C. Massard

Frequency and management of troponin I elevation in patients treated with molecular targeted therapies in phase I trials.

SummaryBackground Cardiotoxicity of Molecular Targeted Therapies (MTT) is poorly understood and is being investigated among patients with metastatic solid tumours. The frequency of cardiac events among patients receiving MTT has been evaluated in various ways, particularly troponin elevations. Patients and methods We prospectively evaluated cardiotoxicity among patients included in Phase 1 trials receiving molecular targeted therapies (MTT) for a metastatic solid tumour. At baseline, all patients were examined before the first cycle and monitored including a clinical examination, ECG and troponin I measurement. A trans-thoracic echocardiography was performed at baseline and before each cycle. Patients were enrolled in different trials investigating : an anti-VEGF monoclonal antibody, anti-VEGFR tyrosine kinase inhibitors, and a kinesin inhibitor. Results Among the 90 patients evaluated, 10 (11%) experienced chest pain and troponin I elevation (nu2009=u20092,20%) or asymptomatic troponin I elevation (nu2009=u20098, 80%) during follow-up. All patients were re-evaluated at the time of symptoms or troponin I elevation with trans-thoracic echocardiography, cardiac magnetic resonance and coronary angiography. All except one patient, had a normal LVEF during their re-evaluation. One patient exhibited ECG changes (T wave inversion). No QTc interval prolongation was found. On cardiac magnetic resonance, no late gadolinium myocardial enhancement was observed. All coronary angiographies were normal (no occlusion, or coronary stenosis >50%). All patients received beta blockers and aspirin. All Patients were re-challenged with the study drug and no cardiotoxicity was observed during follow up. Conclusion Troponin elevations are frequent among patients receiving molecular targeted therapies. Re-challenging these patients after a careful evaluation and under medical treatment seems to be possible. The mechanism underlying troponin elevations does not seem to be associated with coronary occlusion nor with toxic myocarditis.

QT interval prolongation among patients treated with angiogenesis inhibitors.

Among toxicities associated with molecular targeted agents (MTA), cardiovascular toxicities remain largely unknown or underestimated. Their frequency is variable and dependent on the compound. A high incidence of hypertension, symptomatic or asymptomatic left ventricular systolic dysfunction, acute coronary syndrome, arterial and venous thrombosis has been observed in patients receiving MTA. One of the most threatening complications of angiogenic inhibitors (AI) could be QT prolongation with the risk of torsade de pointes (TdP) and sudden death. QT prolongation and torsade de pointes accounted for 29% of cardiac and non-cardiac post-marketing withdrawals. The assessment of the effects of drugs on cardiac repolarization is the subject of recent guidelines and recommendations. Regulatory agencies now require practically every new pharmaceutical compound to undergo a thorough investigation of its propensity to modify cardiac repolarization. To reduce the incidence of QT prolongation and torsade de pointes in patients receiving AI, cancer patients should be closely monitored while receiving AI.

A phase I, dose-escalation study of the Eg5-inhibitor EMD 534085 in patients with advanced solid tumors or lymphoma

SummaryBackground The kinesin spindle protein Eg5 is involved in mitosis, and its inhibition promotes mitotic arrest. EMD 534085, a potent, reversible Eg5 inhibitor, demonstrated significant preclinical antitumor activity. Methods This first-in-man, single-center, open-label, phase I dose-escalation study (3u2009+u20093 design) investigated EMD 534085 safety, pharmacokinetics and antitumor activity in refractory solid tumors, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma. EMD 534085 (starting dose 2xa0mg/m2/day) was administered intravenously every 3xa0weeks. Doses were escalated in 100xa0% steps in successive cohorts of 3 patients until grade 2 toxicity occurred, followed by 50xa0% until the first dose-limiting toxicity (DLT) arose. If <2 of 6 patients experienced a DLT, doses were further increased by 25xa0%. Dose-escalation was stopped if a DLT occurred in ≥2 of 6 patients. Results Forty-four patients received EMD 534085. Median treatment duration was 43xa0days (range, 21–337). Thirty-eight patients (86xa0%) received ≥2xa0cycles. DLTs were grade 4 neutropenia (1 patient each at 108 and 135xa0mg/m2/day), and grade 3 acute coronary syndrome with troponin I elevation (1 patient at 135xa0mg/m2/day). The maximum tolerated dose (MTD) was 108xa0mg/m2/day. The most common treatment-related adverse events were asthenia (50xa0%) and neutropenia (32xa0%). EMD 534085 appeared to have linear pharmacokinetics. Increase in phospho-histone H3 positive cells in paired pre- and on-treatment biopsies showed evidence of target modulation. No complete or partial responses were observed. Best response was stable disease in 23 patients (52xa0%). Conclusions EMD 534085 appeared to be well tolerated; MTD was 108xa0mg/m2/day. Preliminary antitumor results suggested limited activity in monotherapy.

