1. Prevention of Pegfilgrastim-induced Bone Pain (PIP): A URCC CCOP Randomized, Double-blind, Placebo-controlled Trial of 510 Cancer Patients Jeffrey J. Kirshner, Charles E. Heckler, Shaker R. Dakhil, Judith O. Hopkins, Cynthia Coles, Gary R. Morrow. Hematology-Oncology Associates of Central NY CCOP, East Syracuse, NY, U. of Rochester Cancer Center, Rochester, NY, Wichita CCOP, Wichita, KS, SECCC, Winston-Salem, NC, Metro-Minnesota CCOP, Minneapolis, MN

2. Disclosures None to report for any of the investigators

3. Background The development of G-CSF, particularly pegfilgrastim, has enabled oncologists to maintain dose intensity and to utilize “dose-dense” chemotherapy ( by limiting the severity and duration of neutropenia) This may lead to an improvement in patient survival The toxicity of pegfilgrastim is minimal and usually limited to bone pain

4. Background The incidence of pegfilgrastim-induced bone pain ranges from 26-59 % and can be “severe” in up to 24 % of patients Discontinuation of pegfilgrastim could lead to less effective chemotherapy dosing and a decrease in patient survival

5. Community Based Survey of 100 Patients (Kirshner, et al: Community Oncology 2007) 59% incidence of pegfilgrastim-induced pain 24% incidence of severe pain (>5/10) NSAIDs seemed to be the most effective analgesic for relief of pain, particularly naproxen

6. “An Ounce of Prevention Is Worth a Pound of Cure” It is better to prevent pain than to treat it once it occurs This could improve QOL and possibly keep more patients on their chemotherapy schedule NSAIDs seem to be somewhat effective in relieving pegfilgrastim-induced pain NSAIDs have few side-effects and are relatively inexpensive

7. Study Objectives To determine if naproxen can reduce the incidence, severity and duration of pegfilgrastim-induced pain To better assess the true incidence of this pain in a large cross-section of patients treated by community oncologists To determine if there are risk factors which predict the development of such pain To determine if there are factors which predict efficacy of naproxen

8. Study Design Prior to first dose of pegfilgrastim Consent Questionnaires Randomize to naproxen/placebo [Baseline] Prior to first dose of pegfilgrastim Consent Questionnaires Randomize to naproxen/placebo [Baseline] Study participation ends Complete and mail outcome questionnaires [Outcome] Study participation ends Complete and mail outcome questionnaires [Outcome] Day 2, 3 or 4 of chemotherapy cycle pegfilgrastim administered SC Begin Study Medication Return Baseline questionnaires Outcome questionnaires Day 2, 3 or 4 of chemotherapy cycle pegfilgrastim administered SC Begin Study Medication Return Baseline questionnaires Outcome questionnaires Phone Call 3-5 days after pegfilgrastim administration 5 to 8 days of naproxen sodium or placebo

9. Study Drug Naproxen 500 mg or matching placebo was begun at BID dosing on the morning of pegfilgrastim administration Drug was continued for a minimum of 5 days and up to 8 days if pain continued

10. Questionnaires Patient rated their pain on a daily basis, using a scale of 0-10 (Brief Pain Inventory) Quality of Life (QOL) assessments before and after treatment, utilizing “Symptom Inventory” Any additional medications to control pain were documented (additional NSAIDs were excluded)

11. Statistical Measures Primary outcome was measurement of the AUC from baseline to Day 5 (Day 1= Day of pegfilgrastim administration) Incidence of any pain and severe pain (>5/10) was measured as well as duration of pain

12. AUC=13.5 Area Under Curve (AUC)

13. Eligibility Diagnosis of non-myeloid malignancy, scheduled to receive chemotherapy and receive a first dose of pegfilgrastim (6mg sq) on Day 2, 3 or 4 of chemotherapy cycle No history of active or past gastrointestinal bleeding No heart surgery within the past 6 months No allergies to NSAIDs

14. Eligibility Not currently taking any NSAID or steroid medication Not taking any medication for pre-existing chronic pain Not taking therapeutic doses of warfarin Normal renal function (creatinine < 1.5 X ULN)

15. Eligibility Not pregnant or nursing Able to understand English 18 years of age or older Must give written informed consent

16. Demographics at Randomization N=510; 257(Drug), 253 (Placebo). No significant difference in arms for any characteristic. Accrual from 7/08-12/09 N% Female:43786% African American:336% Asian:143% Caucasian:45589% Other:82% Breast:34167% Gynecological:296% Hematological:357% Lung:5310% Other:5010% Married:36071% Some College:34468% High school or less:16032% Mean(Min-Max) Age:56.2(22-89)

17. Patient Population URCC CCOP Research Base Study at 17 CCOP’s throughout the U.S. Accrual ranged from 1 to 110 at the sites

19. Participant Flow 257 Randomized to Drug 253 Randomized to Control N = 232 Analyzed N = 229 Analyzed 1 Ineligible 24 Did Not Complete Outcome Measures 510 Participants 24 Did Not Complete Outcome Measures

20. Results AUC for Pain was reduced from 7.7 (placebo group) to 6.0 (naproxen group) p=0.037

21. DrugPlaceboP Pain65.6%76.3% 0.01 Severe Pain17.6%24.5% 0.06 Incidence of Pain

22. Average Pain across Days Repeated Measures Analysis: P(Arm)=0.04 P(Arm*Day)=0.31 (Curves don’t have significantly different shapes.) N=461

23. Duration of Pain 2.40 days (placebo) vs. 1.92 days (naproxen) P= 0.005

24. Risk Factors for Pain No relationship to age, types of cancer nor chemotherapy Suggestion that pegfilgrastim induced pain may be more frequent in African- Americans (but only 33 patients): AUC 12.88 vs 6.48

25. Relationship to Efficacy of Naproxen No effect of age, race, type of cancer nor chemotherapy regimen

26. Adverse Events None reported on either study arm Specifically, no reports of gastrointestinal bleeding or GI distress

27. Conclusions Naproxen 500 mg BID is effective in reducing the incidence, severity and duration of pegfilgrastim induced bone pain It should be considered for patients beginning pegfilgrastim, providing there are no contraindications A significant percentage of patients still will experience pegfilgrastim induced pain and there is a need to develop more effective preventive treatments

28. Acknowledgments NCI DCP- CCOP Program (PHS Grants: 1R25CA10618 and U10CA37420) CCOP Investigators and Staff Patients, Family and Friends