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IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting Chemotherapy Adjuvant Study for Women at Advanced Age (CASA) Diana Crivellari, MD Centro di Riferimento.

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Presentation on theme: "IBCSG 32-05 / BIG 1-05 CASA Investigator Meeting Chemotherapy Adjuvant Study for Women at Advanced Age (CASA) Diana Crivellari, MD Centro di Riferimento."— Presentation transcript:

1 IBCSG / 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 Age US, Sirovich BE, Sox HC Jr. Surg Clin North Am 79: , 1999

3 Baseline life expectancy for patients with various ages and comorbidity levels Life expectancy (years) Age (years) Healthy Average Sick 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 TrialTotal ptspts > 65pts >70 I - IV V VI VII VIII IX Total (13%) 717 (5.6%)

6 Adjuvant treatment outcome EBCTCG, Lancet ±1354± ±654±58±418± ±837±614±422± ±1045±827±534±5<50 OSDFSOSDFSAge Endocrine TherapyChemotherapy

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

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

9 Adjuvant treatment outcome EBCTCG, Lancet ±1354± ±654±58±418± ±837±614±422± ±1045±827±534±5<50 OSDFSOSDFSAge Endocrine TherapyChemotherapy

10 Adjuvant treatment outcome EBCTCG, Lancet 2005

11 CHEMOTHERAPY RECURRENCE Age < women 35% N+

12 CHEMOTHERAPY RECURRENCE Age 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 ER Poor No TAM 1474 women 29% N +

16 CHEMOTHERAPY RECURRENCE Age ER +/? All with TAM 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 to attitude 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 Because of the separate designs, at the time of randomization the investigator will be asked to select one of the two Randomization Options: Low-dose, metronomic CM RANDOMRANDOM PLD alone q 2w x 8 No adjuvant therapy (nil) RANDOMRANDOM Randomization: within 6 (16) weeks of surgery. All regimens are 16 weeks duration. PLD: 20 mg/m 2 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. PLD alone q 2w x 8 Option 1: CASA-nilOption 2: CASA-CM Trial Design

23 RANDOMRANDOM 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/m 2 iv x 8 doses delivered every 2 weeks CASA-nil

24 Low-dose, metronomic CM RANDOMRANDOM Randomization: within 6 (16) weeks of surgery. All regimens are 16 weeks duration. Caelyx®: 20 mg/m 2 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. Caelyx  alone q 2w x 8 CASA-CM

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 Population Patient Characteristics 1.Women aged 66 years or older with histologically proven, resected breast cancer. 2.Patients must NOT be candidates for endocrine therapy or standard chemotherapy regimen. 3.Performance status (ECOG) 0-2.

27 Patient Population Disease Characteristics 1.Patients must have endocrine nonresponsive tumors (ER < 10% by IHC; if PgR done, < 10% by IHC) 2.Tumor must be confined to the breast and axillary nodes without detected metastases elsewhere. 3.Not eligible: locally advanced inoperable BC including inflammatory BC, supraclavicular node involvement, or enlarged internal mammary nodes (unless path. neg.). 4.Patients with synchronous (diagnosed histologically within 2 months) bilateral invasive breast cancer eligible if all tumors are endocrine nonresponsive and above criteria are met.

28 Patient Population Prior Surgery 1.Patients must have had surgery for primary breast cancer (with or without axillary clearance) with no known clinical residual loco-regional disease. 2.Margins must be negative for invasive breast cancer and DCIS. 3.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 Population Prior/Concurrent Disease: Not eligible 1.Prior ipsilateral or contralateral invasive BC. 2.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. 3.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). 4. Myocardial infarction, pulmonary embolism or DVT within 6 months prior to randomization. 5.Significant malabsorption sdr or disease affecting GI tract function 6.At least one “geriatric syndrome”: dementia, delirium, depression, recent falls, spontaneous bone fractures, neglect and abuse.

30 Patient Population Prior Treatment 1.No prior neoadjuvant or adjuvant therapy for BC. Note: Radiotherapy is allowed prior to randomization. 2.Raloxifene, tamoxifen, or other SERM must be discontinued at least 4 weeks before randomization.

