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. 0 20 40 60 80 100 120 12345 400 mg 800 mg S0033 Percent with Maximum Toxicity at or above Listed Grade by Dose P <.0001

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

6. Imatinib Mesylate Side Effects Medication is well tolerated Medication is well tolerated Majority of patients (90-100%) experience adverse effects at some time most being mild to moderate grade 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 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. Fluid retention is the most common side effect. Superficial edema occurs in periorbital and extremity areas. Reported in about 60% of patients. 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. 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. 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. 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. Management of edema may be accomplished with diuretic usage. Low salt diet is encouraged. 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). 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. 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. 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. 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. Dyspepsia can be managed symptomatically with antacids or proton pump inhibitors. Flatulence occurs in about 23% of patients. Many patients use Simethicone. Flatulence occurs in about 23% of patients. Many patients use Simethicone.

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

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

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

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

16. Hemorrhage Bleeding is noted in 17% of patients. 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. 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. 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. 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. 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. 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 %) Grade 3 or 4 hematological toxicities were observed infrequently. (1 – 7 %)

19. Hematologic Side Effects No neutropenic fever or septic complications were reported. 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. 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. Dose Adjustments for Neutropenia and Thrombocytopenia Absolute neutrophil count (ANC) < 1.0 and/or platelets <50. 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.

21. Hepatotoxicity Liver function studies are monitored before initiation of treatment and monthly or as clinically indicated. 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. 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. 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. It is suggested that Acetaminophen-containing products be avoided. Underlying liver dysfunction may increase the risk for liver toxicity. 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. Imatinib can increase exposure to co medications that are substrates of CYP3A4. Co administration of imatinib with inhibitors of CYP3A4 may increase imatinib exposure. 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. 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. Check with your care provider before beginning any new medications.

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

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

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

27. Gleevec in Summary Medication is well tolerated Medication is well tolerated Majority of patients (90-100%) experience adverse effects at some time, most being mild to moderate grade 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 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%) Fatigue most common (56%) Rash/dermatitis Rash/dermatitis Discoloration of skin Discoloration of skin Hypertension Hypertension Arthralgias Arthralgias Headache Headache Edema Edema

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

31. Hematological Side Effects Neutropenia Neutropenia Thrombocytopenia Thrombocytopenia Anemia Anemia

32. SU011248 Side Effects Generally acceptable and manageable on the 4/2 schedule Generally acceptable and manageable on the 4/2 schedule Mostly reversible upon discontinuation of treatment Mostly reversible upon discontinuation of treatment Degree of severity has been correlated with higher drug exposure 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 Nausea/vomiting Thrombocytopenia Thrombocytopenia Pyrexia Pyrexia Anemia Anemia Headache Headache Cough Cough

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

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

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

38. New Set of Challenges With Oral Therapies Patient compliance Patient compliance Safe administration Safe administration Side effect monitoring Side effect monitoring Drug and food interactions Drug and food interactions Medication costs\Insurance issues Medication costs\Insurance issues Availability Availability

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

40. Questions