Plasma Pharmacokinetic Samples Research Articles

Phase Ib study of a high potent PI3K-mTOR dual inhibitor WX390 combined with toripalimab in patients with advanced solid tumors.

e14627 Background: WX390 is a high potent PI3K-mTOR dual inhibitor targeting pan-PI3K and mTOR. It modulates the tumor immune microenvironment by decreasing tumor Treg and myeloid-derived suppressor cells (MDSC) and improves the immune response to checkpoint inhibitors (CPI) in preclinical models. Methods: The Phase Ib study was designed to evaluate safety, pharmacokinetics (PK), and preliminary clinical activity, to determine recommended phase 2 dose (RP2D) of WX390 combined with Toripalimab in patients with advanced solid tumors. WX390 was administered orally daily at escalating doses of 0.7 mg, 0.9mg and 1.1mg, with Toripalimab at 240 mg IV every 3 weeks until confirmed progressive disease, intolerable toxicity or withdrawal of consent. Plasma PK samples were collected up to 24 hours after the first dose at C1D1, and up to 24 hours before and after the morning dose at C1D21. Results: As of December 31, 2023, total 18 patients had been treated in 3 WX390 cohorts: 0.7 mg (n = 3), 0.9 mg (n = 3), and 1.1 mg (n = 12) once daily (QD). No dose limit toxicity (DLT) was observed, and the RP2D of WX390 in combination was 1.1 mg QD, which was consistent with the single agent RP2D. The treatment related adverse events (TRAEs) (≥20%) included hyperglycemia (17/18, 94.4%), creatinine increased (12/18, 66.7%), weight loss (10/18, 55.6%), diarrhea (9/18, 50%), proteinuria (9/18, 50%), nausea (7/18, 38.9%), lymphocytopenia (7/18, 38.9%), vomiting (7/18, 38.9%), rash (7/18, 38.9%), decreased appetite (6/18, 33.3%), hypokalemia (6/18, 33%), fatigue (5/18, 27.8%), hyponatremia (4/18, 22.2%), and thrombocytopenia (4/18, 22.2%). Grade 3 TRAEs included hyperglycemia (5/18), lymphocytopenia (4/18), rash (2/18), weight loss (2/18), leukopenia (1/18), infusion-related reaction (1/18), nausea (1/18), and stomatitis (1/18). There was no TRAE leading to treatment permanent discontinuation and no grade 4/5 TRAE were observed. PK of WX390 in combination showed similar PK profile with the single agent. Among the 16 efficacy-evaluable patients with cervical (N=8), head and neck (N=5), and urothelial cancer (N=3), 5 patients (31.3%) previously received immune checkpoint inhibitors. 3 of 5 (60%) cervical cancer patients at RP2D and 2 of 5 head and neck cancer patient (40%) have achieved confirmed partial response (PR). In addition, 3 cervical patients who were treated with 0.7 or 0.9mg QD and 1of 3 urothelial carcer patients experienced tumor shrinkage (SD). The medium progression free survival (PFS) was 5.49 months (95% CI: 2.53, 6.37). Conclusions: WX390 in combination with Toripalimab had a manageable safety profile and encouraging antitumor effects in patients with advanced solid tumors. An RP2D of 1.1 mg qd of WX390 in combination was selected to be explored in further phase II study, which is ongoing in different tumor types. Clinical trial information: NCT06117566 .

Phase I study of the pharmacokinetics and safety of rezafungin in subjects with moderate/severe hepatic impairment and matched control subjects.

Rezafungin is a second-generation, once-weekly echinocandin antifungal approved for the treatment of invasive candidiasis, including candidemia. In phase II/III studies of rezafungin versus caspofungin, patients with severe hepatic impairment were excluded due to lack of caspofungin data in this population. This open-label, single-dose, phase I study evaluated the pharmacokinetics (primary objective) and safety of rezafungin in subjects with moderate or severe hepatic impairment versus matched, healthy subjects with normal hepatic function. Eight subjects each with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment were matched 1:1 with healthy subjects for age, sex, and body mass index. Each subject received a single 400-mg, intravenous, 1-h infusion of rezafungin. Plasma pharmacokinetic sampling was performed at various time points through 336 h postdose. Pharmacokinetic parameters were derived by non-compartmental analysis. Safety was assessed throughout. All 32 subjects received study treatment and were included in all analyses. Despite overlapping distributions of total plasma concentrations, based on geometric least-squares (LS) mean ratios, the area under the plasma concentration-time curve from time zero (prior to the start of infusion) to infinity (AUC0-∞) was 32% lower in subjects with moderate (LS mean ratio, 67.55; 90% confidence interval [CI]: 53.91, 84.65) and severe (LS mean ratio, 67.84; 90% CI: 57.49, 80.05) hepatic impairment versus matched healthy subjects. The maximum plasma concentration (Cmax) was 12% lower in moderate hepatic impairment and 28% lower in severe hepatic impairment groups. Linear regression showed no significant trend in the degree of hepatic impairment (based on Child-Pugh score) on AUC0-∞ or Cmax (p > 0.05). Treatment-emergent adverse events were reported in seven subjects (21.9%; three subjects in each of the hepatic impairment groups, and one healthy subject), none of which were severe, serious, or resulted in withdrawal. Rezafungin is well tolerated and can be administered to patients with moderate or severe hepatic impairment without the need for dose adjustment. The modest reduction in exposures in subjects with hepatic impairment is not clinically meaningful and is unlikely to impact efficacy.

Development of a population pharmacokinetic model to characterize the pharmacokinetics of intrathecally administered tominersen in cerebrospinal fluid and plasma.

