Search

438 Background: HER2 overexpression has been found in invasive UC, suggesting a role for HER2 in disease progression and prognosis (Kruger Int J Oncol 2002). T-DXd is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload. Preclinical models showed that T-DXd combined with an anti-PD-1 antibody had greater efficacy versus either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, 2-part, open-label, multicenter study of T-DXd in combination with nivo in pts with HER2-expressing advanced/metastatic UC (NCT03523572). Methods: Pts aged ≥18 y had pathologically documented advanced/metastatic UC with centrally confirmed HER2 expression by immunohistochemistry (IHC) 2+/3+ (cohort 3; high expression) or IHC 1+ (cohort 4; low expression) who received prior platinum-based therapy with documented progression. Pts received T-DXd at 5.4 mg/kg and nivo 360 mg IV every 3 weeks (recommended dose for expansion). The primary endpoint was confirmed objective response rate (ORR) assessed by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints (assessed by ICR) included duration of response (DOR), progression-free survival (PFS), time to response (TTR), and overall survival (OS), and safety. Results: At the primary analysis data cutoff (July 22, 2021), 34 pts (cohort 3, n = 30; cohort 4, n = 4) received T-DXd and nivo. Median age was 70.9 y (range, 41.4-80.5), 88.2% were male, 61.8% received ≥1 prior regimens for locally advanced/metastatic disease, and 26.5% had a history of liver metastases. Median treatment duration (all pts) was 3.2 mo (range, 1-21) for T-DXd and 4.1 mo (range, 1-20) for nivo. In cohort 3, ORR by ICR was 36.7% (95% CI, 19.9-56.1; complete response, 13.3%; partial response, 23.3%), median DOR was 13.1 mo (95% CI, 4.1- NE), median PFS was 6.9 mo (95% CI, 2.7-14.4), median TTR was 1.9 mo (range 1.2-6.9), and median OS was 11.0 mo (95% CI, 7.2-NE). Grade (G) ≥3 treatment-emergent adverse events (TEAEs) occurred in 73.5% of all pts (44.1% related to T-DXd; 26.5% related to nivo). TEAEs leading to drug discontinuation occurred in 32.4% of all pts (17.6% related to T-DXd; 23.5% related to nivo). The most common any-grade TEAEs were nausea (73.5%), fatigue (52.9%), and vomiting (44.1%). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 23.5% of all pts (2 G1; 4 G2; 1 G3; 1 G5). Conclusions: T-DXd combined with nivo showed antitumor activity in pts with high-expressing HER2 UC. The safety profile was consistent with prior studies for T-DXd in other indications and nivo monotherapy in UC pts. Adjudicated ILD/pneumonitis was within the range observed in other T-DXd monotherapy studies. Ongoing clinical trials are further exploring T-DXd in this population. Clinical trial information: NCT03523572.

TPS183 Background: Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen that is highly expressed in prostate cancer. AMG 509 is a potent bispecific XmAb 2+1 immune therapy designed to direct T effector cells to STEAP1-expressing cells. AMG 509 contains two identical humanized anti-STEAP1 Fab domains that bind STEAP1-expressing cells, an anti-CD3 scFv domain that binds T cells, and an Fc domain, engineered to lack effector function, that extends serum half-life. In preclinical studies, AMG 509 induced potent and specific T-cell-mediated lysis of STEAP1-expressing cancer models. Methods: This open-label, phase 1, first-in-human study will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 509 in patients with relapsed/refractory mCRPC. The dose exploration phase (n=40) will estimate the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) using a Bayesian logistic regression model. The dose expansion phase (n=30) will confirm safety, PK, and pharmacodynamics at the MTD or RP2D and collect further safety, efficacy, and biomarker data. Efficacy will be assessed by prostate-specific antigen response, circulating tumor cell response, and objective tumor response per RECIST 1.1 with Prostate Cancer Working Group 3 modifications. Key inclusion criteria: men ≥18 years with histologically/cytologically confirmed mCRPC who are refractory to novel hormonal therapy (e.g., abiraterone and/or enzalutamide) and have failed 1–2 taxane regimens or are medically unsuitable for or have refused taxanes; ongoing castration with total serum testosterone ≤50 ng/dL; evidence of progressive disease; ECOG performance status 0–1; life expectancy ≥3 months; and adequate hematologic, renal, hepatic, and cardiac function. In the dose exploration phase, novel antiandrogen therapy must have been given in the metastatic setting. Key exclusion criteria: pure small cell or neuroendocrine carcinoma of the prostate; untreated CNS metastases or leptomeningeal disease; any anticancer therapy or immunotherapy, radiation therapy, or major surgery

TPS5589 Background: Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen that is highly expressed in prostate cancer. AMG 509 is a potent bispecific XmAb 2+1 immune therapy designed to direct T-effector cells to STEAP1-expressing cells. AMG 509 contains two identical humanized anti-STEAP1 Fab domains that bind STEAP1-expressing cells, an anti-CD3 scFv domain that binds T cells, and an Fc domain, engineered to lack effector function, that extends serum half-life. In preclinical studies, AMG 509 induced potent and specific T-cell-mediated lysis of STEAP1-expressing cancer models. Methods: This open-label, phase I, first-in-human study will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 509 in patients with relapsed/refractory mCRPC. The dose exploration phase (n=40) will estimate the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) using a Bayesian logistic regression model. The dose expansion phase (n=30) will confirm safety, PK, and pharmacodynamics at the MTD or RP2D and collect further safety, efficacy, and biomarker data. Efficacy will be assessed by prostate-specific antigen response, circulating tumor cell response, and objective tumor response per RECIST 1.1 with Prostate Cancer Working Group 3 modifications. Key inclusion criteria: men ≥18 years with histologically/cytologically confirmed mCRPC who are refractory to novel hormonal therapy (e.g., abiraterone and/or enzalutamide) and have failed 1–2 taxane regimens or are medically unsuitable for or have refused taxanes; ongoing castration with total serum testosterone ≤50 ng/dL; evidence of progressive disease; ECOG performance status 0–1; life expectancy ≥3 months; and adequate hematologic, renal, hepatic, and cardiac function. In the dose exploration phase, novel antiandrogen therapy must have been given in the metastatic setting. Key exclusion criteria: pure small-cell or neuroendocrine carcinoma of the prostate; untreated CNS metastases or leptomeningeal disease; any anticancer therapy or immunotherapy, radiation therapy, or major surgery