31 Patient Population Concurrent Treatment (at the time of randomization pts should not be receiving these treatments) 1.No hormone replacement therapy (HRT). 2.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. 3.No treatment with bisphosphonates, except for the treatment of osteoporosis.

32 Patient Population Organ 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  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 Population Organ 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 Population Protocol Requirements BEFORE Randomization 1.Written Informed Consent (IC) signed and dated by patient and investigator prior to completing QL Forms and prior to randomization. 2.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 Population Protocol Requirements BEFORE Randomization 3.Pathology material should be available for submission for central review as part of the quality control measures for this protocol. 4.Patients must be accessible for follow-up. 5.Patients must be informed of and agree to data and tissue material transfer and handling, in accordance with national data protection guidelines. 6.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. 2 nd malignancies and deaths) Sites of failure Second (non-breast) malignancy OS Causes of death

37  Primary objective: investigate role of PLD as adjuvant chemotherapy for older postmenopausal women  Stratified (pooled) analysis combining 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 analyses for 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) Statistical considerations, sample size and anticipated study duration

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

39 Background: PLD in 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 developed to improve therapeutic index of conventional anthracyclines by maintaining antitumor efficacy while improving the safety profile

40 Background: PLD in 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: PLD in metastatic breast cancer Treatment = Caelyx® 20 mg/m 2 iv every 2 weeks Characteristics of eligible patients Accrual period: January 2005 – September 2005 Entered/eligible28/25 Median age (Range)53 (31–69) Postmenopausal at entry 21 Pretreated with CT All Advanced disease 24  2 previous regimens 19 EIO experience, data not published

42 Background: PLD in metastatic breast cancer EIO experience, data not published Tumor Characteristics Endocrine responsiveness ER+ or PgR+16 ER & PgR - 8 Receptors not available1 c-erbB2 some overexpression5 no overexpression 9 not determined11

43 Background: PLD in metastatic breast cancer EIO experience, data not published Toxicity Hematologic toxicitymax grade 2 leucopenia Not Hematologic side effectsmax grade 2 Nausea/Vomiting 5% HFS9% Asthenia 5% Skin9%

44 Background: PLD in metastatic breast cancer EIO experience, data not published Response (18 pts evaluable) CR0 (0%) PR2 (11%) SD7 (33%) Early PD (within 1 month)3 (17%) PD 7 (39%) TTPmedian 2 months (1-6+)

45 Background: low dose CM in 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 CM in metastatic breast cancer Colleoni M, et al. Ann Oncol. 13: 73-80, 2002 DrugDose Day MTX2,5 mg x 2 oral   CTX50 mg oral       

47 Background: low dose CM in metastatic breast cancer Characteristics of eligible patients Entered/eligible64/63 Median age (range)57 (36–80) Nr of pts  70 years old 10 Menopausal status pre/post12/51 PD at study entry51 ER and/or PgR positive31 Nr of involved sites 1/2/>213/23/27 Colleoni M, et al. Ann Oncol. 13: 73-80, 2002

48 Background: low dose CM in metastatic breast cancer Characteristics of eligible patients Tumor sites Lung16 Liver24 Soft Tissues38 Bone34 Other14 Colleoni M, et al. Ann Oncol. 13: 73-80, 2002

49 Background: low dose CM in metastatic breast cancer Characteristics of eligible patients Previously untreated11 Chemotherapy Adjuvant - Neoadjuvant41 For metastatic disease52 1 line32 2 lines11  3 lines 9 Colleoni M, et al. Ann Oncol. 13: 73-80, 2002