Tominersen is an intrathecally administered antisense oligonucleotide targeting huntingtin mRNA which leads to a dose-dependent, reversible lowering of cerebrospinal fluid (CSF) mutant huntingtin protein concentration in individuals with Huntington's disease. Nonlinear mixed-effect population pharmacokinetic (PopPK) modeling was conducted to characterize the CSF and plasma pharmacokinetics (PK) of tominersen, and to identify and quantify the covariates that affect tominersen PKs. A total of 750 participants from five clinical studies with a dose range from 10 to 120 mg contributed CSF (n = 6302) and plasma (n = 5454) PK samples. CSF PK was adequately described by a three-compartment model with first-order transfer from CSF to plasma. Plasma PK was adequately described by a three-compartment model with first-order elimination from plasma. Baseline total CSF protein, age, and antidrug antibodies (ADAs) were the significant covariates for CSF clearance. Body weight was a significant covariate for clearances and volumes in plasma. ADAs and sex were significant covariates for plasma clearance. The developed PopPK model was able to describe tominersen PK in plasma and CSF after intrathecal administration across a range of dose levels, and relevant covariate relationships were identified. This model has been applied to guide dose selection for future clinical trials of tominersen in patients with Huntington's disease.

A Model-Based Approach to Bridging Plasma and Dried Blood Spot Concentration Data for Phase 3 Verubecestat Trials

In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS-plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling. To enable inclusion of DBS data in population PK analyses, a conversion algorithm for calculating plasma-equivalent concentrations (accounting for DBS sample instability) was developed using paired (time-matched) plasma and DBS data from the EPOCH study. Verubecestat population PK models developed from pooled phase 1/1b and EPOCH data using either (1) plasma-only data or (2) plasma and plasma-equivalent concentrations (calculated from non-paired DBS samples) yielded similar results. The algorithm robustness was demonstrated using DBS data from paired samples from the APECS study and comparison between plasma and plasma-equivalent concentrations. The population PK model was updated with APECS data (both plasma and, if no plasma sample available, plasma equivalents). The results demonstrated similar PK in the two phase 3 populations and exposures consistent with expectations from phase 1 data. This case study illustrates challenges with employing new sampling techniques in large, global trials and describes lessons learned.

Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion.

Background:Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson’s disease (aPD).Objective:The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients.Methods:This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study.Results:LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups.Conclusion:Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.

IV and oral fosfomycin pharmacokinetics in neonates with suspected clinical sepsis.

BackgroundFosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking.ObjectivesTo generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data.MethodsThe NeoFosfo study (NCT03453177) was a randomized trial that examined the safety and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model was developed in NONMEM and simulations were performed.ResultsIn total, 238 plasma and 15 CSF concentrations were collected. A two-compartment disposition model, with an additional CSF compartment and first-order absorption, best described the data. Bioavailability was estimated as 0.48 (95% CI = 0.347–0.775) and the CSF/plasma ratio as 0.32 (95% CI = 0.272–0.409). Allometric weight and postmenstrual age (PMA) scaling was applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on CSF/plasma ratio.ConclusionsThrough this analysis a population pharmacokinetic model has been developed that can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin dose based on an infant’s PMA, PNA and weight.

Venetoclax Crosses the Blood Brain Barrier: A Pharmacokinetic Analysis of the Cerebrospinal Fluid in Pediatric Leukemia Patients

Introduction: Venetoclax is a selective BCL2 inhibitor approved for the treatment of CLL and AML in adults and is currently being evaluated in several hematologic and solid malignancies. While plasma pharmacokinetics (PK) of venetoclax is well documented, data regarding the accumulation of venetoclax into the central nervous system (CNS) are limited. Venetoclax has a molecular weight of 868.44 which was hypothesized to limit its passage through the tight junctions of the blood brain barrier (BBB). Moreover, venetoclax is a substrate of the P- glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters, expressed by endothelial cells at the BBB, which presents an extra hurdle for penetration into the CNS. In this analysis we characterized the passage of venetoclax into the CNS using PK samples collected during a phase 1 study (NCT03236857) of pediatric patients with relapsed and refractory acute leukemia receiving venetoclax in combination with chemotherapy. Methods: PK samples from cerebrospinal fluid (CSF) were collected at screening and if a lumbar puncture was performed as standard of care during treatment. Plasma PK samples were collected throughout the study. CSF and plasma concentrations of venetoclax were determined using liquid-liquid extraction followed by liquid chromatography (LC) with tandem mass spectrometric detection (MS/MS). The lower limit of quantitation for venetoclax was 2.14 ng/mL in plasma and 0.1ng/mL in CSF. Results: There was a total of 66 samples from 33 patients with relapsed or refractory AML or ALL. The venetoclax concentration in CSF ranged between <0.1 and 13 ng/mL with a mean concentration of 3 ng/mL. Of the 66 CSF samples collected, 17 CSF samples (from 9 patients) had a plasma PK sample collected on the same day. The venetoclax CSF concentrations in this subgroup were consistent with the overall group and ranged between <0.1 and 11 ng/mL with a mean concentration of 2.8 ng/mL. Venetoclax plasma concentrations ranged from <2 ng/mL to 4.3 ug/mL. The mean plasma-to-CSF ratio was 300 with a range of 67-1003. This mean is more than 4-fold higher than the blood-to-brain ratio observed preclinically in mice. The plasma-to-CSF ratios did not show a trend over the dosing interval. Conclusion: To our knowledge this is the first study reporting venetoclax CSF pharmacokinetics in the AML and ALL setting. The lower disposition observed in humans is contrary to our expectation, given the significantly higher expression of P-gp in mice BBB compared to humans and suggests that other factors are involved in venetoclax disposition to the CSF. The ability of venetoclax to cross the blood brain barrier may explain the reported activity of venetoclax in treatment of hematologic malignancies with CNS involvement1,2.

