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A Phase I Trial of Olanzapine (Zyprexa) for the Prevention of Delayed Emesis in Cancer Patients: A Hoosier Oncology Group Study Steven D. Passik1,2, Patrick Loehrer1,3, Rudolph M. Navari1,4 , Sin-Ho Jung5, Cynthia Nagy 1,4, Jake Vinson1 1. Hoosier Oncology Group, a program of the Walther Cancer Institute: 3266 N. Meridian St. #902, Indianapolis, IN 46208 2. Markey Cancer Center, University of Kentucky 3. Indiana University Cancer Center, 535 Barnhill Dr. RT 473, Indianapolis, IN 46202 4. Northern Indiana Oncology Associates, 720 Cedar St. #210, South Bend, IN 46617 5. Department of Biostatistics and Bioinformatics, Duke University ABSTRACT Chemotherapy induced delayed emesis (DE) affects approximately 50-70% of patients receiving moderately and highly emetogenic chemotherapy. DE most commonly occurs within the first 24-48 hours of chemotherapy administration and can persist for 2-5 days. Olanzapine, due to its activity at multiple dopaminergic, serotonergic, muscarinic and histaminic receptor sites, has potential as an anti-emetic. We designed a Phase I study of olanzapine, utilizing a 4 cohort dose escalation of 3-6 patients per cohort, for prevention of DE in cancer patients receiving their first cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, platinum and/or irinotecan. All patients received standard pre- medication. Olanzapine was administered on days –2 and –1 prior to chemotherapy and continued for 8 days (days 0-7.) Episodes of vomiting, daily measurements for nausea, sedation, appetite and restlessness were recorded using visual analog scales. Toxicity was monitored at each dose level. FACT-G was administered to follow overall quality of life. Fifteen patients completed the protocol. No grade 4 toxicities were seen and three patients experienced a dose limiting toxicity (grade 3) of a depressed level of consciousness during the study. The maximum tolerated dose was determined to be 5 mg, days -2 and -1 and 10 mg, days 0-7. Four of 6 patients receiving highly emetogenic chemotherapy (cisplatin, >70mg/m2) and 9 of 9 patients receiving moderately emetogenic chemotherapy (doxorubicin, >50mg/m2) had complete control (no vomiting episodes) of DE. Olanzapine may be an effective agent for the prevention of chemotherapy induced DE. A phase II trial is underway. TREATMENT REGIMEN • Chemotherapy regimen containing cisplatin, cyclophosphimide, irinotecan or doxorubicin calling for treatment on Day 0 and allowing >13 days before the next treatment with chemotherapy. • Standard pretreatment antiemetic regimen consisting of dexamethasone 20 mg p.o. or I.V. and granisetron (10 micrograms/kg or 1-2 mg) 30–60 minutes prior to chemotherapy administration. • Olanzapine beginning two days before chemotherapy, the day of chemotherapy and for 7 days following chemotherapy administration. • Rescue doses (for all groups of patients will be set at 5.0 mgs of olanzapine) will be administered if patients have an episode of vomiting or experience wretching. STUDY SCHEMA FOR DOSAGE COHORTS DOSAGES OF OLANZAPINE (mg. P.O. q.am.) PER DAY OF TREATMENT Days Prior to Days After Cohort Chemotherapy Chemotherapy -2 -1 0* 1 2 3 4 5 6 7 1 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 2 5.0 5.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 3 5.0 5.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 4 10.0 10.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 *Day of Chemotherapy EVALUABLE PATIENT CHARACTERISTICS Disease Site: Non Small Cell Lung 3 Small Cell Lung 1 Prostate 1 Breast 4 Rectal/Perianal 2 Lymphoma 2 Multiple Myeloma 1 Unknown 1 Median Age 52 ECOG PS-01 13 ECOG Unknown 2 Dose Limiting Toxicities (Depressed Level of Consciousness) 3 Highly Emetogenic Regimens 6 Moderately Emetogenic Regimens 9 Patients with Emesis 2 Patients Requiring Rescue with Olanzapine 3 TOXICITY & EFFICACY Number of Patients with Patients Cohort Patients Dose Limiting Toxicity Emesis Episodes Requiring Rescue 1 3 None 1 1 2 3 None 0 1 (1) Depressed Level of 3 7 1 1 Consciousness (2) Depressed Level of 4 2 0 0 Consciousness & Fatigue CONCLUSIONS • The maximum tolerated dose was determined to be 5 mg days –2 and –1, then 10 mg on the day of chemotherapy and for 7 days following chemotherapy (cohort 2). Although cohort 3 (5 mg days –2 and –1, 15 mg days 0-7) was the highest cohort which was tolerated, following review of the data, the side effects observed in the third cohort outweighed the potential benefit of the increased dose and therefore, the clinical experience indicated that cohort 2 would be utilized as the maximum tolerated dose for future study. • Four of 6 patients receiving highly emetogenic chemotherapy (cisplatin > 70mg/m2) and 9 of 9 patients receiving moderately emetogenic chemotherapy (doxorubicin, > 50mg/m2) had complete control (no vomiting episodes) of delayed emesis. Three patients on highly emetogenic chemotherapy required rescue doses of olanzapine. • This trial suggests that olanzapine can be used for delayed emesis prevention with acceptable toxicities and therefore, a phase 2 trial with the Hoosier Oncology Group is now set to begin.
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