الفهرس 
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Abstract
I- EVESOR study
Rationale of EVESOR study
• The development of everolimus and sorafenib combination was stopped by drug companies, due to the high toxicity index and the lack of a clear benefit/toxicity ratio to guide dose recommendations for a phase II trial. Daily monotherapy regimens of both drugs were used. However, sorafenib dosing schedule may impact on everolimus tumor delivery and thus on toxicity & efficacy. It should be possible to determine the optimized doses and dosing schedules of both drugs, which are able to maximize the benefit/toxicity ratio, using modeling and simulation studies. We designed the first multi-parameter phase I study (EVESOR), based on mathematical modeling of data provided from an adequately designed trial with this objective.
Design of EVESOR trial
• EVESOR trial was a four-arm, multiparameter Phase I trial of everolimus and sorafenib. This is an open-label, phase Ib trial where patients with metastatic or locally advanced cancers who are deemed eligible were treated with the combination of sorafenib and everolimus.
• The four schedules were presented as follows: In schedules A and B, respectively, either everolimus or sorafenib will be given alone during a 2-week run-in period before starting continuous administration of the combination (once a day [q.d.] for everolimus; twice a day [b.i.d.] for sorafenib) to assess the ability of each drug to affect the
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concentrations and PD parameters of the other drug. In schedule C, sorafenib will be given b.i.d. for a week alternating with q.d. everolimus every other week. In schedule D, sorafenib will be given b.i.d. for 3 days-on 4 days-off, while everolimus will be administered q.d. on a continuous basis.
Assessments of EVESOR study
PK assessments
The PK profiles of sorafenib and everolimus were modeled independently. The structural model for sorafenib was a 1-compartment model with first order absorption; the structural model for everolimus was a 2-compartment model with first order absorption.
PD assessments
We serially measured inhibition of PI3K–AKT–mTor and RAS–RAF–ERK signaling pathways in peripheral blood mononuclear cells (PBMCs), by assessing expression of AKT total, pAKT, total S6K, pS6K, ERK total, pERK using ELISA kits from Invitrogen. Antiangiogenic markers VEGF, VEGFR1, VEGFR2 were measured serially in serum (during cycle one and two and at the same times as PBMCs) using the human ELISA kits from Abcam.
Summary of preliminary results of EVESOR study
• The preliminary efficacy outcomes in this EVESOR trial indicated that everolimus and sorafenib combination exhibited promising anti-cancer activity in patients with solid tumors, as shown by the overall response rates (ORRs) : partial response : 11% ; stable disease : 78%.
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• Everolimus and sorafenib combination showed antitumor activity especially for patients with gynaecological adenocarcinomas and cholangiocarcinomas. These patients were included in admnistration schedules B, C and D all at dose level 1. (everolimus 5 mg qid and sorafenib 200 mg bid).
• The two tested intermittent dosing schedules tested were better tolerated and showed at least comparable, if not better, efficacy compared to continuous schedules. (ORR in intermittent schedules: PR 20% and SD 80% vs. ORR in continuous schedules: PR 25% and SD 75%)
• The preliminary efficacy outcomes suggest that intermittent dosing schedules may not be less effective at least, if not better, than continuous schedules.
• No clear relationships between PK parameters and toxicity were observed, which suggests that there were no significant PK interactions between everolimus and sorafenib. It may be a ‘proof of concept’ of model-based early-phase trials of targeted agent combinations.
• No relationships between PK parameters and toxicity of efficacy were found Although, we noted a higher risk of adverse events in continuous arms A and B than in intermittent arms C and D, no correlations between the different administration schedules and adverse events of all grades were found, nor were between calculated pharmacokinetic parameters (AUC and Cmax) of both drugs and toxicities.
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• Our study suggests that changing dosing regimen of the two combined drugs according to administration schedules A, B, C and D had no impact on the outcomes of overall toxicities.
• Preliminary PD outcomes may suggest potential PD interactions between both drugs, in terms of inhibitions of the two PI3K-AKT-mTor & RAS-RAF-ARK signalling pathways, or anti-angiogenic effects induced by the combination as previously show
• Preliminary PD outcomes may suggest potential PD interactions between both drugs, in terms of inhibitions of the two PI3K-AKT-mTor & RAS-RAF-ARK signalling pathways, or anti-angiogenic effects induced by the combination as previously show.
Conclusion
When everolimus was given concurrently with sorafenib on a daily basis, stable disease and response rates were comprised in between 30% to 76% and 5% to 100% respectively. These outcomes suggest dual inhibition of PI3K-AKT-mTor and RAS-RAF-ERK signaling pathway is associated with increased anti-tumor activity. Moreover, there are elements for considering sorafenib might alter delivery of everolimus in tumor site. There is no data about efficacy of intermittent administration of everolimus or sorafenib. We selected tumor sites which may be sensitive to everolimus and sorafenib.
II- Data Analysis of the literature review
An extensive research analysis of the literature review was conducted. to identify all publications of early phase trials defining an OBD for
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molecular targeted therapies in oncology between 2000 and 2016. The publications of subsequent phases II and III clinical trials of involved drugs were reviewed, along with potential approvals, to compare approved doses to OBDs identified earlier. A final FDA approval was found for 56.2 % drugs with defined OBD. The approved doses were consistent with the reported OBD for 83.3 % drugs. There were exception for 3 drugs. The analysis suggests that, despite being rarely investigated, OBD may be a relevant endpoint for early phase trials, as it was found to be consistent with subsequent dose approved by FDA, in 83.3 % cases.