Talazoparib has no clinically relevant effect on QTc interval in patients with advanced solid tumors.

The aims of this study were (i) to evaluate the effect of talazoparib (1 mg once daily) on cardiac repolarization in patients with advanced solid tumors by assessing corrected QT interval (QTc) and (ii) to examine the relationship between plasma talazoparib concentration and QTc. In this open-label phase 1 study, patients had continuous 12-lead ECG recordings at baseline followed by time-matched continuous ECG recordings and collection of talazoparib plasma pharmacokinetic samples predose and at 1, 2, 4, and 6 h postdose on treatment days 1 and 22 and before talazoparib administration on day 2. ECG recordings were submitted for independent central review where triplicate 10-s ECGs, extracted up to 15 min before pharmacokinetic samples, were assessed for RR, PR, QRS, and QT intervals and ECG morphology. QT interval was corrected for heart rate using Fridericia's (QTcF) and Bazett's (QTcB) formulae. Linear mixed-effects modeling was used to examine the relationship between QTc and RR interval change from baseline and plasma talazoparib concentration. Thirty-seven patients received talazoparib. Mean change in QTcF from time-matched baseline ranged from -3.5 to 6.9 ms, with the greatest change 1 h postdose on day 22. No clinically relevant changes in PR, QRS, QTcB, QTcF, or RR intervals, heart rate, or ECG morphology were observed. No concentration-dependent effect on heart rate or QTc was observed. No deaths, permanent treatment discontinuations due to adverse events were reported. Talazoparib (1 mg once daily) had no clinically relevant effects on cardiac repolarization.

1421. IV Brincidofovir (BCV): Pharmacokinetics (PK) and Safety of Multiple Ascending Doses (MAD) in Healthy Subjects

BackgroundBCV is a lipid conjugated nucleotide analog that has shown rapid viral clearance with oral administration in patients with adenovirus infection, and improved survival in animal models of smallpox. Phase I single ascending dose evaluation of IV BCV demonstrated that 2 hour infusions of 10, 25, and 50 mg were well tolerated and not associated with significant adverse events (AEs) or laboratory abnormalities. This study evaluated the safety and PK of multiple ascending doses of IV BCV in healthy subjects.MethodsTwenty-eight subjects were to be randomized 3:1 to receive blinded IV BCV or placebo in sequential MAD cohorts (Table A). Study drug was given twice a week (BIW) for 2 weeks or once a week (QW) for 4 weeks. Plasma PK samples were collected on Day 1 and after the last dose and assayed by HPLC-MS. Plasma BCV PK parameters were determined by noncompartmental analysis and dose proportionality and accumulation was assessed. Safety assessments were performed during the dosing period through 14 days post last dose.ResultsTwenty-seven male and female subjects (29–65 years, 93% White) were enrolled and 26 completed the study. Plasma BCV Cmax and AUC∞ increased in proportion to dose with no accumulation (Table A). AEs were generally mild and included diarrhea and headache. Alanine aminotransferase (ALT) elevations were asymptomatic and resolved upon cessation of dosing. No serious AEs occurred.Table A.BCV PK on Day 1 and SafetyPlasma BCV PK1BCV 10 mg BIW 2-hour Infusion (n = 9)BCV 20 mg QW 2-hour Infusion (n = 6)BCV 20 mg QW 1-hour Infusion (n = 5)Pooled Placebo (n = 7) C max (ng/mL)553 (33%)1,110 (19%)1,720 (19%)NAAUC∞ (ng*h/mL)1,374 (34%)2,982 (23%)2,919 (18%)NADrug-related AEs in >2 subjectsDiarrhea03 (50%)1 (20%)0Headache4 (44%)3 (50%)3 (60%) 4 (57%)Fatigue02 (33%)02 (29%)1. Cmax and AUC∞: geometric means (%CVb).ConclusionMultiple doses of IV BCV given as 10 mg BIW or 20 mg QW were generally safe and well tolerated. Mild diarrhea was reported only after IV BCV 20 mg QW. As seen with oral BCV, ALT increases were reversible upon cessation of drug, and were not associated with hyperbilirubinemia. BCV exposure was dose-proportional and no accumulation was observed. The data support evaluation of repeat dose administration in virally infected patients.Disclosures O. Naderer, Chimerix: Employee, Salary. V. Schuck, Chimerix: Research Contractor, Consulting fee. M. Morrison, Chimerix: Employee, Salary. M. Anderson, Chimerix: Employee, Salary. T. Arumugham, Chimerix: Employee, Salary. J. Dunn, Chimerix: Employee, Salary.

Abstract PD5-10: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC)

