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Characterize the population PK and exposure–response (ER) relationships of selinexor in patients with diffuse large B-cell lymphoma (DLBCL) (efficacy endpoints) or other non-Hodgkin’s lymphoma (NHL) patients (safety endpoints) to determine the optimal dose in patients with DLBCL. This work included patients from seven clinical studies, with 800 patients for PK, 175 patients for efficacy and 322 patients for safety analyses. Logistic regression models and Cox-regression models were used for binary and time-to-event endpoints, respectively. Model-based simulations were performed to justify dose based on balance between efficacy and safety outcome. Selinexor pharmacokinetics were well-described by a two-compartment model with body weight as a significant covariate on clearance and central volume of distribution and gender on clearance. Overall response rate (ORR) in patients with DLBCL increased with day 1 Cmax and decreased in patients with higher baseline tumor size (p

Ivosidenib is a once daily (q.d.), orally available, potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for treatment of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and intensive chemotherapy ineligible AML with a susceptible IDH1 mutation. Population pharmacokinetics (PKs; N = 253), exposure‐response (efficacy [n = 201] and safety [n = 253]), and concentration‐corrected electrocardiogram QT interval (QTc; n = 171) analyses were performed using phase I data (100 mg twice daily and 300–1200 mg q.d.). Ivosidenib disposition was well‐described by a two‐compartment PK model with first‐order absorption and elimination. Between‐subject variability was moderate for PK parameters. Intrinsic factors did not affect ivosidenib PKs. Moderate/strong CYP3A4 inhibitors increased the area under the plasma ivosidenib concentration‐time curve at steady state (AUCss) by 60%. Efficacy responders and nonresponders had similar ivosidenib exposures. Based on AUCss, there was no apparent relationship between ivosidenib exposure and efficacy or adverse events. The plasma ivosidenib concentration‐QT analysis showed a mean change in QTc using Fridericia’s method (ΔQTcF) of 17.2 msec at the approved 500 mg q.d. dose. Because of the direct association between ivosidenib exposure and QTcF, patients should have their electrocardiograms and electrolytes monitored, and comedications that increase ivosidenib exposure or prolong the QT interval should be avoided. These model‐based analyses quantitatively provide a framework to describe the relationship among ivosidenib dose, exposure, and clinical end points. With precautions for QTc prolongation, the exposure‐response analyses support the 500 mg q.d. dose in patients with AML with a susceptible IDH1 mutation.

Trastuzumab deruxtecan (DS-8201) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate with a novel enzyme-cleavable linker, a topoisomerase I inhibitor payload, and a drug-to-antibody ratio of ≈ 8. We have characterized the population pharmacokinetics (PK) of trastuzumab deruxtecan and released drug (topoisomerase I inhibitor) in patients with HER2-positive breast cancer or other solid tumor malignancies. This analysis includes pooled data from five clinical studies with 639 patients. Trastuzumab deruxtecan doses ranged from 0.8 to 8.0 mg/kg every 3 weeks. Serum concentrations of trastuzumab deruxtecan and released drug were analyzed using a sequential two-step approach, with the nonlinear mixed-effects modeling methods. Covariate assessment was based upon stepwise forward-addition and backward-elimination process, followed by both univariate and multivariate analysis quantifying their impact on steady-state exposure of trastuzumab deruxtecan and released drug. A two-compartment model with linear elimination best described PK profiles of intact trastuzumab deruxtecan, while a one-compartment model with time-varying release-rate constant and linear elimination described released-drug PK profiles. Statistically significant covariates (country, tumor size, sex, formulation, age, body weight, albumin, total bilirubin, and aspartate aminotransferase) resulted in < 20% change in steady-state area under the concentration-time curve of trastuzumab deruxtecan and released drug, except for increased body weight (95th percentile, 86 kg) and decreased albumin (5th percentile, 31 g/L). Analysis of patients stratified by country, race, renal function, and hepatic function found no clinically meaningful differences in steady-state exposure of intact trastuzumab deruxtecan or released drug. Overall, results suggest that no dose adjustment based on tested covariates or in specific patient populations is warranted.

Background The iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study. Methods Patients aged

The aims of this work were to characterize ipatasertib exposure–response (E‐R) relationships in a phase II study and to quantitatively assess benefit‐risk using a clinical utility index approach to support ipatasertib phase III dose selection in patients with metastatic castration‐resistant prostate cancer. Logistic regression and Cox proportional‐hazards models characterized E‐R relationships for safety and efficacy endpoints, respectively. Exposure metrics with and without considering dose interruptions/reductions (modifications) were tested in the E‐R models. Despite a steeper E‐R relationship when accounting for dose modifications, similar dose‐response projections were generated. The clinical utility index analysis assessed important attributes, weights, and clinically meaningful cutoff/tradeoff values based on predefined minimal, target, and optimistic product profiles. Ipatasertib 400 mg daily, showing the highest probability of achieving the minimal product profiles and better benefit‐risk balance than other doses (200–500 mg daily), was selected for further development in metastatic castration‐resistant prostate cancer.

