Population pharmacokinetics (Pop PK) of MYL-1402O (a proposed biosimilar to bevacizumab) and reference product (Avastin) in patients with nonsquamous non-small cell lung cancer (nsNSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21087-e21087
Author(s):  
Joel Owen ◽  
Russell J. Rackley ◽  
Matthew A. Hummel ◽  
Stefan Roepcke ◽  
Hannah Huang ◽  
...  
Keyword(s):  
Reference Product ◽  
Phase 1 ◽  
Model Development ◽  
Stage Iv ◽  
Parameter Estimates ◽  
Model Parameters ◽  
Test Model ◽  
Phase 3 ◽  
Double Blind ◽  
Model Based

e21087 Background: MYL-1402O (MYL) is a proposed biosimilar to bevacizumab reference product. A multicenter, double blind randomized, phase 3 study compared the efficacy, safety, PK, and immunogenicity of MYL and Avastin in patients with Stage IV metastatic nsNSCLC. Patients received either MYL or reference product, in combination with carboplatin-paclitaxel up to 18 weeks (6 cycles) followed by monotherapy for up to an additional 24 weeks (8 cycles). The objective was to develop a Pop PK model based on data from a phase 3 study pooled with a single dose healthy volunteer phase 1 study data; to assess PK linearity across the dose levels of 1 mg/kg to 15 mg/kg in 2 clinical studies; to assess the PK similarity of MYL and reference product in patients with nsNSCLC; and to explore potential covariates to account for variability in Pop PK model parameters. Methods: A Pop PK model was developed based on preliminary analyses of MYL phase 1 data and published population analyses of reference product using a 2-compartment linear model (Han K et al., 2016). Individual empiric Bayesian parameter estimates of nsNSCLC patients were used to predict PK measures reflecting exposure to drug and were compared qualitatively between treatments. Results: The data subset used for model development consisted of 8724 records from 771 subjects. Population PK analyses indicated no differences between PK profiles of patients in the MYL and reference product arms. Importantly, treatment was not a significant covariate of clearance ( P = 0.453) or volume of the central compartment ( P = 0.161) using the likelihood ratio χ2 test. Model-based steady state exposure measures, predicted based on the final model for all patients, were also similar between treatment arms (Table). Conclusions: The model supported linear PK at clinical doses in patients with nsNSCLC; there were no clinically relevant/significant differences between the PK of MYL and reference product; and the findings were consistent with the PK study in normal, healthy volunteers. Bayesian Parameter Clinical trial information: 2015-005141-32. [Table: see text]

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9500-9500
Author(s):  
Alexander M. Eggermont ◽  
Andrey Meshcheryakov ◽  
Victoria Atkinson ◽  
Christian U. Blank ◽  
Mario Mandalà ◽  
...  
Keyword(s):  
Disease Progression ◽  
Objective Response ◽  
Stage Iv ◽  
Median Number ◽  
Complete Resection ◽  
Stage Iii ◽  
Phase 3 ◽  
Double Blind ◽  
Grade 3 ◽  
To Receive

9500 Background: The phase 3 double-blind EORTC 1325/KEYNOTE-054 trial evaluated pembrolizumab (pembro) vs placebo in stage III cutaneous melanoma patients (pts) with complete resection of lymph nodes. Pembro improved RFS (hazard ratio [HR] 0.57) and DMFS (HR 0.60) (Eggermont, NEJM 2018, TLO 2021). In the pembro group, the incidence of immune related AE (irAE) grade 1-5 was 37%, and of grade 3-5 was 7%. We present the safety profile, response rate and PFS for the subset of pts who had a recurrence and crossed over or were rechallenged with pembrolizumab, within protocol. Methods: Pts were randomized to receive iv. pembro 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year). Upon recurrence with no brain metastases, pts with an ECOG PS 0-2 were eligible to enter part 2 of the study, i.e. to receive pembro 200 mg iv. every 3 weeks for a maximum of 2 years, for crossover (those who received placebo) or rechallenge (those who recurred ≥6 months after completing one year of pembro therapy). Treatment was stopped in case of disease progression (RECIST 1.1) or unacceptable toxicity. Results: At the clinical cut-off (16-Oct-2020), 298 (59%) pts had a disease recurrence in the placebo group; 155 pts participated in the crossover part 2 of the trial. A total of 297 (58%) pts completed the 1-yr pembro adjuvant treatment, of whom 47 had a recurrence ≥6 mths from the stop of treatment and 20 entered in the rechallenge part of the trial. Among 175 pts who started pembro in Part 2, 160 discontinued due to completion of therapy (N=24), disease progression (N=88), toxicity (N=20), investigator's decision (N=21), or other reason (N=7); 15 pts were still on-treatment. Results for the 2 groups are provided in the table. The median number of doses was 12 and 5.5, respectively (resp), and the median follow-up was 41 and 19 mts, resp. Among the 175 pts, 51 (29%) had a grade 1-4 irAE (by group: 47 [30%] and 4 [20%] resp) and 11 (6%) a grade 3-4 irAE. Conclusions: Pembrolizumab treatment after crossover yielded a 39% ORR in evaluable pts and an overall 3-yr PFS of ̃32%, but after rechallenge the efficacy was lower. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA The median PFS (95% CI) from start of Part 2 was 14 (5-27) and 8 (5-15) mts for stage III-resected and III/IV various, resp. Among the 80 stage IV crossover pts with evaluable disease, 31 (39%) had an objective response: 14 (18%) CR, 17 (21%) PR. The 2-yr PFS rate from response was 69% (95% CI 48-83%). For these 80 pts, the median PFS was 6.1 mts and the 3-yr PFS rate was 31% (95% CI 21-41%). Among 9 stage IV rechallenged pts with an evaluable disease, 1 (11%) reached CR, 3 had SD and 5 PD. Clinical trial information: NCT02362594. [Table: see text]