Abstract Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of ER+ BC. However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen. ER antagonists that are efficacious against ligand-dependent and ligand-independent, constitutively active ESR1 mutant tumors may be of substantial therapeutic benefit. GDC-0927 (formerly known as SRN-927) is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader (SERD) that induces tumor regression in ER+ BC patient-derived xenograft models. Methods: A phase I dose escalation study with 3+3 design was conductedin postmenopausal women with ER+ (HER2-) metastatic BC (progressing ≥ 6 months on endocrine therapy and with ≤ 2 prior chemotherapies in the advanced or metastatic setting) to determine the safety, pharmacokinetics (PK) and the recommended Phase 2 dose (RP2D) of GDC-0927. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples (after single dose and at steady state), CT scans, and when feasible, pre and on-study tumor biopsies were obtained Results: From March 16, 2015 to March 17, 2017 patients (pts) with a median age of 53 years (range 44-69) and a median number of prior therapies for MBC 4 (range 1-7) were enrolled at 3 total daily dose levels (600, 1000, 1400 mg) once daily (QD) given orally with fasting (n = 12). Increases in GDC-0927 exposure were approximately dose proportional. Treatment related adverse events (AEs) were all grade 1 or 2. The most common treatment-related AEs were nausea (54%, n = 7), diarrhea (46%, n = 6), elevated aspartate aminotransferase (39%, n = 5) and anemia, constipation, (each 31%, n = 4). Treatment interruption was required for 2 pts due to nausea and vomiting. Of those pts with FES-PET avid disease at baseline (9 of 12), all post-therapy scans showed complete or near complete (> 90%) suppression of FES uptake to background levels, including pts with ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-treatment biopsies. Five of 12 pts (1 at 600 mg and 4 at 1400 mg) were on study ≥ 24 weeks (CBR = 41.6 %) with the best overall response of stable disease with 1 patient (ESR1 mt+ D538G) on study for over 490 days. There were no dose limiting toxicities and no SAEs related to study drug. R2PD was 1400 mg and was selected for single arm dose-expansion which is now complete with last patient enrolled on March 17, 2017. Updated results from dose-escalation and dose-expansion will be presented at the meeting (N = 43). Conclusions: GDC-0927 appears well-tolerated to date with PK exposure supporting QD dosing, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated pts with advanced or metastatic ER+ BC, including pts with ESR1 mutations. Citation Format: Dickler MN, Villanueva R, Perez Fidalgo JA, Mayer IA, Boni V, Winer EP, Hamilton EP, Bellet M, Urruticoechea A, Gonzalez-Martin A, Cortes J, Martin M, Giltnane J, Gates M, Cheeti S, Fredrickson J, Wang X, Friedman LS, Spoerke JM, Metcalfe C, Liu L, Li R, Morley R, McCurry U, Chan IT, Mueller L, Milan S, Lauchle J, Humke EW, Bardia A. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-10.

Abstract P5-21-23: Evaluation of the drug interaction potential of palbociclib and exemestane – Results from the PEARL pharmacokinetic sub-Study

Abstract Background: Palbociclib (PAL) is an oral cyclin-dependent kinase (CDK) 4/6 inhibitor that is under investigation in multiple oncologic clinical trials and is currently approved for use in combination with aromatase inhibitors (AIs) or fulvestrant (FUL) in patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (BC). The PEARL Study is an ongoing international, open label, controlled, randomized Phase 3 study comparing the efficacy and safety of PAL in combination with endocrine therapy (exemestane [EXE] or FUL) versus capecitabine in postmenopausal women with HR+/ HER2– metastatic BC whose disease progressed on AIs. A secondary objective of the study was to evaluate the pharmacokinetics (PK) of PAL (125mg QD, 3 weeks on/1 week off) and EXE (25mg QD, continuously) when coadministered. This is the first study to investigate the drug-drug interaction (DDI) potential of the combination of PAL and the AI EXE. Methods: Patients (pts) randomized to the PAL+EXE arm of the PEARL Study in seven selected sites had the option of participating in the PK sub-study. Those who enrolled in the PK sub-study received EXE alone in a 7-day lead-in period immediately prior to Cycle 1 Day 1, when both drugs were coadministered on their standard dosing regimens. Sub-study pts were to have 2 pre-dose plasma PK samples drawn at steady-state (ss) during the lead-in period ("EXE Alone") for EXE determination, and 2 ss PK samples drawn for EXE and PAL determination (2 per analyte) during coadministration ("PAL+EXE"). Plasma concentrations of PAL and EXE were measured using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The withinpatient mean concentration of the PK samples which met ss acceptance criteria (WPM-Ctrough) for each analyte were generated for each treatment period as the input for DDI analyses. To assess the effect of coadministration of PAL on EXE PK, the WPM-Ctrough of EXE was compared within patients between the "PAL+EXE" (Test) and "EXE Alone" (Reference) treatment periods using a one-way analysis of variance (ANOVA) model with treatment as a fixed effect and patient as a random effect. To assess the effect of coadministration of EXE on PAL PK, the WPM-Ctrough of PAL was compared between the "PAL+EXE" period (Test) and historical data (Reference) using an ANOVA model. Analysis of covariance (ANCOVA) models were used to assess the impact of demographic differences between analysis populations in covariates known to impact PAL PK on the ANOVA model conclusions. Results: A total of 26 pts randomized to the PAL+EXE arm were enrolled in the PK sub-study and had PK samples analysed, of which 23 meet ss acceptance criteria. The ratio of the adjusted geometric means for EXE WPM-Ctrough was 106.9% (90%CI: 82.4-138.8), when EXE was administered with PAL, compared with its administration alone. Likewise, the models to assess potential for EXE to perpetrate DDI on PAL PK showed ratios of adjusted geometric means of 102.4% (90%CI: 82.0-127.9) and 111.6% (90%CI: 90.3137.8), when adjusted for covariates. Conclusion: The PK data indicate a lack of a clinically meaningful DDI between PAL and EXE when the 2 drugs are coadministered. Sponsor: GEICAM Citation Format: Martín M, Hoffman J, Ruiz-Borrego M, Muñoz M, Calvo L, Crownover P, García-Sáenz JA, Alba E, Wang D, Thallinger C, Stradella A, Montaño Á, Adamo B, Antolín S, Moreno-Antón F, Falo C, Ruiz V, Martín N, Caballero R, Carrasco E, Gil-Gil M. Evaluation of the drug interaction potential of palbociclib and exemestane – Results from the PEARL pharmacokinetic sub-Study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-23.

Test Dose Pharmacokinetics in Pediatric Patients Receiving Once-Daily IV Busulfan Conditioning for Hematopoietic Stem Cell Transplant: A Reliable Approach?