50 Background: low dose CM in 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

51 Background: low dose CM in metastatic breast cancer Colleoni M, et al. Ann Oncol. 13: 73-80, 2002 Side EffectsNCIC-CTC Grade Leukopenia28 (44%)22 (35%)12 (19%)01 (2%) Neutropenia42 (66%)14 (22%)6 (10%)01 (2%) Thrombocytopenia60 (95%)3 (5%)000 Anemia54 (86%)8 (12%)01 (2%)0 Alopecia58 (92%)4 (6%)1 (2%)00 Nausea/Vomiting47 (75%)13 (20%)3 (5%)00 Gastric pain61 (97%)2 (3%)000 Mucositis60 (95%)3 (5%)000 Transaminases31 (49%)11 (17%)12 (19%)9 (15%)0

52 Background: low dose CM  TLM in metastatic breast cancer Orlando L, et al. ASCO meeting 2004 DrugDose Day Arm A MTX2,5 mg x 2 oral   CTX50 mg oral        Arm B MTX2,5 mg x 2 oral   CTX50 mg oral        TLM200 mgoral x x x x x x x

53 Background: low dose CM  TLM in metastatic breast cancer Orlando L, et al. ASCO meeting 2004 Patients Characteristics (Total entered: 178) Tumor sites Liver74 Lung40 Soft tissues71 Bone79 Other30 Chemotherapy for metastatic disease109 1 line63 2 lines28 >3 lines18

54 Background: low dose CM  TLM in metastatic breast cancer Orlando L, et al. ASCO meeting 2004 Results (n = 171) Arm AArm B CR3 (3.5%)3 (3.5%) PR15 (18%)7 (8%) SD35 (41%)38 (44%) SD  24 weeks18 (21%)25 (29%) PD33 (38%)37 (44%) Overall RR18 (21%)10 (12%)(p = 0.11) Clinical Benefit36 (42%)35 (41%)(p = 0.19)

55 Background: low dose CM  TLM in metastatic breast cancer Orlando L, et al. ASCO meeting 2004 Hematologic toxicity: arm A (n = 87) Side EffectsNCIC-CTC Grade 1234 Leukopenia23 (26%)16 (18%)2 (2%)1 (1%) Neutropenia17 (20%)6 (7%)3 (3%)1 (1%) Thrombocyto- penia 4 (5%)1 (1%) 0 Anemia10 (11%)2 (2%) 0

56 We expect significant participation. Thank You. With a significant aid of

57

58 IBCSG / BIG 1-05 CASA Investigator Meeting A global trial: Challenges and opportunities Rudolf Maibach, PhD Executive Officer for International Trial Activities IBCSG Coordinating Center, Berne

59 IBCSG: Worldwide cooperation Patients and investigators from five continents cooperate by participating in large IBCSG clinical trials in the adjuvant breast cancer setting

60 A worldwide collaboration

61 Collaboration with B.I.G. the Breast International Group (B.I.G) actively supports the trial

62 IBCSG: a reliable structure The network is supported by: Coordinating Center in Berne Data Management Center in Amherst Statistical Center in Boston Independent scientific review by Data Safety and Monitoring Committee (DSMC)

63 Communication…... is always a challenge! Participants are in contact with IBCSG through newsletters

64 IBCSG website:

65 Trial-specific documents b

66 IBCSG annual meeting Featuring Personal contacts Lively discussions General assembly Scientific Committee meeting open to all IBCSG members  Nice, France, March 25-26, 2006 (5th European Breast Cancer Conference)

67 Trial Coordination

68 Documentation: CRFs CRFs are complete yet user-friendly Data manager manual: careful explanation Extent of data collection:  Allows many additional evaluations from database at very little cost

69 IBCSG publications IBCSG has published 164 publications, among them –only 12 main trial publications, PLUS –publications from database –publications on quality of life –publications on biological params –reviews and commentaries  Opportunity for all participants!

70 Quality of life Continuous commitment to evaluation of patient reported quality of life since 1986 Core module and trial related modules available in many languages

71 IBCSG biobank (1) IBCSG has collected paraffin blocks since 1981 for Central pathology review Translational research Submission of block is currently rewarded with $ 50.-

72 IBCSG biobank (2) The IBCSG Biological Protocol Working Group (BPWG) carefully examines all applications for (retrospective) evaluations All participants are welcome to submit project proposals!

