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Piha-Paul S.A.,University of Houston | Munster P.N.,University of California at San Francisco | Hollebecque A.,DITEP | Argiles G.,Vall Dhebron University Hospital | And 6 more authors.
European Journal of Cancer | Year: 2015

Background The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K-AKT-mTOR) signalling pathway is aberrantly activated in several cancers. Notch signalling maintains cell proliferation, growth and metabolism in part by driving the PI3K pathway. Combining the mTOR inhibitor ridaforolimus with the Notch inhibitor MK-0752 may increase blockade of the PI3K pathway. Methods This phase I dose-escalation study (NCT01295632) aimed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of combination oral ridaforolimus (rising doses starting at 20 mg, 5 days/week) and oral MK-0752 (1800 mg once weekly) in patients with solid tumours. No intrapatient dose escalation was permitted. Results Twenty eight patients were treated on study. Ridaforolimus doses were escalated from 20 to 30 mg/day. Among 14 evaluable patients receiving ridaforolimus 20 mg, one DLT (grade 2 stomatitis, second episode) was reported. Among eight evaluable patients receiving ridaforolimus 30 mg, three DLTs were reported (one each grade 3 stomatitis, grade 3 diarrhoea, and grade 3 asthenia). The MTD was 20 mg daily ridaforolimus 5 days/week + 1800 mg weekly MK-0752. The most common drug-related adverse events included stomatitis, diarrhoea, decreased appetite, hyperglycaemia, thrombocytopenia, asthenia and rash. Two of 15 (13%) patients with head and neck squamous cell carcinoma (HNSCC) had responses: one with complete response and one with partial response. In addition, one patient experienced stable disease ≥6 months. Conclusions Combined ridaforolimus and MK-0752 showed activity in HNSCC. However, a high number of adverse events were reported at the MTD, which would require careful management during future clinical development. © 2015 Elsevier Ltd. Source

Andre F.,French Institute of Health and Medical Research | Mardis E.,University of Washington | Salm M.,Cancer Research UK Research Institute | Soria J.-C.,DITEP | And 2 more authors.
Annals of oncology : official journal of the European Society for Medical Oncology / ESMO | Year: 2014

The implementation of cancer genomic testing into the clinical setting has brought major opportunities. However, as our understanding of cancer initiation, maintenance and progression improves through detailed cancer genomic studies, the challenges associated with driver identification and target classification in the clinical setting become clearer. Here, we review recent insights into cancer genomic testing in the clinical setting, and suggest a target classification approach that considers the levels of evidence supporting the prioritization of tumour drivers for therapeutic targeting in light of complex cancer clonal and sub-clonal structures and clinical successes and failures in the field. We argue that such classification approaches, together with transparent reporting of both positive and negative clinical data and continued research to identify the sub-clonal dynamics of driver events during the disease course, will facilitate inter-trial comparisons, optimize patient informed consent and provide a critically balanced evaluation of genomic testing in clinical practice. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. Source

Gupta S.,H. Lee Moffitt Cancer Center and Research Institute | Argiles G.,University of Barcelona | Munster P.N.,University of California at San Francisco | Hollebecque A.,DITEP | And 6 more authors.
Clinical Cancer Research | Year: 2015

Purpose: The PI3K/Akt/mTOR signaling pathway is aberrantly activated in many cancers. Combining ridaforolimus, an mTOR inhibitor, with MK-2206, an Akt inhibitor, may more completely block the PI3K pathway and inhibit tumor growth. Experimental Design: This phase I study assessed dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of oral ridaforolimus plus oral MK-2206 in patients with advanced solid tumors. Efficacy was evaluated in patients with biomarker-identified estrogen receptor-positive breast cancer (low RAS gene signature and high Ki67 index) or castrationresistant prostate cancer (PTEN deficiency) with PI3K pathway addiction. Results: Thirty-five patients were enrolled: 11 patients in part A (three breast cancer) and 24 biomarker-eligible patients in part B (16 breast cancer, eight prostate cancer). One patient with breast cancer from part A was also found to be biomarker-eligible when tested after she had clinical response. The MTD was 10 mg/d ridaforolimus 5 d/wk + 90 mg/wk MK-2206; 1 of 17 patients experienced DLT (grade 3 rash) at this dose. The most common adverse events at MTD were rash (44.4%), stomatitis (38.9%), diarrhea (27.8%), and decreased appetite (27.8%). By investigator assessment, 2 of 16 (12.5%) evaluable patients with breast cancer had partial response; by central assessment, 2 of 14 (14.3%) evaluable patients had complete response. Two patients had durable stable disease (SD) for 416 and 285 days, respectively. No patients with prostate cancer responded; one patient had SD for ≥6 months. Conclusions: Combination ridaforolimus and MK-2206 showed promising activity and good tolerability in heavily pretreated patients with hormone-positive and -negative breast cancer exhibiting PI3K pathway dependence. © 2015 American Association for Cancer Research. Source

Manson G.,Rennes University Hospital Center | Norwood J.,Rennes University Hospital Center | Marabelle A.,DITEP | Marabelle A.,French Institute of Health and Medical Research | And 3 more authors.
Annals of Oncology | Year: 2016

Checkpoint inhibitors (CPI), namely anti-CTLA4 and anti-PD1/PD-L1 antibodies, demonstrated efficacy across multiple types of cancer. However, only subgroups of patients respond to these therapies. Additionally, CPI can induce severe immune-related adverse events (irAE). Biomarkers that predict efficacy and toxicity may help define the patients who may benefit the most from these costly and potentially toxic therapies. In this study, we review the main biomarkers that have been associated with the efficacy (pharmacodynamics and clinical benefit) and the toxicity (irAE) of CPIs in patients. © The Author 2016. Source

Bellesoeur A.,AERIO | Brunot A.,AERIO | Calcagno F.,AERIO | Grellety T.,AERIO | And 7 more authors.
Oncologie | Year: 2014

Major innovations about targeted anticancer therapies were discussed during the TAT 2014 congress, in Washington, March 5-7, 2014. Dr Patricia M. LoRusso (Detroit), one of the most productive oncology phase 1 investigators, introduced the congress with her speech about "The Changing Landscape of Early Phase Trials." Then, various presentations on a broad range of new promising targeted cancer therapeutics and their development issues confirmed this idea. As a major topic, immunotherapy began the congress, wondering about the role of Programmed Death Ligand 1 (PDL1) as efficacy biomarker and possibilities of immunologic agents association. Among the promising molecules, the congress presented inhibitors of cdk4/6 as cell cycle targets and FGFR inhibitors with their major challenge of identifying accessible response biomarker. Special sessions were devoted to methodological evolutions such as preclinical models development, circulating tumoral DNA, or the role of genomics in early-phase drug development. The French basket trial SHIVA was presented to illustrate the place of genomics in newly conceived trials. SHIVA is a phase II trial evaluating efficacy and feasibility of a targeted treatment according to the molecular profile versus standard treatment. Finally, methodological issues in early drug development were discussed with biomarker's challenge, correlating signaling inhibition and drug resistance to targeted agents. © 2014 Springer-Verlag. Source

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