Intravenous (IV) busulfan test dose pharmacokinetics (PK) has been shown to accurately predict once-daily dose requirements and improve outcomes in adult transplant patients, but there are limited data to support this approach in children. Test doses of busulfan ∼0.8mg/kg were infused over 2 to 3hours, followed by serial sampling to 4-6hours postinfusion in pediatric hematopoietic stem cell transplant recipients (n=5). Once-daily busulfan doses were calculated based on a myelosuppressive area under the concentration-time curve (AUC) target of ∼3700 to 4000μmol·min/L and assumed dose-proportionality to the test dose. PK analysis was then repeated at full daily doses within 6-8 days of test dose administration. Plasma PK samples collected under test and full-dose conditions were analyzed using validated commercial assays and noncompartmental methods. In 4 out of 5 patients, PK estimates after once-daily IV busulfan administration differed in comparison to test dose estimates (AUC range -38.2% to +49.7%, clearance range -34.3% to +61.8%). Patients 1, 2, and 3 required increases in remaining daily busulfan doses to achieve AUC targets, and no adjustment was required in patient 4. Patient 5's AUC was 49.7% higher than expected, and he subsequently developed fatal sinusoidal obstruction syndrome. In our experience with pediatric patients, test dose PK failed to reliably predict daily dosing requirements with large discrepancies from predicted AUC targets. This article highlights the necessity for therapeutic drug monitoring of IV busulfan and inadvisability of relying solely on test-dose busulfan PK in pediatric patients. Furthermore, clinicians should consider strategies to expedite dose adjustments in real time.

Pharmacokinetics (PK) and Safety of Intravenous (IV) Brincidofovir (BCV) in Healthy Adult Subjects

BackgroundBCV is a lipid conjugate nucleotide that has shown rapid viral clearance in patients with adenovirus infection and improved survival in animal models of smallpox. In preclinical studies in rats, IV BCV dosed twice weekly for up to 29 days was not associated with gastrointestinal (GI), hematopoietic, hepatic, or renal toxicity. This study evaluated the safety and PK of IV BCV in healthy subjects.MethodsIn this double-blind study, subjects were randomized 3:1 to receive IV BCV or placebo in sequential single ascending dose cohorts (Table 1). Plasma PK samples were collected over 7 days and assayed by HPLC-MS. Plasma BCV PK parameters were determined by non-compartmental analysis and dose proportionality was assessed. Safety assessments were collected over 14 days.ResultsForty healthy male subjects (18–46 years, 83% White) were enrolled and completed the study. Plasma BCV Cmax and AUC∞ increased in proportion to dose (Table 1). AEs and alanine aminotransferase (ALT) elevations were dose- and infusion duration-related (Table 1). GI AEs were mild. All AEs and ALT elevations were transient and no serious AEs occurred.Table 1. IV BCV PK and SafetyBCV 10 mg 2 h Infusion (n = 6)BCV 25 mg 2 h Infusion (n = 6)BCV 50 mg 2 h Infusion (n = 9)BCV 50 mg 4 h Infusion (n = 9)Pooled Placebo (n = 10)Plasma BCV PKCmax (ng/mL)613 (25%)1412 (27%)2952 (19%)1586 (14%)NAAUC∞ (ng h/mL)1312 (26%)2889 (37%)5948 (19%)6570 (15%)NADrug-related AEsDiarrhea001 (11%)3 (33%)0Nausea0002 (22%)0Decreased appetite0001 (11%)Headache002 (22%)2 (22%)0Pain, phlebitis at infusion site001 (11%)00Elevated liver transaminasesa0001 (11%)0Cmax and AUC∞ presented as geometric mean (%CVb). aALT >2x ULN in 2 BCV 50 mg 4h infusion and 1 placebo subjects; 1 ALT elevation considered an AE.Conclusion Single doses of BCV 10–50 mg administered as a 2h IV infusion were well tolerated and not associated with significant clinical or laboratory abnormalities. BCV IV 10 mg and BCV IV 50 mg achieved geometric mean plasma BCV AUC∞ similar to and 4.5-fold, respectively, values achieved with BCV oral 100 mg tablets (Cmax = 251 ng/mL and AUC∞ = 1394 ng hours/mL). These data support evaluation of repeat dose administration in healthy subjects and virally-infected patients.Disclosures M. B. Wire, Chimerix: Employee and Shareholder, Salary. M. Morrison, Chimerix: Employee and Shareholder, Salary.M. Anderson, Chimerix: Employee and Shareholder, Salary. T. Arumugham, Chimerix: Employee and Shareholder, Salary. J. Dunn, Chimerix: Employee and Shareholder, Salary. O. Naderer, Chimerix: Employee and Shareholder, Salary.

Pharmacokinetics in Children with Sickle Cell Anemia Following Single Dose Versus Chronic Treatment with Hydroxyurea