Background DS-8201a is a HER2-targeting antibody-drug conjugate with a high drug-to-antibody ratio of 7 to 8. A novel cleavable peptide-based linker joins the humanized HER2 antibody to a topoisomerase I inhibitor payload. In an ongoing phase 1 study (J101), DS-8201a was tested at doses of 0.8 to 8.0 mg/kg and tolerated with no predefined dose-limiting toxicities; 5.4 and 6.4 mg/kg doses were recommended for expansion. Subjects with HER2-positive breast cancer (BC) treated at these 2 doses had an overall response rate (ORR) of 54.5% (54/99). The phase 2 DESTINY-BREAST01 trial began enrollment in August 2017 with a dose-finding stage, including 5.4, 6.4, and 7.4 mg/kg. To determine the recommended dose for continued development in HER2-positive BC, a comprehensive analysis of observed data and exposure-response (ER) from both trials was performed. Methods A population-PK (PPK) model was developed using data from all subjects with available concentration data. Individual exposure parameters (Cmin, Cmax, AUC) were estimated from the PPK model and used in the ER analyses. ER analyses were conducted using logistic regression or Cox proportional hazard modeling for efficacy (ORR, duration of response, and PFS) and safety (nausea, diarrhea, left ventricular ejection fraction, neutropenia, anemia, thrombocytopenia, dose reductions due to TEAE, discontinuations due to TEAE, and interstitial lung disease [ILD]). Results As of 18 Apr 2018, in J101, there are 111 HER2-positive BC subjects treated at 5.4- or 6.4-mg/kg doses. As of 25 Apr 2018, DESTINY-BREAST01 enrolled 65 HER2-positive BC subjects across 3 doses (5.4, 6.4, and 7.4 mg/kg). Confirmed ORRs in J101 for HER2-positive BC subjects at 5.4 and 6.4 mg/kg were 52.6% (20/38) and 55.7% (34/61), respectively. In J101, AEs Grade ≥3 were reported in 35.6% (16/45) at 5.4 mg/kg and 50% (33/66) at 6.4 mg/kg. The relationship between DS-8201a intact Cmin and ORR was statistically significant (P=0.035). There was a trend of improved PFS with higher intact exposures (P=0.238). Statistically significant relationships were observed between exposures and the following safety endpoints based on logistic regression: neutropenia (any grade, P=0.003; Grade ≥3, P=0.037), anemia (any grade, P=0.002; Grade ≥3, P Conclusions In J101, DS-8201a demonstrated an acceptable safety profile and high response rates in HER2-positive BC at both doses. The ER analyses showed a statistically significant relationship between exposures and ORR (with a trend for higher PFS at higher doses), as well as exposures and risk of key adverse events. Considering the predicted benefit/risk profile, 5.4 mg/kg is the recommended dose for continued development of DS-8201a in the DESTINY-BREAST01 trial and in phase 3 clinical trials in HER2-positive BC. Citation Format: Tamura K, Modi S, Tsurutani J, Takahashi S, Krop IE, Iwata H, Wada R, Yin O, Garimella T, Sugihara M, Zhang L, Lee C, Yver A, Baselga J. Dose justification for DS-8201a, a HER2-targeted antibody-drug conjugate, for HER2-positive breast cancer: Observed clinical data and exposure-response analyses [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-10.

Adding pertuzumab to trastuzumab (both monoclonal antibodies targeting human epidermal growth factor receptor 2 [HER2]) has proven survival benefits when combined with chemotherapy for patients with HER2‐positive breast cancer. The combination of pertuzumab and trastuzumab together in 1 vial for subcutaneous (SC) administration is being developed as a ready‐to‐use formulation to reduce the treatment burden on patients while improving healthcare efficiency. An open‐label, 2‐part, phase Ib dose‐finding study ({"type":"clinical-trial","attrs":{"text":"NCT02738970","term_id":"NCT02738970"}}NCT02738970) was undertaken in healthy male volunteers (part 1) and female patients with HER2‐postive early breast cancer who had completed standard (neo)adjuvant treatment (part 2). This study aimed to identify an SC pertuzumab dose given with recombinant human hyaluronidase that results in comparable exposure to that of the intravenous (IV) pertuzumab dose, based on pertuzumab serum trough concentration and area under the serum concentration–time curve. Pharmacokinetics (PK), safety, and tolerability of a single dose of SC pertuzumab given alone or in a fixed‐dose combination (comixed or coformulated) with trastuzumab were also assessed. A maintenance dose of 600 mg for SC pertuzumab resulted in an equivalent exposure to that of IV pertuzumab, and no new safety signals were identified for SC pertuzumab or trastuzumab. A loading dose of 1200 mg for SC pertuzumab was selected based on approximate dose proportionality. The PK and safety results support further development of a fixed‐dose coformulation combination of pertuzumab and trastuzumab for SC administration, which will be investigated in an upcoming phase III trial in patients with HER2‐positive early breast cancer.

