Olanzapine Combines Granisetron And Dexamethasone For The Prevention Of Chemotherapy-induced Emesis And Nausea In Cancer Patients: A Phase Ⅰ Trial

Olanzapin is one of thiobenzodiazepin atypical antipsychotic and was found sideeffects of increasing appetite and weight gain in these patients. Many advanced cancerpatients have maransis and even cachexia result from anorexia and nutrition metabolicdisorder. Therefore Olanzapin may be the suitable durg for these patients. Meanwhilebecause of affinity for a variety of receptors（5-HT2a,5-HT2c,5-HT3, and5-HT6, D1-4,α1，M1-5and H1receptors）, Olanzapin has much more other efficacyy such asantiemesis, relieving pain, antianxiety, and treating delirium. Recent years, many trials arestudying in Olanzapin preventing chemotherapy-induced emesis and nausea in cancerpatients, most of which have short administration time and limited observed index. Fewclinical trial works on observing appetite and weight of cancer patients. This open-labeldose-escalation phase I clinical trial is to identify the dose-limiting toxicity (DLT) andmaximum tolerated dose (MTD) of Olanzapin administered once daily for15days inChinese cancer patients receiving chemotherapy for further investigation in phase II trial.ObjectiveTo identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) ofOlanzapine for preventing CINV in Chinese cancer patients receiving chemotherapy.MethodsThis open-label phase I study enrolled patients who received Olanzapine combiningGranisetron and Dexamethasone or the prevention CINV in cancer patients in sixdose-escalation cohorts in a standard3+3design. The initial dose cohort of Olanzapinewas2.5mg and cohort could be expanded to6evaluable patients if a DLT was observedin the first dose cohort among the initial3patients. If2DLTs were observed during onedose cohort, dose-escalation was halted and dose finding continued at a lower level untilthe MTD (the highest dose level for which the incidence of first dose cohort DLT was<33%) was identified. In the absence of DLTs, the dose was escalated until the terminalcohort (20mg).ResultsEighteen patients were enrolled and fifteen patients were evaluable. DLTs wereobserved in two patients at15mg once daily dose levels. The MTD and recommendedphase II dose of Olanzapine was10mg once daily. The DLTs include dry mouth and somnolence. Grade2somnolence, sedation, dizziness, akathisia, constipation, fatigue andbone marrow suppression occurred in these patients, respectively. Loss of appetiteoccurred in all15evaluable patients during chemotherapy. The control rate of appetite losswas60%and the appetite was recoveried as before chemotherapy within the first week.The body weight began to increase at day-15comparing baseline. The complete responseand effective rate of vomiting were87%and93%for the acute period and53%and67%for delayed period and overall period, respectively. The complete response and effectiverate of nausea were73%and87%for the acute period;13%and33%for delayed periodand overall period, respectively. The quality of life, function and fatigue improved at day15comparing with baseline, while insomnia relieved instantly after drug treatment.ConclusionOlanzapine is well tolerated and safe in using recommended dose10mg on days-1to14per night in Chinese cancer patients receiving chemotherapy.