73 Regulatory issues Major headache for any academic research The IBCSG Safety and Regulatory Office offers competent support

74 How to participate As a current member of IBCSG As a member of a cooperative group participating in the trial As an individual non-IBCSG center As an individual center wishing to become an IBCSG center

75

76 IBCSG / BIG 1-05 CASA Investigator Meeting Quality of Life Study Karin Ribi IBCSG Quality of Life Office Coordinating Center, Bern

77 Background Tolerance of cancer treatment and life expectancy are limited for breast cancer patients at advanced age Quality of life (QL) of particular importance Patients at advanced age are underrepresented in cancer treatment trials Very few studies have focused on QL

78 Methodological Considerations Potential confounding of co-morbidities with real impact of cancer symptoms and treatment on QL Higher frequency of reading and understanding impairment in older patients

79 Consequences for QL Assessment Short and simple assessment tools Inclusion of baseline assessment of physical and cognitive functioning

80 Primary Objective Comparing PLD-containing regimens versus non PLD-containing regimens regarding –Patient rated QL –Physician-documented physical functioning –Physician-documented cognitive functioning during and after adjuvant treatment

81 Longitudinal QL Study Design Months from Randomization Adjuvant phase = QL Assessments: QL Form, Mini-Cog, VES-13 PLD for 16 weeks vs. no adj. treatment PLD for 16 weeks vs. CM for 16 weeks

82 QL Study: Instruments To be filled in by patients: Adapted version of the IBCSG QL Core Form (Form QL) To be conducted by physicians: Cognitive Functioning: Mini-Cog (Form MC) Physical Functioning: VES-13 (Form VES) Assessment Checklist (Form AC)

83 Quality of Life 5 global LASA scales: physical wellbeing, mood, coping, functional performance, overall disease/treatment burden 6 symptom-specific LASA scales: tiredness, appetite, nausea/vomiting, hair loss, stomatitis, restrictions in arm movement Example: How have you been within the last two weeks? None Good Appetite

84 Cognitive Functioning Mini-Cog: A brief cognitive screening test and composite of: –3-item registration-recall task (taken from MMSE) –Clock-drawing test (CDT) Requires 3 minutes for administration Includes CDT scoring sheet

85 Physical Functioning Vulnerable Elders Survey (VES-13) –Screening tool to identify older persons at risk for health deterioration –Functioned-based considering age, self- rated health, functional disabilities –Needs less than 5 minutes for completion –Score range 0-10: a score >3 pointing to a 4x higher risk of functional decline or death

86 Order of QL Forms Administration Sequence of form administration is standardized as follows: 1. IBCSG CASA QL Form (Form QL) 2. Mini-Cog Test (Form MC) 3. VES-13 Test (Form VES) 4. Assessment Checklist (Form AC)

87 General Considerations QL assessments should be done prior to any relevant diagnostic procedures communication of diagnostic information any treatment application exception: previous information about diagnosis at baseline

88 Data Management Issues Compliance: Good acceptance by patients and staff (problem of missing data) Timing: Crucial to detect the effects of disease and treatment on QL Completeness: Crucial to investigate changes, i.e.we need a reference value = baseline

89 Please Consider Instruct patient carefully at the first assessment Check for completeness while patient is still present Check that the header is filled out properly before faxing it to the DMC Fax the forms in proper time

90 In case of questions… … you are very welcome to contact the Quality of Life Office!

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92 IBCSG / BIG 1-05 CASA Investigator Meeting How to participate Gerda Egli, MD Head Quality Assurance & Audits IBCSG Coordinating Center, Berne

93 How to participate: Current IBCSG members you have already received the complete documentation! Refer to the “activation letter” for all steps to be taken Do not hesitate to contact the CASA trial coordinator at

94 How to participate: New member/Non-member Contact the CASA Trial coordinator at Return completed application form Prepare for Initial visit by QA team Receive approval for participation

95 How to participate: As a Cooperative Group Contact the CASA trial coordinator at Specify group coordinator/coordinating office for your group Return completed Application forms (1 for each participating center) Act as gateway to your member institutions Clarify logistics : Adapt the template „Appendix VII participating group specific logistical information“

