Transcript 32-05 CASA Investigators Meeting Paris November 2005

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
Annual Incidence by Age
US, 1995
http://merck.micromedex.com
Sirovich BE, Sox HC Jr. Surg Clin North Am 79: 961-90, 1999
Baseline life expectancy for patients
with various ages and comorbidity levels
Life expectancy (years)
Age (years)
65
70
75
80
85
Healthy
20.0
15.8
12.1
8.8
6.1
Average
Sick
18.5
14.8
11. 5
8.4
5.9
9.7
8.6
7.3
5.9
4.5
Extermann et al, JCO, 2000.
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).
Patients on IBCSG Trials I-14 according
to age > 65 years old at entry
Trial
I - IV
V
VI
VII
VIII
IX
10
11
12
13
14
Total
Total pts
pts > 65
1601
320
2504
53
1475
0
1212
264
1111
0
1669
392
473
446
174
0
344
108
1294
0
969
96
12813
1666 (13%)
pts >70
137
7
0
85
0
91
382
0
22
0
2
717 (5.6%)
Adjuvant treatment outcome
EBCTCG, Lancet 1998
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
Endocrine therapy vs. Nil
IBCSG Trial IV
1978-1981, 320 pts, age 66-80yrs; N+
Within 6
weeks
after
surgery
R
A
N
D
O
M
I
Z
E
Observation
p+T x 12 mos
p= prednisone 7.5 mg/d
T= tamoxifen 20 mg/d
IBCSG Trial IV
Crivellari D, et al. J Clin Oncol 21: 5417-23, 2003
Adjuvant treatment outcome
EBCTCG, Lancet 1998
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 outcome
EBCTCG, Lancet 2005
CHEMOTHERAPY
RECURRENCE
Age < 50
6901 women
35% N+
CHEMOTHERAPY
RECURRENCE
Age 50 - 69
18629 women
70% N+
CHEMOTHERAPY
RECURRENCE
Age < 50
ER Poor
No TAM
1673 women
12% N +
CHEMOTHERAPY
RECURRENCE
Age < 50
ER +/? All
with TAM
2254 women
34% N + 87% ER+
CHEMOTHERAPY
RECURRENCE
Age 50 - 69
ER Poor
No TAM
1474 women
29% N +
CHEMOTHERAPY
RECURRENCE
Age 50 - 69
ER +/? All
with TAM
11333 women
73% N + 88% ER+
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.
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.
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
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
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.
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
R
A PLD alone q 2w x 8
N
D
O No adjuvant therapy (nil)
M
Option 2: CASA-CM
R
A PLD alone q 2w x 8
N
D
Low-dose, metronomic CM
O
M
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.
CASA-nil
R
A Caelyx alone q 2w x 8
N
D
O No adjuvant therapy (nil)
M
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
CASA-CM
R
A Caelyx alone q 2w x 8
N
D
Low-dose, metronomic CM
O
M
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.
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.
Patient Population
Patient Characteristics
1.
2.
3.
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.
Patient Population
Disease Characteristics
1.
2.
3.
4.
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) bilateral invasive breast cancer eligible if all tumors
are endocrine nonresponsive and above criteria are met.
Patient Population
Prior Surgery
1.
2.
3.
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).
Patient Population
Prior/Concurrent Disease: Not eligible
1.
2.
3.
4.
5.
6.
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.
Patient Population
Prior Treatment
1.
2.
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.
Patient Population
Concurrent Treatment
(at the time of randomization pts should not be receiving these treatments)
1.
2.
3.
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.
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  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
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
Patient Population
Protocol Requirements BEFORE Randomization
1.
2.



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.
Patient Population
Protocol Requirements BEFORE Randomization
3.
4.
5.
6.
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.
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
Statistical considerations, sample
size and anticipated study duration
 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)
CASA Trial…
 Is about to start accrual.
 Additional background for PLD or
metronomic CT is available.
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
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.
Background: PLD
in metastatic breast cancer
Treatment = Caelyx® 20 mg/m2 iv every 2 weeks
Characteristics of eligible patients
Accrual period: January 2005 – September 2005
Entered/eligible
Median age (Range)
Postmenopausal at entry
Pretreated with CT
Advanced disease
 2 previous regimens
28/25
53 (31–69)
21
All
24
19
EIO experience, data not published
Background: PLD
in metastatic breast cancer
Tumor Characteristics
Endocrine responsiveness
ER+ or PgR+
ER & PgR Receptors not available
c-erbB2
some overexpression
no overexpression
not determined
16
8
1
5
9
11
EIO experience, data not published
Background: PLD
in metastatic breast cancer
Toxicity
Hematologic toxicity
Not Hematologic side effects
Nausea/Vomiting
HFS
Asthenia
Skin
max grade 2 leucopenia
max grade 2
5%
9%
5%
9%
EIO experience, data not published
Background: PLD
in metastatic breast cancer
Response (18 pts evaluable)
CR
PR
SD
Early PD (within 1 month)
PD
TTP
0 (0%)
2 (11%)
7 (33%)
3 (17%)
7 (39%)
median 2 months (1-6+)
EIO experience, data not published
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
Background: low dose CM
in metastatic breast cancer
Drug
Dose
Day
1234567
MTX
CTX
2,5 mg x 2 oral
50 mg oral


