Accelerating development and managing risk

and industrial biopharmaceutical communities. While the benefits to patients and to sponsors of accelerating development are obvious, the risks of accelerating development are less clear. This talk will attempt to address some of the CMC risks associated with accelerating development and how they might be managed. FDA (and analogous regulatory bodies outside the USA) have announced the availability of rapid regulatory paradigms for products which meet currently unmet medical needs. The details of these programs vary from country to country, but they are similar in that most may permit the product to be marketed based upon submission of Phase 2 clinical data. This may reduce the time required for clinical development from 8 - 12 years to as little as 3 – 4.5 years, and may reduce the number of patients needed from thousands to hundreds. While this has clear benefits in terms of saving time and expense for large clinical trials, there is relatively less benefit for the CMC package, as in general, the standards and expectations for the CMC package for an accelerated approval remain largely the same as for a market authorization application from a 8 – 12 year program. This creates a significant effort to complete what is normally an 8 – 12 year CMC effort in 3 – 4.5 years. While effective planning and management can achieve much of this, the time required to complete certain long term studies cannot be easily condensed. This requires realization of these needs early, and spending at risk in order to complete the needed work in time for the filing. Examples of these situations will be discussed. There may also be technical requirements or target product profile requirements which can change the typical time and/or investment required to complete CMC studies in support of the filing. Examples of these might include a delivery device, a co-diagnostic, a special administration need (ultralow doses or ultrahigh volumes of administration), or an improved manufacturing process. The development timelines and/or investments need to take such considerations into the planning and budgeting for the project, and well as the risk-reward scenarios. These will inevitably lead to discussions with senior management about whether the requirements are absolutely required or nice-to-have, and will translate to what CMC studies are required for the market authorization and what can be accomplished as a post approval change. There are multiple ways to make these decisions, and several will be illustrated during the presentation

Structural evolution of deformation bands

Deformation bands are the most common strain features observed in deformed upper crustal sections of porous sedimentary rocks, like sandstone and carbonate grainstone. A deformation band is a tabular zone of localised strain that forms as a result of compaction due to sediment loading and high deviatoric stress. These bands of strain exhibit considerable variation in structural kinematic styles (compaction band, shear band, dilation band, and hybrids) and formation mechanics (disaggregation band, cataclastic band, phyllosilicate band, and cement/ dissolution band). The variations may enhance or retard subsurface fluid flow and create permeability anisotropy, especially surrounding fault zones. Uranium is mobilised easily by fluids in sedimentary basins, thus this project explores practical uses for sedimentary-hosted mineral exploration, specifically targeting faulting. Fault-induced deformation bands reflect the stress state at the time of formation, creating a foundation for palaeostress reconstructions using deformation bands as indicators of discrete changes to the local and far-field stress. Despite considerable research to siliciclastic-hosted bands, research bias has contributed to a lack of understanding of carbonate-hosted cataclasic bands and dilation bands. This study presents an investigation of the structural styles that govern the formation mechanisms of newly described deformations bands observed at Marion Bay, Stenhouse Bay, Port Vincent, Port Willunga, and Sellicks Beach in the southern Mount Lofty Ranges; the Dead Tree section and Parabarana Hill in the northern Flinders Ranges in South Australia; and the Athabasca Basin in northern Saskatchewan, Canada. Detailed face mapping and structural analysis of 737 deformation bands and 397 fractures observed near the Port Vincent Fault, Marion Bay Fault, Stenhouse Bay Fault, Willunga Fault, and Paralana Fault infers the structural evolution of the Mount Lofty Ranges is remarkably similar to the palaeostress evolution of the northern Flinders Ranges. These results define a five stage evolution sequence for the region: Stage 1) NW–SE extension (early Palaeocene– early Eocene); Stage 2) N–S extension (middle Eocene–middle Miocene); Stage 3) N–S compression (late Miocene); Stage 4) NW – SE compression (Pliocene–middle Pleistocene); Stage 5) E–W compression (late Pleistocene–Present-day). Detailed face mapping, permeameter, and transmitted light microscopy results confirms 286 dilation bands are hosted within the Eyre Formation at the Dead Tree section in the northern Flinders Ranges. Integration of this data with our palaeostress model and Paralana Fault geometry reveals the region underwent transtension during Stages 2 and 4 of our palaeostress model, resulting in the formation of dilation bands observed at the Dead Tree section. I suggest these events enhanced localised effective permeability between the Mount Painter uranium source and Four Mile uranium deposit. Detailed face mapping, permeameter, and transmitted light microscopy results confirms 221 cataclastic bands with differing intensities of cataclasis, pressure solution, disaggregation, and cementation are hosted within the Port Willunga Formation at Sellicks Beach. To standardize the nomenclature, I suggest the fault rock classification scheme of cataclasis intensity for carbonate-hosted deformation bands. In the Athabasca Basin, I mapped 1713 deformation bands in detail within the Manitou Falls Formation. Six stage palaeostress model is inferred for the Manitou Falls Formation: Stage 1) NW–SE extension; Stage 2) E–W extension; Stage 3) NE–SW extension (1.3 Ga); Stage 4) NW–SE transpression; Stage 5) N–S compression; Stage 6) E-W compression. Scanning electron microscopy indicates cataclasis, dissolution, dilation, and fracture control formation mechanics in the Manitou Falls Formation. For the first time ever, I document the occurrence of reactivated cataclastic bands. This study confirms deformation bands are excellent indicators of discrete changes to the local and far- field stress regime, enhance our understanding of the evolution of Earth’s crust, and present a useful tool to understand fault history and fluid flow, especially for sedimentary hosted uranium exploration.Thesis (Ph.D.) -- University of Adelaide, School of Physical Sciences, 201