96 How to participate: Next steps Collect necessary documents as specified in the IBCSG activation letter Adapt PIS/IC – submit to IBCSG CC Contact the CASA trial coordinator before submission to EC or regulatory authorities Submit documents to local Ethics committee Submit all documents to IBCSG CC Prepare Investigator folder Drug supply - Activation – first patient

97 Investigator folder (1) TOC provided by IBCSG CC Binder containing all general documents available from CC Add copy of all center-specific documents needed for activation (see previous slide)

98 Investigator folder (2) Add additional required documents: - Patient identification log - Drug accountability log - Copy of signed informed consents Keep updated - SAE-reports - Amendments - Correspondence with EC and sponsor

99 Quality control / Quality assurance Initial site visits Data manager review Medical review Quality control reports Audits No on-site monitoring

100 IBCSG audits (1) Long-standing IBCSG tradition Performed according to IBCSG Audit SOPs For members and non-members Not for participating Collaborative Groups Needed to ensure data Quality and Patient Safety No “police action” But a good opportunity to…

101 IBCSG audits (2) Establish personal contacts Improve Communication and Collaboration Exchange information Present new trials Receive feed-back from investigators

102 Audit intervals Initial site visit 1-year audit 3-year audit Special audits (rapid accrual/for cause)

103 Audit case selection Random selection At least 10% of cases Relapses included

104 Audit procedures Evaluation of QC reports Source data verification (10%) Signed informed consents (100%) Investigator folder Drug accountability Discussion with investigator/DM’s

105 Audit follow-up: QA-team General audit report Patient case reports Corrective action plan

106 Audit follow-up: Investigator Discuss and correct any deficiencies noted Provide requested additional information Provide information on corrective actions taken Return signed audit report (general & case reports) to CC File copy of audit report

107

108 IBCSG / BIG 1-05 CASA Investigator Meeting Regulatory Issues Barbara Ruepp Head Safety & Regulatory Office IBCSG Coordinating Center, Bern

109 How to participate: Regulatory Issues Preparation of center-specific documents Regulatory procedures: obtaining Ethics Committee (EC) and Health Authority (HA) approvals

110 Preparation of Center-specific Documents Adapt patient information and informed consent according local requirements Summary in national language (if requested) Collect information, signatures for –Protocol signature page –Authorization log –CVs –Obvious correction document signature page

111 Patient Information/Informed Consent (1) Template in 7 languages available Information to be added –Name of Ethics Committee responsible for evaluation of clinical trial application –Contact persons (Principle Inv., Co-Inv.) –Date, version number, place or name of institution

112 Patient Information/Informed Consent (2) Necessary modifications –Insurance paragraph (provided by IBCSG with national policy) Modifications only recommended if required by local regulations –Highlighted sections in particular Confidentiality Collection of biological material

113 Regulatory Procedures: obtaining EC/HA approvals in EU Submission of Clinical Trial Application (CTA) by coordinating investigator/institution or group to –leading Ethics Committee (EC) –Competent Authority (usually Health Authority, HA) All participating centers should be included in application Parallel submission to EC and HA possible Local EC may adopt positive opinion of leading EC and can request modifications of PIS/IC

114 Information and Documents to be included with CTA Trial related (Protocol including appendices, CRFs, patient information and informed consent) Trial Drug related (Investigators Brochure, Summary of Product Characteristics, labels) Staff/Facility related (CVs of Investigators) Finance related (Insurance policy, contract)

115 Regulatory Support offered by IBCSG CC For EU countries XML-file of CTA Documents to be enclosed with CTA (eg Investigators Brochure, labels) Information of approvals from other countries

116 Navigating Regulatory Hurdles Coordination of centers within one country is crucial For specific requests and questions contact us at competent and prompt assistance is our

117

118 IBCSG / BIG 1-05 CASA Investigator Meeting How to start participation: Patient Entry Regula Studer Head Trial Coordination IBCSG Coordinating Center, Berne

