IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting

1. IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting Chemotherapy Adjuvant Study for Women at Advanced Age (CASA) Diana Crivellari, MD Centro di Riferimento Oncologico, Aviano (PN), Italy Silvia Dellapasqua, MD European Institute of Oncology, Milan, Italy

2. Annual Incidence by AgeUS, 1995 http://merck.micromedex.com Sirovich BE, Sox HC Jr. Surg Clin North Am 79: 961-90, 1999

3. Baseline life expectancy for patients with various ages and comorbidity levels Life expectancy (years) Age (years) Healthy Average Sick 65 20.0 18.5 9.7 70 15.8 14.8 8.6 75 12.1 11. 5 7.3 80 8.8 8.4 5.9 85 6.1 5.9 4.5 Extermann et al, JCO, 2000.

4. Available information Use of adjuvant chemotherapy for elderly women with breast cancer is controversial. Lack of clear guidelines for patients aged > 70 years. Decreasing use of chemotherapy with age. No age-related differences in drug regimens neither recommended nor preferred by pts. No clinical trials specifically conducted in elderly women with endocrine non-responsive breast cancer. EBCTCG 1998 & 2005 Overview publications: no information (too few women > 70 years).

5. Patients on IBCSG Trials I-14 according to age > 65 years old at entry Trial Total pts pts > 65 pts >70 I - IV 1601 320 137 V 2504 53 7 VI 1475 0 0 VII 1212 264 85 VIII 1111 0 0 IX 1669 392 91 10 473 446 382 11 174 0 0 12 344 108 22 13 1294 0 0 14 969 96 2 Total 12813 1666 (13%) 717 (5.6%)

6. Chemotherapy Endocrine Therapy Age DFS OS DFS OS <50 34±5 27±5 45±8 32±10 50-59 22±4 14±4 37±6 11±8 60-69 18±4 8±4 54±5 33±6 70+ - - 54±13 34±13 Adjuvant treatment outcomeEBCTCG, Lancet 1998

7. Endocrine therapy vs. NilIBCSG Trial IV 1978-1981, 320 pts, age 66-80yrs; N+ R ANDOMIZE Within 6 weeks after surgery Observation p+T x 12 mos p= prednisone 7.5 mg/d T= tamoxifen 20 mg/d

8. IBCSG Trial IV Crivellari D, et al. J Clin Oncol 21: 5417-23, 2003

9. Chemotherapy Endocrine Therapy Age DFS OS DFS OS <50 34±5 27±5 45±8 32±10 50-59 22±4 14±4 37±6 11±8 60-69 18±4 8±4 54±5 33±6 70+ - - 54±13 34±13 Adjuvant treatment outcomeEBCTCG, Lancet 1998

10. Adjuvant treatment outcomeEBCTCG, Lancet 2005

11. CHEMOTHERAPY RECURRENCE Age < 50 6901 women 35% N+

12. CHEMOTHERAPY RECURRENCE Age 50 - 69 18629 women 70% N+

13. CHEMOTHERAPY RECURRENCE Age < 50 ER Poor No TAM 1673 women 12% N +

14. CHEMOTHERAPY RECURRENCE Age < 50 ER +/? All with TAM 2254 women 34% N + 87% ER+

15. CHEMOTHERAPY RECURRENCE Age 50 - 69 ER Poor No TAM 1474 women 29% N +

16. CHEMOTHERAPY RECURRENCE Age 50 - 69 ER +/? All with TAM 11333 women 73% N + 88% ER+

17. Approaches: adjuvant CT Advanced age and endocrine non-responsive breast cancer represent a therapeutic dilemma. The physician may decide not to offer a relatively frail patient any treatment for fear of possible subjective or severe toxic effects of chemotherapy. Patients may be treated in a heterogeneous way, by arbitrarily reduced doses or modified schedules of adjuvant CT regimens studied in younger women. Such dilemma does not exist if the patient is biologically (and functionally) young, and a “standard” chemotherapy regimen may be offered with no concern.