Background: A fixed-dose combination (FDC) of subcutaneous (SC) pertuzumab (F. Hoffmann-La Roche Ltd, Basel, Switzerland) + SC trastuzumab (F. Hoffmann-La Roche Ltd) is being developed to reduce the treatment burden on patients while improving treatment facility efficiency. This phase Ib dose-finding study (NCT02738970) aimed to identify the SC pertuzumab dose that is comparable to the intravenous (IV) dose, based on serum trough concentrations (Ctrough) and area under the concentration–time curve (AUC) when administered with or without SC trastuzumab. Methods: This two-part study consisted of SC pertuzumab dose determination in healthy male volunteers (HMVs) (Part 1) and a subsequent SC pertuzumab dose confirmation in patients with early breast cancer (EBC) (Part 2). Part 1 of the study was comprised of 48 HMVs who received various SC pertuzumab doses (400–1200 mg) or the standard IV dose (420 mg), administered alone or co-mixed with SC trastuzumab 600 mg. Non-compartmental and statistical methods were used to test the pharmacokinetic (PK) interaction between SC pertuzumab and SC trastuzumab when administered with recombinant human hyaluronidase, a permeation enhancer. Two population PK (popPK) models were built to estimate PK parameters and PK variability. Model 1 used IV/SC PK data from Part 1 of the current study only. Model 2 used Part 1 SC PK data and PK parameters from the published IV pertuzumab popPK model (Garg A, et al. Cancer Chemother Pharmacol 2014; 74: 819–829). Each popPK model was used to simulate 400 phase III clinical trials. Per simulated trial, the geometric mean ratio (GMR) of Cycle 8 Ctrough at steady state and AUC at steady state for SC/IV were calculated. The percentage of trials with the 5th percentile confidence interval of the GMR above 0.8 was tabulated. Results: In Part 1 of the study, there was no impact on pertuzumab or trastuzumab PK from co-mixing SC trastuzumab with SC pertuzumab. The absolute bioavailability of SC pertuzumab in HMVs was approximately 70–80%, with a median time to reach maximum concentrations of 4–5 days. Clinical trial simulations indicated that an SC pertuzumab dose of 600 mg will achieve the target Ctrough and AUC SC/IV GMRs > 99% of the time. Results were consistent between the models. Safety data supported the selection of an SC pertuzumab maintenance dose of 600 mg. The 600 mg SC pertuzumab dose determined in HMVs was confirmed in Part 2 of the study in patients with EBC. Conclusions: These data support the development of an SC pertuzumab + SC trastuzumab FDC product. Citation Format: Kirschbrown WP, Wynne C, Kagedal M, Wada R, Li H, Nijem I, Badovinac Crnjevic T, Heeson S, Eng-Wong J, Garg A. A phase Ib dose-finding study of subcutaneous pertuzumab in combination with subcutaneous trastuzumab in healthy male volunteers and female patients with early breast cancer [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 P5-20-07.

To gain a better understanding of the impact of dose and other prognostic factors on safety and efficacy of docetaxel in second-line non-small-cell lung cancer patients.A model-based meta-analysis (MBMA) of a published docetaxel monotherapy data in 6085 second-line non-small-cell lung cancer patients from 46 trials was conducted.The logit of grade 3/4 neutropenia incidence was a linear function of dose, with a 5% increase in the odds of neutropenia per mg/m(2) increase in dose [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.04-1.06], and a Japanese study effect (OR 17.1, 95% CI 6.05-48.4). The logit of overall response rate (ORR) was a linear function of cumulative dose (0.4% increase in the odds of response per mg/m(2) increase; OR 1.004, 95% CI 1.001-1.008) and median population age (OR 1.08 per year, 95% CI 1.02-1.15). A Japanese study effect was identified for overall survival (OS) in addition to prognostic factors identified by a previous meta-analysis.This current MBMA identified docetaxel dose-response relationships for both neutropenia and ORR, an effect of age on ORR, and Japanese study effects on both neutropenia and OS.

