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A Phase Trial of olanzapine Zyprexa for the Prevention of

VIEWS: 4 PAGES: 8

									  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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