The effects of GS-4997 (apoptosis signal-regulating kinase 1 inhibitor) on cardiac repolarization were evaluated using a systematic modeling approach in a first-in-human (FIH) study. High quality, intensive, time-matched 12-lead electrocardiograms (ECGs) were obtained in this placebo-controlled, single and multiple-ascending dose study in healthy subjects. Model development entailed linearity and hysteresis assessments; GS-4997/metabolite concentration vs. baseline-adjusted QTcF (ΔQTcF) relationships were determined using linear mixed effects models. Bootstrapping was used to obtain 90% confidence intervals (CIs) of predicted placebo-corrected ΔQTcF (ΔΔQTcF). The upper bound of 90% CI for predicted ΔΔQTcF was

There are n cards serially numbered from 1 to n. The cards are shuffled and placed in a line one after the other on top of a table with faces up. The numbers on the faces are read from left to right. If there are consecutive numbers in increasing order of magnitude the corresponding cards are merged into one. After the merger, the cards are numbered serially from one to whatever the number of cards we now have. The cards are shuffled and placed in a line one after another on top of the table with faces up. The process continues until we have only one card left. In this paper, we develop a probabilistic recurrence relation approach to obtain the mean, variance, and distribution of the number of shuffles needed. A Markov chain formulation and its properties are discussed in the paper as well.

In this paper, the test for equality of several intraclass correlation coefficients is proposed when the sample size is small. First, we consider a case with two populations. The exact null distribution of the test statistic is derived. We use a Monte Carlo simulation study and find that the performance of our new test is superior to the tests that were proposed by Young and Bhandary (1998). Work is then extended to develop a test for three intraclass correlation coefficients. Monte Carlo simulation studies are also conducted to compare our new test and the test that was proposed by Bhandary and Alam (2000). Based on our simulation result, we recommend our new test in practice when the sample sizes are small.

Whittemore (1981) and Hsieh et al. (1998) have proposed different methods for determining sample size in the context of testing the significance of a slope parameter in logistic regression. Their sample size formulas have been incorporated in some statistical software packages. In this paper, we use a variation of Whittemore (1981) method to calculate sample size. We compare these three sample size formulas to assess closeness of the nominal and observed powers via simulations. These studies lead us to propose another method, which is a combination of Hsieh et al. (1998) method and the proposed variation of the Whittemore (1981) method for calculating sample size when the covariate is normally distributed. However, when the covariate has a Bernoulli distribution, sample size calculations widely diverge between the Hsieh et al. (1998) method and the proposed method. Interestingly, the proposed method gives a better account of power than the Hsieh et al. (1998) method.

e14097Background: Entospletinib (ENTO), a Syk inhibitor, has shown clinical activity in R/R CLL subjects. In vitro, ENTO inhibited OATP1B1/1B3, BCRP, P-gp and UGT1A1; ENTO metabolism is mediated by CYP2C9 and CYP3A. These studies evaluate the drug interaction (DDI) profile and mass balance (MB) of ENTO. Methods: Healthy subjects received ENTO alone, or with cobicistat (COBI; CYP3A inhibitor), rifampin (RIF; CYP3A inducer), fluconazole (FLU; CYP2C9/CYP3A inhibitor), rosuvastatin (ROS; OATP1B1/1B3, BCRP substrate) or digoxin (DIG, P-gp substrate). For the MB study, healthy subjects received a single dose of ENTO containing [14C]-labeled ENTO. Results: DDI results are shown below. ENTO was extensively metabolized to 14 metabolites in the MB study; ~91% and ~2% of the dose was recovered in feces and urine, respectively. The majority of circulating radioactivity was associated with unchanged ENTO. ENTO was generally well tolerated in these studies. Conclusions: Co-administration with strong CYP3A inducers may ...

Science educators have the common goal of helping students develop scientific literacy, including understanding of the nature of science (NOS). University faculties are challenged with the need to develop informed NOS views in several major student subpopulations, including science majors and nonscience majors. Research into NOS views of undergraduates, particularly science majors, has been limited. In this study, NOS views of undergraduates in introductory environmental science and upper-level animal behavior courses were measured using Likert items and open-ended prompts. Analysis revealed similarities in students' views between the two courses; both populations held a mix of naïve, transitional, and moderately informed views. Comparison of pre- and postcourse mean scores revealed significant changes in NOS views only in select aspects of NOS. Student scores on sections addressing six aspects of NOS were significantly different in most cases, showing notably uninformed views of the distinctions between scientific theories and laws. Evidence-based insight into student NOS views can aid in reforming undergraduate science courses and will add to faculty and researcher understanding of the impressions of science held by undergraduates, helping educators improve scientific literacy in future scientists and diverse college graduates.