Considerations for the Design of Future Clinical Trials in Metastatic Renal Cell Carcinoma

Escudier, Bernard; Heng, Daniel Y.C.; Smyth-Medina, Arthur; Porta, Camillo

doi:10.1016/j.clgc.2013.07.004

Cited by 6 publications

(3 citation statements)

References 90 publications

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“…The role of TKI dose escalation has been evaluated in a limited set of clinical studies but it remains an unanswered question (24). Intrapatient dose escalation based on drug tolerability has been reported with sorafenib showing clinical benefit but rising also concerns for feasibility due to increased toxicity (25, 26).…”

Section: Discussionmentioning

confidence: 99%

Sunitinib Dose Escalation Overcomes Transient Resistance in Clear Cell Renal Cell Carcinoma and Is Associated with Epigenetic Modifications

Adelaiye

Ciamporcero

Miles

et al. 2015

Molecular Cancer Therapeutics

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Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). Despite sunitinib clinical efficacy, eventually patients develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDXs) were treated 5 days/week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected prior to dose increments for immunohistochemistry analyses and drug levels. Selected intra-patient sunitinib dose escalation was safe and several patients had added progression free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro anti-tumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Sunitinib Dose Escalation Overcomes Transient Resistance in Clear Cell Renal Cell Carcinoma and Is Associated with Epigenetic Modifications

Adelaiye

Ciamporcero

Miles

et al. 2015

Molecular Cancer Therapeutics

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“…There has been a growing awareness of the need for systems‐biology–based clinical trials 74–75 . Novel clinical trial designs have leveraged dense data for patient stratification, arm assignment, and other innovations 76 .…”

Section: Discussionmentioning

confidence: 99%

“…There has been a growing awareness of the need for systemsbiology-based clinical trials. [74][75] Novel clinical trial designs have leveraged dense data for patient stratification, arm assignment, and other innovations. 76 One goal of systems biology is to use prior knowledge to enable mechanistic inferences from newly generated data.…”

Section: Discussionmentioning

confidence: 99%

The Coaching for Cognition in Alzheimer's (COCOA) trial: Study design

Roach

Hara

Fridman

et al. 2022

A&D Transl Res & Clin Interv

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Comprehensive treatment of Alzheimer's disease (AD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. We present the design and methodology for the Coaching for Cognition in Alzheimer's (COCOA) trial. AD and other dementias result from the interplay of multiple interacting dysfunctional biological systems. Monotherapies have had limited success. More interventional studies are needed to test the effectiveness of multimodal multi-domain therapies for dementia prevention and treatment. Multimodal therapies use multiple interventions to address multiple systemic causes and potentiators of cognitive decline and functional loss; they can be personalized, as different sets of etiologies and systems responsive to therapy may be present in different individuals. COCOA is designed to test the hypothesis that coached multimodal interventions beneficially alter the trajectory of cognitive decline for individuals on the spectrum of AD and related dementias (ADRD). COCOA is a twoarm prospective randomized controlled trial (RCT). COCOA collects psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints across 2 years for each participant. These data enable systems biology analyses. One arm receives standard of care and generic healthy aging recommendations.The other arm receives standard of care and personalized data-driven remote coaching. The primary outcome measure is the Memory Performance Index (MPI), a measure of cognition. The MPI is a summary statistic of the MCI Screen (MCIS). Secondary outcome measures include the Functional Assessment Staging Test (FAST), a measure of function. COCOA began enrollment in January 2018. We hypothesize that multimodal interventions will ameliorate cognitive decline and that data-driven health coachingThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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First-Line Treatments for Poor-Prognosis Metastatic Renal Cell Carcinoma: Experts’ Prescribing Practices and Systematic Literature Review

Saux

Négrier

2016

Clin Drug Investig

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Considerations for the Design of Future Clinical Trials in Metastatic Renal Cell Carcinoma

Cited by 6 publications

References 90 publications

Sunitinib Dose Escalation Overcomes Transient Resistance in Clear Cell Renal Cell Carcinoma and Is Associated with Epigenetic Modifications

Sunitinib Dose Escalation Overcomes Transient Resistance in Clear Cell Renal Cell Carcinoma and Is Associated with Epigenetic Modifications

The Coaching for Cognition in Alzheimer's (COCOA) trial: Study design

First-Line Treatments for Poor-Prognosis Metastatic Renal Cell Carcinoma: Experts’ Prescribing Practices and Systematic Literature Review

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