New agents in metastatic prostate cancer.

Since the identification, in 1941, of the high antitumour activity of androgen deprivation therapy in patients with metastatic prostate cancer, only 3-weekly docetaxel was shown to improve survival, while zoledronic acid reduces the incidence of skeletalrelated events in patients with castration-resistant prostate cancer (CRPC) [1,2]. The addition of estramustine to chemotherapy significantly improved overall survival in patients with CRPC in a metaanalysis of randomised trials [3]. Greater knowledge of prostate cancer biology has led to the isolation of many new and promising targets, and agents targeting these molecules are currently under development. Several studies demonstrated that CRPC remains driven by the androgen receptor (AR) signalling pathway despite castrate androgen levels, indicating that “hormone-refractory prostate cancer” (HRPC) is not an appropriate designation. Abiraterone acetate is an oral and selective inhibitor of CYP17, a key enzyme in androgen synthesis. This agent is usually well-tolerated. In chemotherapy-naive CRPC patients, abiraterone has shown impressive antitumour activity in phase I and phase II trials [4,5]. A large randomised phase III trial which enrolled more than 1000 CRPC patients recently completed its accrual, and is evaluating abiraterone in patients progressing after docetaxel. Other compounds that bind to the androgen receptor with a greater affinity than antiandrogens such as bicalutamide, inducing a strong inhibition of the AR signalling pathway, are in development [6]. For example, MDV3100 showed a promising activity in CRPC in a recent phase I/II trial [7] and a large phase III is starting to evaluate MDV3100 in patients with CRPC progressing after docetaxel. With the demonstration of docetaxel activity in 2004, chemotherapy is still regarded as a potential area of research in prostate cancer: this includes the earlier assessment of docetaxel in hormone-naive, metastatic prostate cancer, with a phase III trial (GETUG 15) having completed its planned accrual of 380 patients in 2008, and the development of newer chemotherapy agents including epothilones and cabazitaxel, a newgeneration taxane, with a recently completed postdocetaxel phase IIII trial. The skeleton is the primary site of metastases in patients with advanced prostate cancer, and virtually all patients who die from prostate cancer have bone metastases. Under normal conditions, bone undergoes continuous remodelling in a tightly coordinated and balanced process of bone resorption (mediated by osteoclasts) and bone formation (mediated by osteoblasts). In bone metastases, a perturbation between osteoblats and osteoclasts is induced by tumour cells, leading to a “vicious cycle” [8]. Besides bisphosphonates, the main and currently most advanced attempts to target osteoclast activation by cancer cells include denosumab, a fully human monoclonal antibody directed to RANK-L. Denosumab was shown to reduce uNTx levels significantly better than zoledronic acid does in patients with bone metastases and elevated levels while on intravenous bisphosphonate [9]. Denosumab is being investigated for its potential to help reduce or prevent skeletal complications due to bone metastases from prostate cancer in a large phase III trial (n> 1700) which completed its accrual in 2008. Dasatinib, a src inhibitor, was also demonstrated to result in decreased uNTx levels in patients with bone metastases and is currently being assessed in a phase III trial in CRPC in combination with docetaxel. Activation of the endothelin A (ETA) receptor by endothelin-1 mediates a signalling cascade which promotes tumour cell growth and survival, angiogenesis, invasion, metastasis, and inhibition of apoptosis. ZD4054 is an oral, specific ETA receptor antagonist with improved overall survival rates in a randomised phase II trial [10]. A large phase III programme (ENTHUSE) is ongoing to evaluate ZD4054 in advanced CRPC in different settings: in prevention of bone metastases, in patients with established bone metastases before chemotherapy, and in combination with docetaxel. Finally, phase I-II clinical data support the use of a bone-targeting strategy combining chemotherapy and bone-specific radiopharmaceuticals like samarium-153 [11].