18. Rationale Relapses may occur earlier in patients with endocrine non-responsive disease, even when pN0. The choice of the population (endocrine non-responsive) is advantageous because the magnitude of CT effect for this postmenopausal cohort is likely to be quite large. Avoiding dilution with patients with endocrine responsive tumors maximizes the chance to observe a benefit in the shortest time with the lowest number of patients.

19. Chemotherapy Adjuvant Study for Women at Advanced Age (CASA) Phase III Trial Evaluating the Role of Adjuvant Pegylated Liposomal Doxorubicin (PLD, Caelyx®, Doxil®) for Women (age 66 years or older) with Endocrine Non-Responsive Breast Cancer Who Are NOT Suitable for Being Offered a “Standard Chemotherapy Regimen” Two Individual Complementary Randomization Options: Option 1: CASA-nil (PLD versus nil) Option 2: CASA-CM (PLD versus CM) Coordinating Group: IBCSG

20. Tailored Treatment Investigations A phase III study, the CASA Study, with two individual complementary randomization options: Investigate the role of adjuvant cytotoxic CT for postmenopausal women at advanced age with endocrine non-responsive early breast cancer Options tailored to the investigator's decision and/or the patient’s preference about what would constitute an appropriate control treatment group

21. Tailored Treatment Investigations Choice between options 1 & 2 allows investigators to “personalize” participation according toattitude towards adjuvant CT in a subpopulation of older women with receptor negative disease. Although incidence of breast cancer in elderly women is high, only about 15% will have a receptor negative (no expression of ER and PgR) disease. Thus, a satisfactory accrual can only be reached through an international collaboration and participation around the world.

22. Trial Design Because of the separate designs, at the time of randomization the investigator will be asked to select one of the two Randomization Options: Option 1: CASA-nil Option 2:CASA-CM R A N D O M R A N D O M PLD alone q 2w x 8 PLD alone q 2w x 8 Low-dose, metronomic CM No adjuvant therapy (nil) Randomization: within 6 (16) weeks of surgery. All regimens are 16 weeks duration. PLD: 20 mg/m2 iv x 8 doses delivered every 2 weeks Low-dose, metronomic Cyclophosphamide and Methotrexate (CM): C = cyclophosphamide 50 mg/day orally continuously for 16 weeks; M = methotrexate 2.5 mg/twice a day orally days 1 and 4 of every week for 16 weeks.

23. CASA-nil R A N D O M Caelyx alone q 2w x 8 No adjuvant therapy (nil) Randomization: within 6 (16) weeks of surgery. All regimens are 16 weeks duration. Caelyx®: 20 mg/m2 iv x 8 doses delivered every 2 weeks

24. CASA-CM R A N D O M Caelyx alone q 2w x 8 Low-dose, metronomic CM Randomization: within 6 (16) weeks of surgery. All regimens are 16 weeks duration. Caelyx®: 20 mg/m2 iv x 8 doses delivered every 2 weeks Low-dose, metronomic Cyclophosphamide and Methotrexate (CM): C = cyclophosphamide 50 mg/day orally continuously for 16 weeks M = methotrexate 2.5 mg/twice a day orally days 1 and 4 of every week for 16 weeks.

25. Tailored Treatment Investigations Due to the separate designs, at the time of randomization the investigator will be asked to select one of the two Randomization Options: Option 1, Caelyx versus nil, is designed for patients who, according to the treating physician and/or to the patient's preferences, are candidates to receive no adjuvant therapy. Option 2, Caelyx versus low dose, metronomic cyclophosphamide and methotrexate (CM), is designed for patients who, according to the treating physician and/or to the patient's preferences, should receive some adjuvant treatment.