119 How to start participation: Patient entry Selection of randomization option Randomization procedures

120 Randomization options (1) Option 1: CASA-nil PLD versus no adjuvant therapy (nil) Option 2: CASA-CM PLD versus low-dose, metronomic cyclophosphamide + methotrexate (CM)

121 Randomization options (2) Option 1 or 2 ?  investigator's decision and/or patient’s preference

122 Select option: Informed Consent

123

124 Randomization (1) Web-based randomization system Patient enrolment: directly from participating center OR through your Group’s randomization center Each participating Group chooses it’s way before starting with the trial

125 Randomization (2) After successful randomization the randomization system issues: –Confirmation of randomization and treatment arm –Projected Idealized Schedule for visits and CRF submission

126 Web-based Randomization

127 Randomization: Select Treatment Option

128 Randomization: Confirmation / Treatment Arm

129 Projected Idealized Schedule

130 Randomization: Useful Tools Registration/Randomization Procedures Manual Test system:  try it out !

131

132 IBCSG / BIG 1-05 CASA Investigator Meeting CRFs / Data Submission Karen Price IBCSG Director of Scientific Administration IBCSG Statistical Center, Boston, MA IBCSG Data Management Center, Amherst, NY

133 CASA CRFs Available in patient packets on IBCSG website Packets for –All CRFs and English QL (A4 or Letter) –Other languages QL Packets are in PDF format

134 Patient CRF Packet

135

136 Baseline CRFs

137 CT and Follow-Up

138

139 General Tips for Completing CRFs Refer to the Data Managers' Manual Record -1 for any unknown answers Be sure to submit required reports – i.e. Pathology and Hormone receptor Remember to black out patient's names and write the Patient ID on each page of the reports Refer to the Circular Letter

140 IBCSG Circular Letter

141 CASA CRFs: Bilateral Patients with bilateral breast cancer –All pts must submit 32-C (Surgery), 32-F (Hormone Receptor), 32-P (Pathology), and 32-R (Radiotherapy, if given) –Patients with bilateral breast cancer must submit additional forms for the opposite breast/side: 32-BC, 32-BF, 32-BP, 32-BR All are due at baseline (32-R and 32-BR after radiotherapy)

142 CASA CRFs: Chemotherapy Not required if randomized to Nil Total of 4 forms due at 4 timepoints Form NameSubmission #Treatment PeriodCycle Form 32-CT Week 4001 Weeks 1–21 Weeks 3–42 Form 32-CT Week 8002 Weeks 5–63 Weeks 7–84 Form 32-CT Week Weeks 9–105 Weeks 11–126 Form 32-CT Week Weeks 13–147 Weeks 15–168

143 Chemotherapy Form

144

145

146 Data Submission

147 DataFax: Paperless System

148 DataFax Data Flow Participating Center 1: Faxes CRFs DataFax System 2. Data Entry Personnel verify data System generates quality checks (QC) Data Manager reviews CRFs & adds queries 3. s QCs 4. Faxes QC ans

149 DataFax: Character Recognition

150 DataFax: QC Report Forms request Quality Checks –Logical checks –Queries Sent via

151 QC Report Part 1

152 QC Report Part 2

153 QC Report Part 3

154 Fax/User Support Direct fax numbers Toll-free numbers (with country-specific access codes) User support by phone or –Business Hours: 7:30 – 18:00 US Eastern Time –Telephone: –

155 Useful DM Documents Data Managers’ Manual for Trial Patient Packets for Trial Obvious Corrections for Trial QL Manuel for Trial Randomization Manual Instructions for Using the DataFax System Toll-Free Numbers Test DataFax Forms Printing PDF

156

157 IBCSG / BIG 1-05 CASA Investigator Meeting Drug Supply & SAE Reporting Procedures Barbara Ruepp Head Safety & Regulatory Office IBCSG Coordinating Center, Bern