Introduction KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602). Study 20120106 was a 2-part Phase 1 dose-exploration/dose-expansion study of KRT-232 in patients with advanced solid tumors or multiple myeloma (Gluck et al. Invest New Drugs in press; NCT01723020). Study 20120234 was a Phase 1b study evaluating KRT-232 alone and combined with trametinib, in patients with relapsed/refractory AML (Erba et al. Blood Adv 2019; NCT02016729). This population PK analysis quantified the KRT-232 PK time-course and variability, and the contribution of subject covariates to PK variability, using data from Amgen studies 20120106 and 20120234. Methods Study 20120106: Subjects received KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6). Doses were administered once daily (QD) for 7 days in 21-day cycles. PK sampling occurred on Cycle 1 days 1 and 7, at nominal sampling times pre-dose and 1, 3, 5, 7, and 24 h post-dose, and 72 h after the day 7 dose. Study 20120234: Subjects received KRT-232 doses of 60 mg (n=14; n=10 co-administered with 2 mg trametinib once daily, n=4 as single agent), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). KRT-232 was administered QD for 7 days in 14-day cycles. PK sampling occurred on days 1 and 7, at nominal sampling times pre-dose and 1, 2, 4, 6, and 24 h post-dose, and 72 h after the day 7 dose. Population PK modeling was conducted using the first-order conditional estimation (FOCE-I) method in NONMEM® 7.3. Model covariates were selected using a forward addition and backward elimination method, based on significance levels of p Results KRT-232 plasma concentrations from 141 subjects with 1783 samples could be described by a two-compartment model with first-order absorption. Apparent oral clearance (CL/F) of KRT-232 was estimated to be 24.9 L/h (CV 61.5%) in subjects with solid tumors. The apparent oral central volume (Vc/F) and peripheral volume (Vp/F) were 62.9 L and 333 L, respectively. The terminal half-life was 17.1 hr. The prediction-corrected visual predictive check in Figure A suggested that the median, 5th and 95th percentiles of the measured plasma KRT-232 concentrations aligned with modeled concentrations for 24 h post-dose; the modeled variability was larger than the measured variability at 72 h post-dose. Residual diagnostics confirmed an adequate model fit. Apparent oral clearance did not change with dose over the studied dose range of 15-480 mg QD, indicating AUC increases were dose-proportional (Figure B). Relative to solid tumor subjects, AML subjects had 61.6% greater steady-state AUC (Figure C). A subject with decreased albumin at the 5th percentile (30 g/L) was modeled to have a 47.7% increase in AUC and an 87.2% increase in Cmin at steady state, relative to a typical subject with a median albumin level of 39 g/L. Trametinib and multiple myeloma model covariates had confidence intervals overlapping the line of unity. Covariates weight, sex, age, race and ethnicity did not affect CL/F or Vc/F. No effects of renal parameters, hepatic parameters, or ECOG performance status on CL/F were detected. Conclusion A two-compartment linear PK model with first-order absorption adequately described KRT-232 PK. Apparent oral clearance did not change with dose, indicating AUC increases were dose-proportional. AML subjects and subjects with decreased albumin had greater steady-state AUC values relative to subjects with solid tumors and normal albumin levels, although the magnitude of these effects were less than 2-fold. Disclosures Ma: Certara Strategic Consulting: Consultancy, Employment. Wada:Certara Strategic Consulting: Consultancy, Employment. Allard:Certara Strategic Consulting: Consultancy, Employment. Slatter:Kartos Therapeutics: Employment, Equity Ownership. OffLabel Disclosure: KRT-232 (formerly AMG 232) is an investigational small molecule MDM2 inhibitor.

Inhibition of platelet aggregation (IPA) has been a drug development target in acute coronary syndrome (ACS) for almost 2 decades. The relationship between IPA and cardiovascular (CV) events has not been quantified. Cardiovascular (non fatal myocardial infarction, death) and major bleeding events were extracted from phase 2 or 3 randomized, double-blind trials that evaluated oral and intravenous glycoprotein 2b/3a (GP2b/3a) antagonists and thienopyridines. IPA was extracted from different sources that studied a similar regimen in a similar population. Events were correlated to IPA using a linear relative-risk mixed-effects model. Covariates included type of drug, mean age, gender percentage, and ADP. Clinical trial simulations were conducted to evaluate the relationship between IPA and the likelihood of observing a CV event in a 6-month end point trial. Data from 81918 subjects in 20 studies were extracted from the literature. To achieve a 20% relative reduction in CV events would require a further 77% (56%-100%) absolute increase in IPA for IV GP2b/3a antagonists or a further 27%(20%-41%) absolute increase for thienopyridines. CV risk reduction was less in studies with older subjects and greater in studies with greater percentages of male subjects. Assuming a 3% major bleeding rate in the control group, these drugs had a 1% increase in absolute risk as absolute platelet inhibition increases by 60% (range, 40%-80%). This relationship in intrinsic bleeding may be different in different population subtypes. Assuming a 12% event rate, a 6-month active-controlled thienopyridine trial with 3000 subjects could detect a relationship between CV events and IPA with 80% likelihood. Target IPA increases in ACS are an absolute increase of 80% for IV GP2b/3a antagonists and 30% for thienopyridines. Quantitative models using literature data on IPA and CV events can be used to select dose regimens in early stages of drug development.