Introduction: Hydroxyurea (HU) reduces vaso-occlusive complications, hospitalizations and transfusion requirements in children with sickle cell anemia (SCA; HbSS and HbSβ0thalassemia). Despite linear pharmacokinetics (PK) and apparent dose dependency for HU effect, there remains unexplained large inter-individual variability in drug response. To better understand this variability, we conducted a PK study of HU to assess: 1) effect of multiple dosing on PK of HU, and 2) explore the utility of using a single post-dose HU plasma concentration as a basis for therapeutic drug monitoring.Methods: Data from two prospective trials, "Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) and "Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease", were utilized for this analysis. Participants were children (≤18 years) with HgbSS and HbSβ0 thalassemia from 8 medical centers in the U.S. One cohort of patients had never been treated with HU and the second cohort had been treated with HU for at least ≥3 months at a stable dose. All participants received a single oral dose of HU and plasma PK samples were collected pre-dose, then at 15, 30, 45, and 60 minutes, and 1.5, 2, 4, 6, and 8 hours after study drug was administered under direct supervision. HU was quantitated from plasma and urine using a validated HPLC method. PK parameters for HU were determined from each patient using a standard model-independent approach (apparent Cmax observed from plasma concentration vs time data; AUC determined via a log-linear approach). PK parameters were compared using parametric (two-sample t-test) or nonparametric (Wilcoxon Rank Sum test) as appropriate based on normality of distribution. The coefficient of determination was used to determine the most predictive relationship between post-peak HU plasma concentrations and systemic exposure (AUC). The significance limit accepted for all statistical analyses was a = 0.05.Results: A complete plasma HU PK profile was obtained for 59 children. Participants with PK after the first dose (n=7, HUfirst) group received an average dose of 17.9 ±2.6 mg/Kg of HU whereas those with PK after multiple doses (n=52, HUchronic group) received an average dose of 23.8 ±5.1 mg/Kg (p < 0.01). Absorption of HU was rapid in both groups with a time to maximal plasma concentration (Tmax) of 0.9 ±0.58 hours in the HUfirst group and 0.8 ±0.47 hours in the HUchronic group (p=0.68). The mean dose/weight- normalized Cmax in the HUfirst group (2.0 mg/L per 1 mg/kg dose) was 1.4 fold higher than in the HUchronic (1.4 mg/L per 1 mg/kg) (p=0.03). A similar relationship was observed in mean dose/weight-normalized AUCinf, where the HUfirst group was 1.3 fold higher than in the HUchronic group (5.9 vs 4.6 mg/L*hr per 1 mg/kg; p=0.002). Weight-normalized mean apparent oral clearance (Cl/F) was significantly lower in the HUfirst cohort (0.17 L/hr/kg) as compared to the HUchronic (0.23 L/hr/kg) (p<0.001). The mean apparent volume of distribution (Vz/F) for the HUfirst cohort (0.52 L/kg) was not significantly different than that in the HUchronic cohort (0.61 L/kg) (Table 1). As suggested by data in Figure 1a, the apparent mean elimination half-life did not vary between the groups (e.g., 2.1 hr in HUfirst vs. 2.3 hr in HUchronic). Finally, between 45 minutes post-dose and through the last blood sampling point, the 4 hour post-dose concentration most accurately predicted the AUC of HU (r2= 0.78) (Figure 1b).Conclusion: Weight and dose-normalized PK parameters for HU suggest potential differences in the bioavailability of the drug with multiple dosing. This finding may contribute to the known wide variability in HU response. Finally, a single 4 hour post-dose HU plasma concentration adequately predicts systemic exposure (AUC) to HU and thus, could provide an approach to facilitate dose individualization / optimization. [Display omitted] [Display omitted] [Display omitted] DisclosuresLiem:National Institute of Health: Research Funding; Ann & Robert H. Lurie Children’s Hospital of Chicago: Research Funding; Ann & Robert H. Lurie Children’s Hospital of Chicago: Employment. Estepp:Daiichi Sankyo: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; National Institute of Health: Research Funding.

Abstract CT024: First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors

Abstract Background: DS-6051b is an orally available small molecule receptor tyrosine kinase inhibitor with high affinity for the ROS1 and NTRK receptors. Non-clinical pharmacology studies demonstrated activity of DS-6051b against tumors harboring ROS1 or NTRK fusion genes in cell culture and xenograft models. The objectives of this first in human (FIH) study are to assess safety and tolerability of DS-6051b in cancer subjects and identify the maximum tolerated dose (MTD) and the tentative RP2D. Pharmacokinetics (PK), QT prolongation, and tumor responses are also assessed in this study (Clinical Trial Information: NCT02279433). Methods: Dose escalation initially followed an accelerated titration design enrolling a single subject at each dose level, and then adopted the modified continuous reassessment method using a Bayesian logistic regression model and escalation with overdose control. Adult subjects with advanced solid tumors harboring ROS1 or NTRK1-3 fusion genes; or with neuroendocrine carcinoma; or with advanced solid tumors with tumor-induced pain are eligible for the study. DS-6051b is orally administered once-daily in 21-day cycles. Tumor assessments are performed every 3 cycles using RECIST 1.1 criteria. Plasma PK samples and time-matched ECG data are collected at multiple time points. Results: A total of 22 subjects have been enrolled at 50, 100, 200, 400, 800, and 1200 mg once daily (QD) dose levels. Enrolled population included 11 subjects with neuroendocrine carcinomas, 9 subjects with advanced solid tumors with tumor-induced pain, 1 subject with ROS1 fusion-positive NSCLC liver metastases, and 1 subject with leiomyosarcoma with a ROS1 point mutation. Two dose-limiting toxicities occurred in subjects who received 1200 mg QD, consisting of grade 3 transaminase elevations. The MTD is 800 mg QD. The most frequent (?20%) TEAEs were diarrhea, nausea, vomiting, dehydration, dizziness, dysgeusia, and fatigue, which were predominantly grade ?2. Cmax and AUC increased with the dose. Plasma terminal half-life was 11-24 hours. Steady state AUC was approximately 3 to 4-fold higher than that of Cycle 1 Day 1. Two subjects showed partial response: One with neuroendocrine carcinoma, who received 800 mg QD (33% decrease in tumor size), and one with ROS1 fusion-positive NSCLC liver metastases, who received 1200 mg QD (44% decrease in tumor size). Notably, the latter subject had progressed on crizotinib (best objective response stable disease) and ceritinib (progressive disease). Conclusions: DS-6051b has been well tolerated up to 800 mg QD in subjects with advanced solid tumors. The observed efficacy signals in two subjects with partial response warrant further evaluation. This trial is now selectively accruing subjects with ROS1 fusion-positive tumors. Citation Format: Kyriakos P. Papadopoulos, Erkut Borazanci, Daniel Von Hoff, Leena Gandhi, Amita Patnaik, Masaya Tachibana, Hamim Zahir, Roohi Gajee, Terri Goldberg, Giorgio Senaldi, Sai-Hong Ou. First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT024.