Health-related quality of life in KEYNOTE-010 : a phase II/III study of pembrolizumab versus docetaxel in patients with previously treated advanced, programmed death ligand 1-expressing NSCLC

Introduction: In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1-expressing (tumor proportion score >= 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here. Methods: Patients were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks or docetaxel 75 mg/m(2) every 3 weeks. HRQoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLC) Core 30 (C30), EORTC QLQ-Lung Cancer 13 (LC13), and EuroQoL-5D. Key analyses included mean baseline-to-week-12 change in global health status (GHS)/quality of life (QoL) score, functioning and symptom domains, and time to deterioration in a QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain. Results: Patient reported outcomes compliance was high across all three instruments. Pembrolizumab was associated with better QLQ-C30 GHS/QoL scores from baseline to 12 weeks than docetaxel, regardless of pembrolizumab dose or tumor proportion score status (not significant). Compared with docetaxel, fewer pembrolizumab-treated patients had "deteriorated" status and more had "improved" status in GHS/QoL. Nominally significant improvement was reported in many EORTC symptom domains with pembrolizumab, and nominally significant worsening was reported with docetaxel. Significant prolongation in true time to deterioration for the QLQ-LC13 composite endpoint emerged for pembrolizumab 10 mg/kg compared to docetaxel (nominal two-sided p = 0.03), but not for the 2-mg/kg dose. Conclusions: These findings suggest that HRQoL and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival : an updated analysis of KEYNOTE-010 trial

Background: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. Patients and methods: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) 50% and 1%; pembrolizumab doses were pooled in this analysis. Results: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS 50%. For TPS 50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS 1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS 50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS 1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. Conclusion: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples

A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108599/1/bjh13016.pd

Phase 3 KEYNOTE-042 Study: Pembrolizumab vs Platinum-Based Chemotherapy as 1l Therapy for Advanced NSCLC with a PD-L1 TPS ≥1%

First-line (1L) therapy with pembrolizumab in patients with metastatic NSCLC without targetable aberrations and programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% significantly improved the primary endpoint of PFS, and OS (secondary endpoint) compared to chemotherapy in the KEYNOTE-024 study. In KEYNOTE-042 (NCT02220894), we evaluated pembrolizumab vs chemotherapy at the lower PD-L1 TPS of ≥1%

lba4long term follow up in the keynote 010 study of pembrolizumab pembro for advanced nsclc including in patients pts who completed 2 years of pembro and pts who received a second course of pembro

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Long-term survival in patients (pts) with advanced NSCLC in the KEYNOTE-010 study overall and in pts who completed two years of pembrolizumab (pembro)

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Systematic evaluation of pembrolizumab dosing in patients with advanced non-small cell lung cancer

International audienceBACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n=55), 10 mg/kg Q3W (n=238), or 10 mg/kg Q2W (n=156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady-state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and nonlinear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events of interest based on their immune etiology. RESULTS: Overall response rates were 15% (95% confidence interval [CI] 7%-28%) at 2 Q3W, 25% (18%-33%) at 10 Q3W, and 21% (95% CI 14% to 30%) at 10 Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6week indicated a flat relationship (regression slope P\textgreater0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the adverse event incidence to be similar among the clinically tested doses. CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2 mg/kg to 10 mg/kg. These results support the use of a 2-mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.ClinicalTrials.gov registry: NCT0129582