158 Trial Medication PLD: Doxorubicin encapsulated in pegylated liposomes (Caelyx®, Doxil®) → provided (investigational treatment) CM: Cyclophosphamide, Methotrexate → not provided (standard chemotherapy)

159 Supply Chain of PLD (Caelyx®/Doxil®) Activities/ResponsibilitiesWho Manufactering & Vial FillingSchering-Plough/Ben Venue Laboratories Ohio USA Labeling for Clinical Trial use Final release Shipment to Schering-Plough Country Offices Distributor: Fisher Clinical Services, UK Distribution to centersSP Country Offices

160 Requirements for Release of Drug Supply from Distributor All regulatory documents must be in place –country specific authorizations (Health Authority/EC approvals) –EU countries only: copy of section on trial drug (IMPD section) of clinical trial application

161 Center Supply Not patient specific SP country office ships starter supply of 4 vials to center/local pharmacy once all regulatory requirements are met Following randomization of a patient 16 vials will be sent automatically from SP country office to center/local pharmacy

162 Drug Shipment and Storage: Points to Consider Cool chain must be maintained during shipment → PLD only shipped Mo – Wed in order to guarantee delivery to the sites until Friday → provide IBCSG CC with exact name of shipment address where proper storage (refrigerator 2-4°C) is guaranteed

163 Drug Accountability Drug accountability is mandatory for PLD Already existing forms at your institution may be used Alternatively download Drug Accountability Form from File Drug Accountability Form in Investigator‘s Folder

164 Drug Destruction Expired vials can be destroyed on site according to local guidelines Complete Study Destruction Certificate and file in Investigators Folder Record drug destruction on Drug Accountability Form In case of expiration or breakage: re- supply will be provided

165 Coordination of Drug Supply All drug supply-related activities are coordinated by IBCSG CC in Berne, Switzerland Questions, requests?

166 Serious Adverse Event Reporting Obligations of the Investigators Collect, record, assess and report SAEs during and until ≤ 4 weeks after trial treatment stop → all adverse events qualifying as serious ≥ 4 weeks after trial treatment stop → all deaths and other SAEs at least possibly related to trial treatment → all 2nd non-breast malignancies → all congenital abnormalities

167 Serious Adverse Event Reporting How to report SAEs Submit (datafax) initial SAE-report within 24 hours after occurrence of the event → use Form 32 SAE-A Upon resolution of the event or within 15 days after initial report complete and submit Follow-up report → use Form 32 SAE-B

168 Processing of SAE-Reports Responsibilities of IBCSG CC Medical review including seriousness and causality Assessment of expectedness Distribution of the SAE-reports to appropriate persons and parties Notification of investigators and regulatory authorities if expedited reporting is required (unexpected serious adverse reactions) Preparation of periodic reports (monthly, annual)

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170 IBCSG / BIG 1-05 CASA Investigator Meeting Administrative Issues Anita Hiltbrunner Executive Director IBCSG Coordinating Center, Berne

171 Administrative Issues Insurance Funding Contracts

172 Insurance (1) IBCSG provides clinical trial insurance according to local laws IBCSG CC centrally organizes policies in individual countries – please refer to IBCSG CC for assistance (no direct contacts between centers and local insurance affiliates)

173 Insurance (2) Requested information to issue policy: estimated accrual per year per country / list of centers per country Patient information/Informed consent: insurance paragraph to reflect local policy and country laws  please submit to IBCSG CC for approval

174 Funding (1) Trial supported by Schering- Plough/ITGI Per patient fee 1’700 € (700 € upon randomization, 500 € after 3 years, 500 € after 5 years, payment twice a year)

175 Funding (2) Support available for coordinating groups with ACTIVE involvement Up to 1’000 € per patient Payment upon randomization

176 Contracts (1) Main contract Schering-Plough/ITGI with IBCSG Subcontracts IBCSG with groups/centers Contract template is based on main contract

177 Contracts (2) Contract discussions between lawyers can cause serious delay  contract discussions with your hospital administration to start asap Signed contract needed for activation

178 Administrative Issues Bureaucracy – hopefully as much as necessary and as few as possible !

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