26. Patient PopulationPatient Characteristics Women aged 66 years or older with histologically proven, resected breast cancer. Patients must NOT be candidates for endocrine therapy or standard chemotherapy regimen. Performance status (ECOG) 0-2.

27. Patient PopulationDisease Characteristics Patients must have endocrine nonresponsive tumors (ER < 10% by IHC; if PgR done, < 10% by IHC) Tumor must be confined to the breast and axillary nodes without detected metastases elsewhere. Not eligible: locally advanced inoperable BC including inflammatory BC, supraclavicular node involvement, or enlarged internal mammary nodes (unless path. neg.). Patients with synchronous (diagnosed histologically within 2 months) bilateralinvasive breast cancer eligible if all tumors are endocrine nonresponsive and above criteria are met.

28. Patient PopulationPrior Surgery Patients must have had surgery for primary breast cancer (with or without axillary clearance) with no known clinical residual loco-regional disease. Margins must be negative for invasive breast cancer and DCIS. Patients should be randomized and start treatment as close to definitive surgery as possible; within 6 weeks is recommended and not more than 16 weeks (from last surgery in case of bilateral breast cancer).

29. Patient PopulationPrior/Concurrent Disease: Not eligible Prior ipsilateral or contralateral invasive BC. Previous or concomitant malignancy within the past 5 years. Adequately treated basal or squamous cell ca. of the skin, in situ ca. of the cervix or bladder, contra- or ipsilateral in situ breast ca. are eligible regardless of date of diagnosis. Other non-malignant uncontrolled systemic diseases that would preclude trial entry according to PI (e.g. uncontrolled active or chronic infection such as active HBV or HCV). Myocardial infarction, pulmonary embolism or DVT within 6 months prior to randomization. Significant malabsorption sdr or disease affecting GI tract function At least one “geriatric syndrome”: dementia, delirium, depression, recent falls, spontaneous bone fractures, neglect and abuse.

30. Patient PopulationPrior Treatment No prior neoadjuvant or adjuvant therapy for BC. Note: Radiotherapy is allowed prior to randomization. Raloxifene, tamoxifen, or other SERM must be discontinued at least 4 weeks before randomization.

31. Patient PopulationConcurrent Treatment(at the time of randomization pts should not be receiving these treatments) No hormone replacement therapy (HRT). No hormonal therapy, except steroids for adrenal failure, hormones for non-breast cancer related conditions (e.g., insulin for diabetes), or intermittent dexamethasone as an antiemetic. No treatment with bisphosphonates, except for the treatment of osteoporosis.

32. Patient PopulationOrgan function at the time of randomization (within 2 months before randomization) 1. Adequate bone marrow, renal, and hepatic function. Values must meet the following criteria: WBC  3.0 x 109/L Granulocyte count  1.500 x 109/L Platelet count  100 x 109/L Serum creatinine < 120 mol/L (< 1.35 mg/dl) Calculated creatinine clearance at least 50 mL/min Serum bilirubin within normal/reference range AST/ALT within 1.5 x upper normal limit

33. Patient PopulationOrgan function at the time of randomization(within 2 months before randomization) 2. Adequate cardiovascular function defined as the following: LVEF  50% by echocardiography, radionuclide ventriculography or Multigated Angiography (MUGA) No ECG evidence of acute ischemia No evidence of medically relevant conduction system abnormalities, which in the opinion of the PI would preclude trial entry No myocardial infarction within the past 6 months No NYHA class III or IV congestive heart failure

34. Patient PopulationProtocol Requirements BEFORE Randomization Written Informed Consent (IC) signed and dated by patient and investigator prior to completing QL Forms and prior to randomization. Baseline QL assessment: Quality of Life Questionnaire Form QL Mini-Cog test (cognitive functioning) Vulnerable Elders Survey [VES-13] test (physical functioning) Only exceptions: physical impairment that interferes with QL assessment, inability to read any of the languages available.