Abstract CT231: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor+ HER2-, advanced/metastatic breast cancer

Abstract Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of estrogen receptor (ER)+ breast cancer (BC). However, many patients (pts) relapse or develop resistance to available hormonal agents via estrogen-dependent and estrogen-independent mechanisms. Furthermore, mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen can mediate resistance. Therefore, next generation ER targeting agents with robust activity in both wild type and mutant ER tumors are needed. GDC-0810 is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader that induces tumor regression in tamoxifen-sensitive and resistant ER+ BC xenograft models. Methods: A phase I dose escalation study with 3+3 design was conducted in postmenopausal women with ER+ (HER2-) locally advanced or metastatic BC (progressing after ≥ 6 months on endocrine therapy; ≤ 2 prior chemotherapies) to determine the safety, pharmacokinetic (PK) and recommended phase II dose (RP2D) of GDC-0810. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples, CT scans, and when feasible, paired pre and on-study tumor biopsies were obtained. Results: Forty-one pts (median # of prior therapies: 4) were enrolled at 5 total daily dose levels (100-800 mg) and 2 regimens: once (QD) or twice (BID) daily given orally with and without fasting. Increases in GDC-0810 exposure were dose-dependent. The common treatment-related adverse events (AEs) were grade 1/2 diarrhea (63%), fatigue (46%), nausea (44%), flatulence (24%), vomiting (22%), and anemia (22%). Diarrhea was mostly Grade 1, intermittent in nature, and manageable with dose modifications, dietary adjustments, and treatment with PRN loperamide. There was one dose limiting toxicity of Grade 3 diarrhea at 800 mg QD (fasting). 600 mg QD given with food was determined to be single agent R2PD. Complete/near complete (&amp;gt;90%) suppression of FES uptake was observed in 90% of pts with FES-PET scans, including 5 pts with known ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-study biopsies. At a median follow-up of 8 months 13 of 31 (42%) pts on study achieved stable disease &amp;gt; 6 months while 10 pts remain active on study with followup &amp;lt; 6 months. Conclusions: GDC-0810 has a tolerable safety profile to date, with predictable PK, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER+ BC. A phase IIa study of GDC-0810 is ongoing in postmenopausal women with ER+ (HER2-) advanced or metastatic BC who have been previously treated with an aromatase inhibitor, including tumors with ESR1 mutations (clinicaltrials.gov NCT01823835). Citation Format: Maura Dickler, Aditya Bardia, Ingrid Mayer, Eric Winer, Peter Rix, Jeff Hager, Meng Chen, Iris Chan, Edna Chow-Maneval, Carlos Arteaga, Jose Baselga. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor+ HER2-, advanced/metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT231. doi:10.1158/1538-7445.AM2015-CT231

Abstract A252: A phase 1 study of ARRY-382, an oral inhibitor of colony-stimulating factor-1 receptor (CSF1R), in patients with advanced or metastatic cancers.

Abstract Introduction: Within the tumor microenvironment, CSF1R signaling is thought to play an important role in recruitment and differentiation of tumor-associated macrophages and osteoclasts, promoting disease progression through suppression of anti-tumor immune response, promotion of angiogenesis, tumor cell metastasis and tumor-induced osteolysis. ARRY-382 is a potent, highly selective, oral inhibitor of CSF1R. This Phase 1 dose-escalation study was designed to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ARRY-382 in patients (pts) with advanced or metastatic cancers refractory to standard treatment. Methods: Pts received ARRY-382 orally once daily (QD) in 28-day cycles. Study design included an initial accelerated titration phase, followed by 3+3 dose escalation and an expansion phase. Safety was assessed by adverse events (AEs), ECGs, clinical laboratory tests, physical exams and vital signs. PK parameters were estimated based on serial plasma PK samples. Levels of pERK in pt monocytes stimulated with CSF1 ex vivo, circulating CD14dim/CD16+ nonclassical monocytes (NCM) and CSF1 were evaluated as markers of CSF1R inhibition. Urinary collagen type 1 cross-linked N[[Unable to Display Character: &amp;#8209;]]telopeptide (NTX) was evaluated as a marker of bone turnover. Results: Twenty-six pts received ARRY-382 at doses ranging from 25 to 500 mg QD. The MTD of ARRY-382 was 400 mg QD. Dose-limiting toxicities were increased creatine kinase (CK), increased AST and pyrexia (1 pt each, all Grade 3). The most common drug-related AEs were fatigue (42%), increased CK (27%), nausea (23%), decreased appetite (15%) and vomiting (12%). Grade 3/4 AEs in &amp;gt;1 pt were increased CK (23%), pneumonia (15%), anemia (8%) and vomiting (8%). Increases in ARRY-382 exposure were approximately dose proportional. At the MTD, a Cmax of 3.06 µg/mL was achieved with a Ctrough &amp;gt; 1 µg/mL after repeated dosing. Doses ≥ 200 mg QD resulted in &amp;gt; 80% mean reduction from Baseline in monocyte pERK, consistent with exposures above the ARRY-382 IC50 value. The PD activity of ARRY-382 was consistent with CSF1R inhibition. Reductions in NCM were observed at doses ≥ 200 mg QD, with a 96% mean decrease from Baseline observed at the MTD. Reductions in urinary NTX were observed at doses ≥ 50 mg QD. Five of 7 pts with elevated urinary NTX at Baseline experienced reductions to within the normal range in the first cycle, including 3 pts with bone metastases. Increases in CSF1 appeared dose-dependent with ∼28-fold maximal increase from Baseline observed at the MTD in the first cycle. No objective responses were observed, although 4 pts (15%) experienced stable disease which lasted &amp;gt; 3 months for 2 pts. Conclusions: ARRY-382 was generally well tolerated in pts with advanced or metastatic cancers. Exposure and PD activity of ARRY[[Unable to Display Character: &amp;#8209;]]382 indicate that CSF1R was significantly inhibited at tolerated doses. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A252. Citation Format: Johanna C. Bendell, Anthony W. Tolcher, Suzanne F. Jones, Muralidhar Beeram, Jeffrey R. Infante, Paul Larsen, Kevin Rasor, Jennifer E. Garrus, Jinfang Li, P. Louann Cable, Christine Eberhardt, Jennifer Schreiber, Selena Rush, Kenneth W. Wood, Emma Barrett, Amita Patnaik. A phase 1 study of ARRY-382, an oral inhibitor of colony-stimulating factor-1 receptor (CSF1R), in patients with advanced or metastatic cancers. [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 A252.