Background Pacritinib (SB1518) is a novel oral JAK2-FLT3 inhibitor. To date, once-daily (QD) dosing of pacritinib has been evaluated in two pharmacokinetic studies in healthy volunteers (n = 42) and in two phase 1/2 clinical trials in patients with advanced myeloid malignancies (n = 129). Due to less-than-proportional increase in systemic exposure with dose, administration of QD doses higher than 400 mg does not appreciably increase systemic exposure of pacritinib. Hence, the twice-daily (BID) regimen was conceived as an alternate dosing regimen to achieve higher systemic pacritinib exposure and potentially enhance clinical response of pacritinib. Aims Characterize exposure-response relationship of pacritinib in early stage clinical development. Methods Two pharmacokinetic (PK) studies were conducted in healthy volunteers to assess the inter- and intra-individual PK variability and the effect of food on the PK of pacritinib. Two Phase 1/2 trials were also undertaken to characterize the population pharmacokinetics, safety, and efficacy of pacritinib in patients with advanced myeloid malignancies following oral administration of 100-600 mg QD. Safety (i.e., incidence and severity of key AEs including GI, thrombocytopenia and anemia) and efficacy (i.e., spleen size reduction) of pacritinib were assessed in patients. Based on the safety, tolerability and anti-tumor activity observed in the completed Phase 1/2 trials, the 400 mg QD regimen of pacritinib was selected for further clinical development in MF. A total of 65 patients received 400 mg QD regimen in Phase 2 trials for pacritinib. To construct the exposure-response relationship following QD dosing of pacritinib, patients with pharmacokinetic exposure data from completed Phase 1/2 trials (n = 129) were divided into quartiles [Q1-Q4] based on their model predicted area under the curve at steady-state (AUCss). For each exposure quartile, the mean reduction in spleen size was determined. In addition, exposure-response analysis on key safety parameters was similarly performed by comparing AE distributions across exposure quartiles. The key PK parameters were simulated for the 200 mg BID regimen and distribution of patients that fell into QD regimen-defined exposure quartiles was determined. Results PK simulation data indicated that administration of the 200 mg BID regimen is likely to result in a mean systemic exposure that is 41% higher relative to that of the 400 mg QD regimen. This is thought to be due to higher drug accumulation and reduced effect of saturable absorption processes on oral pacritinib bioavailability with the BID regimen. Evaluation of the efficacy time-course by exposure quartile revealed that patients in the highest quartile (Q4) exhibited the highest maximal response as well as the most durable clinical response over time relative to those that fell in the lower exposure quartiles (Figure 1). Whereas approximately 25% of patients from the completed Phase 1/2 trials fell in Q4 exposure zone with the 400 mg QD regimen, approximately 48% of patients on the 200 mg BID regimen are projected to fall in this exposure zone or higher. Moreover, assessment of key AEs including GI, anemia, and thrombocytopenia AEs by the exposure quartile, showed that these AEs were not worse with higher systemic exposure of pacritinib. Conclusions Together, the exposure-safety and exposure-efficacy analyses support the potential utility of the 200 mg BID regimen of pacritinib in addition to the 400 mg QD regimen for the clinical development of pacritinib for myelofibrosis as well as other indications such as FLT3 mutated AML. The higher proportion of patients expected to achieve the Q4 exposure levels with the 200 mg BID regimen is predicted to correlate with higher splenic response rates relative to the 400 mg QD regimen. There was no significant exposure-response relationship on key AEs including GI, anemia and thrombocytopenia AEs. The lower local concentration of pacritinib in the GI tract with BID regimen may potentially decrease the incidence of GI adverse events such as diarrhea. Disclosures: Al-Fayoumi: Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc.: Employment. Li:Cell Therapeutics, Inc: Consultancy. Dean:Cell Therapeutics, Inc: Employment.