35. Patient PopulationProtocol Requirements BEFORE Randomization Pathology material should be available for submission for central review as part of the quality control measures for this protocol. Patients must be accessible for follow-up. Patients must be informed of and agree to data and tissue material transfer and handling, in accordance with national data protection guidelines. Patients should have no psychiatric, addictive, or cognitive disorder that would prevent compliance with protocol requirements.

36. Endpoints Primary:Breast cancer free interval (events are reappearance of invasive breast cancer at any site including contralateral disease) Secondary:Tolerability (treatment completion) Adverse events Quality of life DFS (incl. 2nd malignancies and deaths) Sites of failure Second (non-breast) malignancy OS Causes of death

37. Statistical considerations, sample size and anticipated study duration • Primary objective: investigate role of PLD as adjuvant chemotherapy for older postmenopausal women • Stratified (pooled) analysiscombining the results of both randomization options to assess the primary evidence on effectiveness of PLD (PLD versus non-PLD-containing control groups, either nil or CM) • Separate analysesfor each of the 2 randomization options to assess each of the individual pair-wise contributions to the overall result • 1296 patients (432 per year for 3 yrs with 1.76 years of additional follow up – total study duration of 4.76 years)

38. CASA Trial… • Is about to start accrual. • Additional background for PLD or metronomic CT is available.

39. Background: PLDin metastatic breast cancer Anthracyclines, most widely used in all settings Conventional doxorubicin= low therapeutic index due to myelosuppression, alopecia, nausea& vomiting, mucositis & cumulative cardiotoxicity Elderly = increased cardiotoxicity PLD developedto improve therapeutic index of conventional anthracyclines by maintaining antitumor efficacy while improving the safetyprofile

40. Background: PLDin metastatic breast cancer PLD = doxorubicin in polyethylene glycol-coated liposomes (retain drug in circulation, accumulating preferentially in tissues with  microvascular permeability, as is the case of tumors) Lower toxicity in comparison to free doxorubicin (cardiotoxicity, vesicant effects, nausea, vomiting, alopecia and myelotoxicity) Typical toxicities (acute infusion reaction) = mucositis and PPE (especially at higher doses or short dosing intervals) PLD is commonly administered in 4-weeks intervals. Studies in pts with KS indicate that 2-week dosing is better tolerated.

41. Background: PLDin metastatic breast cancer EIO experience, data not published

42. Background: PLDin metastatic breast cancer EIO experience, data not published

43. Background: PLDin metastatic breast cancer EIO experience, data not published

44. Background: PLDin metastatic breast cancer EIO experience, data not published

45. Background: low dose CMin metastatic breast cancer Anticancer chemotherapy is thought to be effective by means of direct cytotoxicity on tumor cells. Alternative mechanisms of efficacy have been ascribed to several common anticancer agents, including Cyclophosphamide and Methotrexate, postulating an antiangiogenic activity

46. Background: low dose CMin metastatic breast cancer DrugDose Day 1 2 3 4 5 6 7 MTX 2,5 mg x 2 oral CTX 50 mg oral • Colleoni M, et al. Ann Oncol. 13: 73-80, 2002

47. Background: low dose CMin metastatic breast cancer • Colleoni M, et al. Ann Oncol. 13: 73-80, 2002

48. Background: low dose CMin metastatic breast cancer • Colleoni M, et al. Ann Oncol. 13: 73-80, 2002

49. Background: low dose CMin metastatic breast cancer • Colleoni M, et al. Ann Oncol. 13: 73-80, 2002

50. Background: low dose CMin metastatic breast cancer Results2 CR + 10 PR + 8 SD  24 weeks Overall response rate (CR + PR): 19% Overall clinical benefit (CR + PR + SD): 31.7% Median time to response: 2.7 mos Median duration of response (in responders): 6.8 mos Median time to progression: 2.8 mos Median administration time per pt: 2.5 mos • Colleoni M, et al. Ann Oncol. 13: 73-80, 2002