Effectiveness of Aprepitant in Addition to Ondansetron in the Prevention of Nausea and Vomiting Caused by Upper Abdominal Radiotherapy

Condition(s) targeted: Nausea; Vomiting

Intervention: aprepitant (Drug); Ondansetron (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: University of Vermont

Official(s) and/or principal investigator(s):
Steven Ades, MD MSc, Principal Investigator, Affiliation: University of Vermont

Overall contact:
Steven Ades, MD MSc, Phone: 802-656-5487, Email: steven.ades@uvm.edu

Severe nausea and/or vomiting in patients receiving radiotherapy to the upper abdomen is common despite having received pre-medication with ondansetron, a standard preventive treatment. This study aims to reduce the incidence of significant nausea and/or vomiting with the addition of the NK1-antagonist aprepitant to standard ondansetron treatment. This study will also assess the safety and tolerability of prolonged administration of aprepitant over the 4 to 6 week period of radiation treatment.

Official title: Effectiveness of Aprepitant in Addition to Ondansetron in the Prevention of Nausea and Vomiting Caused by Fractionated Radiotherapy to the Upper Abdomen

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Complete Response rate (no vomiting and no rescue anti-emetic therapy)

Secondary outcome:

Complete Response rate

Proportion of patients who did not vomit

No Significant Nausea: The proportion of patients who did not experience any nausea ≥ 3 on 0 - 10 scale

No Nausea: The proportion of patients who did not experience any nausea. Nausea = 0 on 0 - 10 scale

Complete Protection: The proportion of patients who did not vomit, require rescue therapy, or have nausea ≥ 3 on 0 - 10 scale

Total Protection: The proportion of patients who did not vomit, require rescue therapy, or have any nausea (Nausea = 0 on 0 - 10 scale).

Vomiting frequency: The frequency of vomiting (# episodes per week) in patients who did vomit at least once.

Nausea frequency: The frequency of nausea (Nausea > 0 in a given week/ number of weeks during overall period of radiation treatment)

Significant Nausea frequency: The frequency of significant nausea (Nausea ≥ 3 in a given week/ number of weeks during overall period of radiation treatment)

Frequency of rescue medication use: The number of days in which rescue medication was taken / number of days of radiotherapy

Time to Failure: The time period in days from the start of radiation until the first vomiting episode or use of rescue medication for all patients and for the subset of patients who do not have a Complete Response.

All adverse events that occur during radiation treatment with assessment of severity (CTC v.3) and relationship to study drug.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Any patient with a diagnosis of malignancy localized to the upper abdomen and requiring chemoradiation or radiation alone.

2. Receiving standard-fractionation radiation therapy (> 40 Gy) 3D-conformal radiation therapy or IMRT to a field involving the upper abdomen, either alone or combined with radiosensitizing 5FU, capecitabine, or gemcitabine permitted.

3. Age > 18 years old

4. Life expectancy >3 months

5. Performance status 0-2 inclusive

6. No more than mild to moderate hepatic impairment corresponding to Child-Pugh Class A or B, respectively (Child-Pugh score 5 to 9). See Appendix V for Child Pugh Classification.

7. Women of child-bearing potential and men must agree to use adequate contraception such as abstinence or effective barrier and/or non-hormonal contraception for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

8. Adequate organ reserve to include: Absolute Neutrophil Count ≥ 1500/mcl , Hemoglobin ≥ 8. 0 g/dl, platelet count ≥ 100,000/mcl, creatinine ≤ 2. 0, AST & ALT ≤ 2. 5 x ULN

9. Baseline ECG showing QTc value ≤ 480 millisecond

10. Informed consent

Exclusion Criteria:

1. Use of any other concomitant chemotherapy agent concurrently with radiation therapy aside from capecitabine, gemcitabine, or 5-fluorouracil (none of these agents are CYP 3A4 substrates).

2. Baseline vomiting is not controlled: Patients who have vomited or have nausea requiring antiemetic treatment within 24 hours prior to initiation of treatment.

3. Scheduled to receive treatment within 24 hours prior to day one or during the study periods with other potential or known antiemetic agents including but not limited to serotonin antagonists aside from ondansetron per study protocol, phenothiazines, butyrophenones, substituted benzamides, antihistamines, and cannabinoids. Chronically used benzodiazepines may be continued as a single nightly dose for sleep.

4. Any steroid use except topical steroids. Patients need to be off systemic steroid treatment for 7 days prior to start of chemoradiation therapy.

5. Uncontrolled CNS tumor

6. Other physical causes for nausea or vomiting (such as bowel obstruction) not related to chemoradiation administration

7. Hypersensitivity to either of the study agents

8. Planned simultaneous administration of any other investigational agents

9. Pregnant or nursing women

10. Patients taking other CYP3A4 inducers or inhibitors would be required to discontinue their use for at least 7 days prior to initiation of chemoradiation therapy. Examples of CYP3A4 inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, rifampin, and St. Johns Wort. Examples of CYP3A4 inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.

11. CYP3A4 substrates are not contraindicated. However, patients taking CYP3A4 substrates should be cautioned to consult with their physician to minimize their use, if possible. Example substrates include benzodiazepines, calcium channel blockers, ranolazine, ergot derivatives, mirtazapine, nateglinide, tacrolimus, and venlafaxine.

12. Concomitant use of pimozide, terfenadine, cisapride, and astemizole is contraindicated per the Emend™ [10] product circular as dose-dependent inhibition of CYP 3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious and life-threatening reactions. Patients taking these medications ineligible to participate in this study unless they are discontinued for at least 7 days prior to start of aprepitant.

13. Warfarin: Aprepitant may increase warfarin metabolism and the INR may be decreased. Twice weekly monitoring of INR recommended in the first 2-week period of radiation followed by weekly monitoring in subsequent weeks until discontinuation of aprepitant. Twice weekly monitoring is again recommended after aprepitant discontinuation until INR has stabilized.

14. Contraceptives (estrogens and progestins): Aprepitant may decrease the plasma levels of estrogen and progestin contraceptives. Contraceptive efficacy may be reduced. A nonhormonal form of contraception is necessary during treatment and for 1 month following the last dose of aprepitant.

Steven Ades, MD MSc, Phone: 802-656-5487, Email: steven.ades@uvm.edu

Mayo Clinic Arizona, Scottsdale, Arizona 85259-5499, United States; Recruiting
Clinical Trials Referral Office, Phone: 507-538-7623
Michele Y Halyard, MD, Principal Investigator

Wake Forest Baptist Health, Winston-Salem, North Carolina 27157, United States; Recruiting
Margaret Crowley, Phone: 336-713-6627, Email: mcrowley@wakehealth.edu
Arthur W Blackstock, MD, Principal Investigator

Fletcher Allen Health Care, Burlington, Vermont 05401, United States; Recruiting
Karen Wilson, Phone: 802-656-4101, Email: karen.wilson@uvm.edu
Kimberly Luebbers, Phone: 802-656-2137, Email: kimberly.luebbers@uvm.edu
Steven Ades, MD MSc, Principal Investigator
Steven Grunberg, MD, Sub-Investigator
Ruth Heimann, MD PhD, Sub-Investigator
Marc Greenblatt, MD PhD, Sub-Investigator

Starting date: October 2009
Last updated: March 30, 2012