S. Faivre

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1α-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.

Phase I study of BIBF 1120 with docetaxel and prednisone in metastatic chemo-naive hormone-refractory prostate cancer patients

Background:BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1–3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients.Methods:This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m−2, every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity.Results:Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ⩾50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone.Conclusion:Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m−2 of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.

Aplidine: A Paradigm of How to Handle The Activity and Toxicity of A Novel Marine Anticancer Poison

The marine ecosystem that has contributed to the discovery of cytarabine and its fluorinated derivative gemcitabine is now considered the most productive toll to acquire new natural derived anticancer entities. Few marine anticancer agents have entered clinical development, including bryostatin-1, dolastatin 10, LU103793, ET-743, kahalalide F, didemnin B and aplidine. The marine plitidepsin aplidine derived from the mediterranean tunicate Aplidium albicans is a synthetically produced anticancer agent that is structurally related to didemnins. Aplidines mechanism of action involves several pathways, including cell cycle arrest, inhibition of protein synthesis and antiangiogenic activity. Phase I studies have been reported for a number of several schedules including 1-hour, 3-hour and 24-hour infusion. Evidences of antitumor activity and clinical benefit of aplidine in several tumor types were noted across phase I trials, particularly in advanced medullar thyroid carcinoma. Phase II studies are underway. Within the entire phase I program, dose-limiting toxicities of aplidine were neuromuscular toxicity, asthenia, skin toxicity, and diarrhea. Interestingly, no hematological toxicity was observed. Aplidine displayed a very peculiar delayed neuromuscular toxicity that was found to be closely related to the symptoms described in the adult form of carnitine palmitoyl transferase deficiency type 2, which is a genetic disease treated with L-carnitine. Consistently, concomitant administration of L-carnitine allowed to improve aplidine-induce neuromuscular toxicity. In summary, aplidine is a novel marine anticancer agent with a very particular delayed neuromuscular toxicity that requires careful follow-up with promising antitumor activity.

Antiproliferative effects of sapacitabine (CYC682), a novel 2'-deoxycytidine-derivative, in human cancer cells

This study assessed the antiproliferative activity of sapacitabine (CYC682, CS-682) in a panel of 10 human cancer cell lines with varying degrees of resistance or sensitivity to the commonly used nucleoside analogues ara-C and gemcitabine. Growth inhibition studies using sapacitabine and CNDAC were performed in the panel of cell lines and compared with both nucleoside analogues and other anticancer compounds including oxaliplatin, doxorubicin, docetaxel and seliciclib. Sapacitabine displayed antiproliferative activity across a range of concentrations in a variety of cell lines, including those shown to be resistant to several anticancer drugs. Sapacitabine is biotransformed by plasma, gut and liver amidases into CNDAC and causes cell cycle arrest predominantly in the G2/M phase. No clear correlation was observed between sensitivity to sapacitabine and the expression of critical factors involved in resistance to nucleoside analogues such as deoxycytidine kinase (dCK), human equilibrative nucleoside transporter 1, cytosolic 5′-nucleotidase and DNA polymerase-α. However, sapacitabine showed cytotoxic activity against dCK-deficient L1210 cells indicating that in some cells, a dCK-independent mechanism of action may be involved. In addition, sapacitabine showed a synergistic effect when combined with gemcitabine and sequence-specific synergy with doxorubicin and oxaliplatin. Sapacitabine is therefore a good candidate for further evaluation in combination with currently used anticancer agents in tumour types with unmet needs.

Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells

PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKCδ and inhibiting PKCα. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC50 of PEP005 ranged from 0.01–140 μM. The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 μM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKCδ and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours.

Single agent and combination studies of pralatrexate and molecular correlates of sensitivity

Background:Pralatrexate is a dihydrofolate reductase (DHFR) inhibitor with high affinity for reduced folate carrier 1 (RFC-1) and folylpolyglutamate synthetase (FPGS), resulting in extensive internalization and accumulation in tumour cells. Pralatrexate is approved in the US for the treatment of relapsed or refractory peripheral T-cell lymphoma and is being investigated in various malignancies. Here, we evaluated molecular correlates of sensitivity to pralatrexate and explored combinations with a variety of anticancer agents.Methods:Antiproliferative effects of pralatrexate were evaluated in 15 human-cancer cell lines using the MTT assay. Gene expression was evaluated using qRT–PCR.Results:Pralatrexate and methotrexate had a similar pattern of cytotoxicity, pralatrexate being more potent. Pralatrexate potentiated the effects of platinum drugs, antimetabolites and EGFR inhibitors. Dose- and time-dependent cytotoxicity of pralatrexate correlated with high mRNA expression of FPGS. Acquired resistance to pralatrexate was associated with decreased RFC-1 expression, whereas methotrexate resistance correlated with increased DHFR expression, suggesting different mechanisms of acquired resistance.Conclusion:Pralatrexate was more potent than methotrexate in a panel of solid tumour lines. Our findings support the further clinical development of pralatrexate in combination with certain cytotoxics and targeted therapies, and suggest that RFC-1, FPGS and DHFR may be potential biomarkers of outcome.

996PCETUXIMAB RELATIVE DOSE INTENSITY (RDI) IN RECURRENT/METASTATIC (R/M) SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (SCCHN): FIRST OBSERVATIONAL PROSPECTIVE STUDY IN UNSELECTED PATIENTS (DIRECT TRIAL)

ABSTRACT Aim: Cetuximab combined with platinum is the standard first-line therapy in patients (pts) with R/M SCCHN. DIRECT is the first multicenter prospective observational study evaluating cetuximab RDI in this setting. Methods: Pts were prospectively enrolled. No prior systemic therapy for R/M SCCHN was allowed. Pts received cetuximab in combination with platinum, according to the pivotal study EXTREME schedule, 5-FU if not contra-indicated and maintenance treatment with cetuximab every 2 weeks was allowed. The primary endpoint was the number of pts with cetuximab RDI >80%. Results: High quality of data was obtained by frequent monitoring of sites every 3 months (evaluable data in 93% of pts for baseline characteristics and in 89% of pts for cetuximab RDI). 154 pts were enrolled in 53 centres between 2012/11 and 2013/03: 86% male, median age 59 years, 81% with PS 80% in 68.5%, 64.7% and 93%, during chemotherapy (CT), CT + maintenance or maintenance periods respectively. Planned doses of cetuximab were decreased in 9.7% and delayed in 36% of 154 pts, mostly during CT. 97 pts (63.0%) withdrew the study for progression (48.5%), death (31%), toxicity (6%), lost to follow-up (1%), or other reasons (13.5%). Grade > 2 skin toxicities were observed in 9 (5.8%) pts. Conclusions: In unselected pts, RDI data in DIRECT study confirms the feasibility and the good tolerance of cetuximab combined with platinum previously reported in the pivotal trial. DIRECT study supports the use of cetuximab + CT as standard treatment in clinical practice. Disclosure: J. Guigay: Research funding : GSK; Merck Serono; Novartis Honoraria : Merck Serono; B. Petre-Lazar: Medical advisor: Merck Serono; F. Mornex, P. Ceruse, M. Alfonsi and C. Le Tourneau: Honoraria : Merck Serono; A. Berrier: Research funding : Merck Serono; S. Faivre: membership advisory board : Merck Serono Honoraria : Merck Serono Research funding: Merck Serono; F. Rolland: Honoraria : Merck Serono Expert Testimony : Merck Serono. All other authors have declared no conflicts of interest.