors affecting clearance. The clearance in current smokers was 24% faster than that in former smokers or those who never smoked. There was a statistically significant correlation between drug exposure and rash (P < .05). However, there was significant overlap in the range of values for patients who had no rash (grade = 0) and those who had any grade of rash. No significant correlation was found between exposure and diarrhea.Conclusions: The long half-life of erlotinib supports the current once-daily dosing regimen at 150 mg/d. Effects of covariates on erlotinib clearance and correlations with adverse event severity were provided to aid in the detection of a treatment-emergent effect.

2032 Background: E as a single agent produced a survival benefit in patients with advanced NSCLC after failure of at least one prior chemotherapy regimen. The objective of this analysis was to: 1) describe the PK of E and its active metabolite (OSI-420) using a population approach and 2) identify covariates that impact E PK. Methods: A population PK model was developed using 2670 E concentrations from 708 patients enrolled in 4 Phase II single-agent trials and 2 Phase III trials in combination with chemotherapy. A subsequent analysis was performed using 2576 concentrations in 591 patients from 4 phase II single agent study plus a single-agent Phase III NSCLC trial once its data became available. Results: A one-compartment model described the concentration data well. The covariate effects were similar between the two analyses, where total bilirubin, α-1-glycoprotein, and smoking status were the most important factors affecting clearance (CL/F). The overall contribution of these covariates was modest and may not be clinically relevant considering the large inter-patient variability observed for CL/F (∼50%). Other factors such as chemotherapy, sex, alkaline phosphatase, albumin, and creatinine clearance were also statistically significant effects (p < 0.005), but their overall influence on E PK was small and their estimated coefficient of variation (CV) was large. From single-agent data, the CL/F and volume of distribution (Vc/F) for a typical patient were 3.95 L/hr and 233 L, respectively. Based on the individual PK parameters from 591 patients, the predicted means (± SD) for the steady-state AUCSS, and Cmin,SS were 41.3 ± 22.0 μg/mL · hr, and 1240 ± 826 ng/mL, respectively. Median t1/2 was 36.2 hours in these patients. Conclusions: The long half-life and the modest effects of covariates on CL/F of erlotinib support the current recommended dosing regimen. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche, Genentech, OSI Hoffmann-La Roche, Genentech, OSI