ClarIDHy: A phase 3, multicenter, randomized, double-blind study of AG-120 vs placebo in patients with an advanced cholangiocarcinoma with an IDH1 mutation.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4142-TPS4142 ◽  
Author(s):  
Maeve Aine Lowery ◽  
Ghassan K. Abou-Alfa ◽  
Juan W. Valle ◽  
Robin Kate Kelley ◽  
Lipika Goyal ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase 1 ◽  
Data Monitoring Committee ◽  
Blind Study ◽  
Clinical Activity ◽  
Double Blind Study ◽  
Phase 3 ◽  
Isocitrate Dehydrogenase 1 ◽  
Double Blind ◽  
Eortc Qlq

TPS4142 Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease for which there are limited therapeutic options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in up to 25% of intrahepatic CC cases. mIDH1 lead to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite, D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class oral inhibitor of the mIDH1 enzyme, and is being tested in a phase 1 study that enrolled 73 patients (pts) with mIDH1 CC who had received a median of 2 prior therapies (range 1–5). AG-120 has demonstrated a favorable safety profile and clinical activity in this study. Among the 72 efficacy evaluable pts (≥1 post-baseline response assessment or discontinued prematurely), 6% (n = 4) had a confirmed partial response and 56% (n = 40) had stable disease. Progression-free survival (PFS) rate at 6 months was 40% as of Dec 16, 2016. The 500 mg once daily (QD) dose of AG-120 was selected for the ongoing phase 3 study in mIDH1 CC described here. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind study randomizing 186 pts with mIDH1 CC in a 2:1 ratio to AG-120 (500 mg QD) or matched placebo (NCT02989857). Key eligibility criteria: nonresectable or metastatic CC; documented mIDH1 based on central laboratory testing; ECOG 0–1; measurable disease (RECIST v1.1); documented disease progression following ≤2 prior systemic therapies in the advanced setting, including at least 1 gemcitabine- or 5-fluorouracil-containing regimen; and no prior mIDH inhibitor therapy. Crossover from the placebo arm to the AG-120 arm will be permitted. The primary endpoint is PFS as assessed by an independent review. Secondary endpoints include safety, tolerability, overall response rate, overall survival, pharmacokinetic and pharmacodynamic analyses on plasma, and quality of life as assessed by the EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D-5L instruments. An independent data monitoring committee will monitor the data throughout the study. The ClarIDHy study is currently activated at participating sites in the US and will be activated in centers throughout Europe and in South Korea. Clinical trial information: NCT02989857.

ARASENS: A phase 3 trial of darolutamide in combination with docetaxel for men with metastatic hormone-sensitive prostate cancer (mHSPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS383-TPS383 ◽  
Author(s):  
Matthew Raymond Smith ◽  
Fred Saad ◽  
Maha Hussain ◽  
Cora N. Sternberg ◽  
Karim Fizazi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase 1 ◽  
Performance Status ◽  
Physical Symptoms ◽  
Castration Resistant Prostate Cancer ◽  
Opioid Use ◽  
Phase 3 ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Disease Extent

TPS383 Background: The addition of either docetaxel or abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) improves overall survival (OS) compared with ADT alone in men with mHSPC. It is hypothesized that other androgen receptor (AR)-targeted therapies could be combined with docetaxel for mHSPC. Darolutamide (ODM-201) is an investigational oral AR antagonist with a unique chemical structure and negligible blood-brain barrier penetration that inhibits tumor growth by binding to AR and AR mutants (eg, W742L and F877L) with high affinity and specificity. In phase 1/2 ARADES and phase 1 ARAFOR trials, darolutamide demonstrated antitumor activity and was well tolerated in men with metastatic castration-resistant prostate cancer (mCRPC). ARASENS will evaluate the addition of darolutamide to standard ADT and docetaxel in men with mHSPC. Methods: This international, randomized, double-blind, placebo-controlled phase 3 trial (NCT02799602) is being conducted at > 300 sites in 23 countries. ~1300 men with newly diagnosed mHSPC will be randomized 1:1 to darolutamide (600 mg orally twice daily) or matching placebo. All patients will receive standard ADT + docetaxel (6 cycles). Patients will be stratified by disease extent and alkaline phosphatase level. Key inclusion criteria: histologically or cytologically confirmed PC with documented metastases, started ADT ± first-generation antiandrogen therapy ≤12 weeks before randomization, and ECOG performance status 0-1. The primary end point is OS. Secondary end points include time to mCRPC, initiation of subsequent anticancer therapy, symptomatic skeletal event (SSE)-free survival, time to first SSE, first opioid use, pain progression, and worsening of physical symptoms. Safety will be assessed. ARASENS is actively enrolling at > 280 sites across 23 countries. Clinical trial information: NCT02799602.

