Management of Side Effects

2. Management of Side Effects Monica Davey, RN BSN MEd MBA Clinical Research Nurse Coordinator Sarcoma Program Fox Chase Cancer Center Philadelphia, PA

3. Imatinib Mesylate(Gleevec, STI571, CGP57148B) • Potent inhibitor of ABL, BCR-ABL, PDGFR and KIT tyrosine kinases

4. 400 mg 800 mg S0033Percent with MaximumToxicity at or above Listed Grade by Dose 120 100 80 P <.0001 60 40 20 0 1 2 3 4 5

5. Percent with Toxicity ≥ Grade 3 S0033 400 mg/day (n=224) 800 mg/day (n=234) 18.2 12.3 5.2 4.6 3.7 7.4 2.8 3.4 2.5 1.5 Hematologic Gastrointestinal Cardiovascular Hemorrhage Flu-like Symptoms Pain Dermatologic Infection Liver Lung 20.7 14.8 12.7 9.9 8.0 7.7 7.7 4.6 3.7 3.4 Any Toxicity 35.8 51.8

6. Imatinib Mesylate Side Effects • Medication is well tolerated • Majority of patients (90-100%) experience adverse effects at some time most being mild to moderate grade • Grade 3 and 4 toxicity is seen in only one out of five patients

7. Imatinib Mesylate Side Effects • Fluid retention is the most common side effect. • Superficial edema occurs in periorbital and extremity areas. Reported in about 60% of patients. • Pleural effusion or ascites is uncommon occurring in about 2% of all patients. • Grade 3 or 4 edema is uncommon reported in 5% of patients.

8. Management of Fluid Retention • Weigh yourself twice a week and notify your care provider if you gain more that five pounds from baseline. • Management of edema may be accomplished with diuretic usage. • Low salt diet is encouraged.

9. Management of Fluid Retention • With clinically significant grade 2 edema (symptomatic requiring therapy), you may need to hold Gleevec until the fluid retention resolves to grade 1 (asymptomatic).

10. Gastrointestinal Side Effects • Gleevec is known to be a GI irritant. • This is less if you take the pills with meals, a large glass of water, and remain upright for about an hour. • It should not be taken with grapefruit containing products or caffeine, as they may interfere with drug metabolism. Caffeine should also be avoided for one hour around ingestion.

11. Gastrointestinal Side Effects • Dyspepsia can be managed symptomatically with antacids or proton pump inhibitors. • Flatulence occurs in about 23% of patients. Many patients use Simethicone.

12. Imatinib Mesylate Side Effects • Fatigue occurs in 38% of patients. • May be self limiting.

13. Myalgias • Muscle cramps occurring in the hands, feet, and or legs occurs in 41% of patients. • These are usually occasional in nature. • May be increased with prolonged therapy. • May be mitigated by increasing oral fluid intake on a regular basis. • Quinine can be effective for treatment.

14. Skin Rash • Occurs in 38% of patients. • Rash may be with or without pruritis or pustules. • Usually resolves with topical or oral diphenhydramine hydrochloride (Benadryl).

15. Pain • Abdominal pain and cramping occurs in 37% of patients. • Headache occurs in 35% of patients. • Treatment is symptomatic.

16. Hemorrhage • Bleeding is noted in 17% of patients. • This can be severe occurring as tumor hemorrhage, GI tract hemorrhage or one reported case of cerebral hemorrhage. • Less severe bleeding has been reported such as subconjunctival or guaiac-positive stools. • May be increased in CML patients with abnormal bone marrow function and decreased platelets.

17. Hemorrhage Continued • No therapeutic anticoagulation with warfarin (Coumadin) was permitted in patients that participated in the clinical trials since warfarin is metabolized through the CYP450 system and GI bleeding may occur with Gleevec. Low-molecular weight heparin (Lovenox) was utilized. Mini-dose Coumadin was permitted for prophylaxis of central venous catheter thrombosis. These patients were closely monitored.