Results from a phase I study of enzalutamide in combination with docetaxel in men with prostate cancer.

5066 Background: Enzalutamide (ENZA) is a novel androgen receptor (AR) inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (DOC). DOC also prolongs survival in mCRPC and also appears to have anti-tumor effects mediated through the androgen-receptor axis, providing a compelling rationale for combining the two agents. CYP3A4 plays a role in DOC clearance and is induced by ENZA. We therefore conducted a phase I study to explore the PK and safety profiles of this combination. Methods: This study (NCT01565928) evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: Twenty-two pts were enrolled, 4 did not receive 2 full doses of DOC. As of 21 Sept 2012, preliminary PK and C1 and C2 safety data were available from 15 pts. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC&lt;1000/mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone.Final PK and updated tolerability and efficacy data beyond Cycle 2 will be presented. Conclusions: In mCRPC pts, ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.

A phase I clinical trial of veliparib and temozolomide in children with recurrent central nervous system tumors: A Pediatric Brain Tumor Consortium report.

2036 Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to: 1) estimate the maximum tolerated doses (MTD) or recommended phase II doses (RP2D) of veliparib and TMZ using the Continual Reassessment Method; 2) describe the toxicities of this regimen; and 3) evaluate plasma pharmacokinetics (PK) and peripheral blood mononuclear cell (PBMC) PARP inhibition after veliparib treatment. Methods: TMZ was given once daily and veliparib twice daily for 5 days, every 28 days. Five veliparib/TMZ dose levels were studied: 20/180; 15/180; 15/150; 20/135; and 25/135 mg/m2/dose, respectively. Baseline and serial veliparib PK samples were obtained on days 1 and 4. PBMC poly(ADP-ribose) (PAR) levels were also measured using an ELISA assay. A total of 12 subjects were enrolled at the RP2D. Results: Thirty-one patients (29 evaluable) with a median age of 7.0 years (range 1.3-19.8) were enrolled. Dose-limiting toxicities (DLT) included grade 4 neutropenia and thrombocytopenia at the 20/180 and 15/180 mg/m2/dose levels. Based on the toxicity profile, PKs and PBMC PAR results, the RP2D were veliparib, 25 mg/m2 BID, and TMZ, 135 mg/m2/day, for 5 days every 28 days. No objective responses were observed, although 4 subjects had SD &gt; 6 months duration, including one patient each with glioblastoma multiforme, anaplastic ependymoma, pilocytic astrocytoma, and optic pathway glioma. At the veliparib RP2D, the PK parameters included: Cmax, 1.2 ± 0.7 µM; AUC0-12 hr, 1.53 ± 0.61 µg•hr/mL; and Cl/F, 173 ± ml/min/m2. PARP inhibition was observed in PBMC but did not correlate with veliparib dose levels. Conclusions: The combination of veliparib and TMZ was well tolerated in children with recurrent CNS tumors. Veliparib PK parameters at RP2D are similar to those in adults. PBMC PARP inhibition did not correlate with veliparib dose levels, perhaps due to the smaller number of patients at each dose level and the technical limitations of specimen collection/processing and the ELISA assay. A phase II trial of veliparib/TMZ in children with recurrent primary brain tumors is planned. Clinical trial information: NCT00946335.

Plecanatide, an Oral Guanylate Cyclase C Agonist Acting Locally in the Gastrointestinal Tract, Is Safe and Well-Tolerated in Single Doses

Plecanatide, an analogue of uroguanylin, activates the guanylate cyclase C (GC-C) receptor found on the GI mucosal epithelial cells, leading to secretion of fluid, facilitating bowel movements. Plecanatide is being investigated as a potential treatment for constipating GI disorders. The aim of this investigation was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single doses of plecanatide in healthy volunteers. A total of 72 healthy volunteers at a single site were randomized in 9 cohorts to receive oral plecanatide or placebo from 0.1 to 48.6 mg. Plasma PK samples were collected pre-dose and post-dose. PD assessments included time to first stool, stool frequency, and stool consistency using the Bristol Stool Form Scale. All adverse events were documented. Plecanatide was safe and well-tolerated at all dose levels. A total of 17 of 71 subjects (23.9%) reported 25 treatment-emergent adverse events (TEAEs) during the study. The number of TEAEs reported by subjects who received plecanatide or placebo was comparable (24.5 vs. 22.2%, respectively). There were no dose-related increases in TEAEs or any SAEs reported. No measurable systemic absorption of oral plecanatide was observed at any of the oral doses studied, utilizing an assay sensitive down to 1 ng/mL. Plecanatide, an oral GC-C agonist, acting locally within the GI tract without measurable systemic exposure, was safe and well-tolerated in single doses up to 48.6 mg. The study was not powered for statistical analyses, but trends in PD parameters supported continued clinical development.