piperidines and Asthenia

Angiogenesis does not initiate malignancy but promotes tumor progression and metastasis. Inhibiting angiogenesis is now a validated strategy for treatment of cancer. In order to do it, different ways are under investigation from cellular therapy to oral agents. Nowadays targeting angiogenesis with small molecules mainly concern inhibition of the VEGF receptors tyrosine kinase activity. Five molecules are currently in phase III trials and two of them (sunitinib and sorafenib) have been approved by the FDA for the treatment of advanced renal cancer. Despite those encouraging results, numerous points remain unclear. The toxicity profile seems to be favourable but long term effects could be problematic. Indeed, clinical trials have pointed out the role of VEGF pathway in the maintenance of numerous physiological functions. Moreover, none of the agents are specifically anti-angiogenic and the respective parts of the "off target" effects are difficult to evaluate. Simple and reliable surrogate markers of toxicity and efficacy are still lacking.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Asthenia; Axitinib; Benzenesulfonates; Humans; Hypertension; Imidazoles; Indazoles; Indoles; Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Phthalazines; Piperidines; Proteinuria; Pyridines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments.. In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18-75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8-24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073.. Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2-10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment).. These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis.. AB Science (Paris, France).

Topics: Adult; Aged; Aged, 80 and over; Asthenia; Benzamides; Diarrhea; Double-Blind Method; Exanthema; Female; Humans; Male; Mastocytosis, Systemic; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyridines; Severity of Illness Index; Thiazoles; Treatment Outcome; Urticaria; Young Adult

Flavopiridol is the first cyclin-dependent kinase (cdk) inhibitor to enter clinical trials. Serum levels of flavopiridol obtained during phase I studies were sufficient to inhibit in vitro cancer cell growth. Because responses were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of flavopiridol in this patient population.. Thirty-five minimally pretreated patients were accrued using a standard two-step mechanism. Flavopiridol (50 mg/m(2)/d) was administered by continuous infusion for 72 hours every 2 weeks, and response was evaluated every 8 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, at completion of drug infusion, and on day 7 of the first therapy cycle, and cell cycle parameters after phytohemagglutinin and interleukin-2 stimulation were assessed.. There were two objective responses (response rate = 6%, 95% confidence interval, 1% to 20%). The most common toxicities were asthenia, occurring in 83% of patients (grade 3 or 4 in 9%), and diarrhea, occurring in 77% of patients (grade 3 or 4 in 20%). Also, nine patients (26%) experienced grade 3 or 4 vascular thrombotic events, including one myocardial infarction, two transient neurologic ischemic attacks, four deep venous thrombosis, and two pulmonary emboli. Cell cycle studies did not reveal any effect of flavopiridol on stimulated PBMCs.. Flavopiridol, at the dose and schedule administered in this trial, is ineffective in metastatic renal cancer. In addition to the diarrhea observed in phase I studies, we also observed a higher incidence of asthenia and serious vascular thrombotic events than expected.

Topics: Adult; Aged; Antineoplastic Agents; Asthenia; Bone Neoplasms; Carcinoma, Renal Cell; Diarrhea; Drug Administration Schedule; Female; Flavonoids; Humans; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Piperidines; Thrombosis; Treatment Outcome