scholarly journals Assessing model-based inferences in decision making with single-trial response time decomposition

2020 ◽  
Author(s):  
Gabriel Weindel ◽  
Royce anders ◽  
F.-Xavier Alario ◽  
Boris BURLE
Keyword(s):  
Decision Making ◽  
Decision Processes ◽  
Emg Activity ◽  
Parameter Estimates ◽  
Model Parameters ◽  
Response Force ◽  
Model Based ◽  
Wide Range ◽  
Response Execution ◽  
Speed Accuracy

Decision-making models based on evidence accumulation processes (the most prolific one being the drift-diffusion model – DDM) are widely used to draw inferences about latent psychological processes from chronometric data. While the observed goodness of fit in a wide range of tasks supports the model’s validity, the derived interpretations have yet to be sufficiently cross-validated with other measures that also reflect cognitive processing. To do so, we recorded electromyographic (EMG) activity along with response times (RT), and used it to decompose every RT into two components: a pre-motor (PMT) and motor time (MT). These measures were mapped to the DDM's parameters, thus allowing a test, beyond quality of fit, of the validity of the model’s assumptions and their usual interpretation. In two perceptual decision tasks, performed within a canonical task setting, we manipulated stimulus contrast, speed-accuracy trade-off, and response force, and assessed their effects on PMT, MT, and RT. Contrary to common assumptions, these three factors consistently affected MT. DDM parameter estimates of non-decision processes are thought to include motor execution processes, and they were globally linked to the recorded response execution MT. However, when the assumption of independence between decision and non-decision processes was not met, in the fastest trials, the link was weaker. Overall, the results show a fair concordance between model-based and EMG-based decompositions of RTs, but also establish some limits on the interpretability of decision model parameters linked to response execution.

ATOMIC-Meso: A randomized phase 2/3 trial of ADI-PEG20 or placebo with pemetrexed and cisplatin in patients with argininosuccinate synthetase 1-deficient non-epithelioid mesothelioma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS8582-TPS8582 ◽  
Author(s):  
Peter Wojciech Szlosarek ◽  
Paul Baas ◽  
Giovanni Luca Ceresoli ◽  
Dean Anthony Fennell ◽  
David Gilligan ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Primary Endpoint ◽  
Phase 1 ◽  
Arginine Deiminase ◽  
Pleural Mesothelioma ◽  
Phase 2 ◽  
Argininosuccinate Synthetase ◽  
Phase 3 ◽  
Double Blind ◽  
Arginine Deprivation

TPS8582 Background: Argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM) is sensitive to arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20), which also enhances the cytotoxicity of pemetrexed. The TRAP Phase 1 trial (NCT02029690) of ADI-PEG 20 combined with 1st-line pemetrexed (PEM) and cisplatin (CDDP) chemotherapy revealed a 94% disease control rate in non-epithelioid (biphasic and sarcomatoid) MPM subtypes characterized by a 75% rate of ASS1 loss. Thus, we plan to assess the efficacy of ADI-PEG20 or placebo combined with PEM and CDDP in patients (pts) with poor prognosis MPM in a randomized, placebo-controlled, double-blind phase 2/3 global trial. Methods: Up to 386 good performance (ECOG 0-1) pts with non-epithelioid malignant pleural mesothelioma will be enrolled in a phase 2/3 adaptive, biomarker-driven study design. Biopsies will be required prior to randomization: ASS1-agnostic pts will be enrolled initially (phase 2 stage) with an option to restrict enrolment to ASS1-deficient MPM (phase 3 stage). Pts will be randomized to receive weekly ADI-PEG20 (36 mg/m2 IM) or placebo with standard doses of PEM and CDDP for a maximum of 18 weeks (6 cycles) of treatment. Pts who develop CDDP toxicity may be switched to carboplatin. Pts will be assessed every 6 weeks using modified RECIST (RECIST 1.1 allowed for pts with significant extrathoracic disease). The primary endpoint for the phase 2 stage will be overall response rate (ORR) with secondary endpoints of overall survival (OS), safety and toxicity. The phase 2 will test ORR proportions with the placebo triplet set at 15% vs. 35% for the ADI-PEG 20 triplet, with a 1:1 randomization, 80% power. After recruitment of 176 pts, the phase 2 will convert to a phase 3 study with the primary endpoint of OS. In summary, ATOMIC-Meso is the first triplet chemotherapy study to assess the role of targeted arginine deprivation in aggressive subtypes of mesothelioma. Pt accrual has commenced across the US and Asia, with enrolment due in Europe and Australia by 2nd quarter of 2017. [Trial sponsored by Polaris Group]. Clinical trial information: NCT02709512.

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