18. Hematologic Side Effects • Anemia (94%), Neutropenia (43%), and thrombocytopenia (23%) are common occurrences in GIST patients treated with Gleevec. • Grade 3 or 4 hematological toxicities were observed infrequently. (1 – 7 %)

19. Hematologic Side Effects • No neutropenic fever or septic complications were reported. • Complete blood counts are usually performed weekly for the first month, biweekly for the second month, and then every three months thereafter as clinically indicated.

20. Absolute neutrophil count (ANC) < 1.0 and/or platelets <50. Stop Imatinib Mesylate until ANC is > 1.5 and platelets are > 75. Resume treatment at ordered dose. If recurrence of ANC < 1.0 and/or platelets < 50, repeat first step, then resume treatment with a dose reduction. Dose Adjustments for Neutropenia and Thrombocytopenia

21. Hepatotoxicity • Liver function studies are monitored before initiation of treatment and monthly or as clinically indicated. • Elevation of AST and ALT was observed in 50% and 34% of patients respectively. • Grade 3 or 4 elevations in bilirubin occurred in about 3% of patients. Hepatic metastases were present in those patients observed.

22. Hepatotoxicity continued • It is suggested that Acetaminophen-containing products be avoided. • Underlying liver dysfunction may increase the risk for liver toxicity.

23. Drug-Drug Interactions • Imatinib can increase exposure to co medications that are substrates of CYP3A4. • Co administration of imatinib with inhibitors of CYP3A4 may increase imatinib exposure. • Systemic exposure to substrates of CYP2D6 is expected to be increased when co-administered with Gleevec. • Check with your care provider before beginning any new medications.

24. Drug-Food Interactions • Grapefruit and other foods may alter pharmacokinetics. • Do not take eat Grapefruit or ingest grapefruit juice while taking Gleevec. • Avoid Caffeinated beverages for one hour around Gleevec ingestion.

25. Special Populations • Reliable birth control is to be utilized. • The efficacy of Gleevec was similar in older and younger patients. • Safety and effectiveness in pediatric patients have not been established.

26. Late Side Effects • Thin skin • Easy bruising • Hair thinning with lack of texture • Sub-conjunctival hemorrhages • Fatigue • Anemia

27. Gleevec in Summary • Medication is well tolerated • Majority of patients (90-100%) experience adverse effects at some time, most being mild to moderate grade • Grade 3 and 4 toxicity are seen in only one out of five patients

28. Sutent/SU011248 Multi-targeted tyrosine kinase inhibitor

29. Sutent Side Effects • Fatigue most common (56%) • Rash/dermatitis • Discoloration of skin • Hypertension • Arthralgias • Headache • Edema

30. Gastrointestinal Side Effects • Nausea • Vomiting • Diarrhea • Altered taste • Anorexia • Abdominal pain/distention • Dyspepsia • Stomatitis

31. Hematological Side Effects • Neutropenia • Thrombocytopenia • Anemia

32. SU011248 Side Effects • Generally acceptable and manageable on the 4/2 schedule • Mostly reversible upon discontinuation of treatment • Degree of severity has been correlated with higher drug exposure

33. AMN 107 Nilotinib A Synthetic Second Generation Multi-targeted Tyrosine kinase Inhibitor

34. AMN 107 Side Effects • Nausea/vomiting • Thrombocytopenia • Pyrexia • Anemia • Headache • Cough

35. AMN 107 Side Effects • Diarrhea • Fatigue • Rash • Dyspnea • Peripheral edema • Arthralgias • Elevated transaminases

36. RAD001 Side Effects • Headache • Hyperlipidemia • Neutropenia • Thrombocytopenia

37. Summary • SU011248 /Sutent is currently available for Gleevec resistant GIST • Other drugs are currently in development RAD001, AMN 107

38. New Set of Challenges With Oral Therapies • Patientcompliance • Safe administration • Side effect monitoring • Drug and foodinteractions • Medication costs\Insurance issues • Availability

39. Oral chemotherapy can be effective only if patients adhere to its administration schedule

40. Questions