Colleoni M, et al. Ann Oncol. 13: 73-80, 2002
Background: low dose CM
in metastatic breast cancer
Characteristics of eligible patients
Entered/eligible
Median age (range)
Nr of pts  70 years old
Menopausal status pre/post
64/63
57 (36–80)
10
12/51
PD at study entry
51
ER and/or PgR positive
31
Nr of involved sites 1/2/>2
13/23/27
Colleoni M, et al. Ann Oncol. 13: 73-80, 2002
Background: low dose CM
in metastatic breast cancer
Characteristics of eligible patients
Tumor sites
Lung
16
Liver
24
Soft Tissues
38
Bone
34
Other
14
Colleoni M, et al. Ann Oncol. 13: 73-80, 2002
Background: low dose CM
in metastatic breast cancer
Characteristics of eligible patients
Previously untreated
11
Chemotherapy
Adjuvant - Neoadjuvant
41
For metastatic disease
52
1 line
32
2 lines
11
 3 lines
9
Colleoni M, et al. Ann Oncol. 13: 73-80, 2002
Background: low dose CM
in metastatic breast cancer
Results
2 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
Background: low dose CM
in metastatic breast cancer
Side Effects
NCIC-CTC Grade
0
1
2
3
4
Leukopenia
28 (44%)
22 (35%)
12 (19%)
0
1 (2%)
Neutropenia
42 (66%)
14 (22%)
6 (10%)
0
1 (2%)
Thrombocytopenia
60 (95%)
3 (5%)
0
0
0
Anemia
54 (86%)
8 (12%)
0
1 (2%)
0
Alopecia
58 (92%)
4 (6%)
1 (2%)
0
0
Nausea/Vomiting
47 (75%)
13 (20%)
3 (5%)
0
0
Gastric pain
61 (97%)
2 (3%)
0
0
0
Mucositis
60 (95%)
3 (5%)
0
0
0
Transaminases
31 (49%)
11 (17%)
12 (19%)
9 (15%)
0
Colleoni M, et al. Ann Oncol. 13: 73-80, 2002
Background: low dose CM  TLM
in metastatic breast cancer
Drug
Dose
Day
1234567
Arm A
MTX
2,5 mg x 2 oral


CTX
50 mg oral

MTX
2,5 mg x 2 oral

CTX
50 mg oral

TLM
200 mg oral
xxxxxxx
Arm B

Orlando L, et al. ASCO meeting 2004
Background: low dose CM  TLM
in metastatic breast cancer
Patients Characteristics (Total entered: 178)
Tumor sites
Liver
74
Lung
40
Soft tissues
71
Bone
79
Other
30
Chemotherapy for metastatic disease
109
1 line
63
2 lines
28
>3 lines
18
Orlando L, et al. ASCO meeting 2004
Background: low dose CM  TLM
in metastatic breast cancer
Results (n = 171)
Arm AArm B
CR
3 (3.5%)
3 (3.5%)
PR
15 (18%)
7 (8%)
SD
35 (41%)
38 (44%)
SD  24 weeks
18 (21%)
25 (29%)
PD
33 (38%)
37 (44%)
Overall RR
18 (21%)
10 (12%)
(p = 0.11)
Clinical Benefit
36 (42%)
35 (41%)
(p = 0.19)
Orlando L, et al. ASCO meeting 2004
Background: low dose CM  TLM
in metastatic breast cancer
Hematologic toxicity: arm A (n = 87)
Side Effects
NCIC-CTC Grade
1
2
3
4
Leukopenia
23 (26%)
16 (18%)
2 (2%)
1 (1%)
Neutropenia
17 (20%)
6 (7%)
3 (3%)
1 (1%)
4 (5%)
1 (1%)
1 (1%)
0
10 (11%)
2 (2%)
2 (2%)
0
Thrombocytopenia
Anemia
Orlando L, et al. ASCO meeting 2004
We expect significant
participation.
Thank You.
With a significant aid of
IBCSG 32-05 / 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
IBCSG: Worldwide cooperation
Patients and investigators from five
continents cooperate by participating in
large IBCSG clinical trials in the
adjuvant breast cancer setting
A worldwide collaboration
Collaboration with B.I.G.
the Breast International Group (B.I.G)
actively supports the trial
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)
Communication…
... is always a challenge!
Participants are in contact with IBCSG
through
• www.ibcsg.org
• E-mail: [email protected]
• newsletters
IBCSG website: www.ibcsg.org
Trial-specific documents
b
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)
Trial Coordination
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
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!
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
IBCSG biobank (1)
IBCSG has collected paraffin blocks since
1981 for
• Central pathology review
• Translational research
Submission of block is currently rewarded
with $ 50.-
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!
Regulatory issues
Major headache for any academic
research
The IBCSG Safety and Regulatory Office
offers competent support
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
IBCSG 32-05 / BIG 1-05 CASA
Investigator Meeting
Quality of Life Study
Karin Ribi
IBCSG Quality of Life Office
Coordinating Center, Bern
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
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
Consequences for QL Assessment
• Short and simple assessment tools
• Inclusion of baseline assessment of
physical and cognitive functioning
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
Longitudinal QL Study Design
Months from Randomization
0
3
6
12
Adjuvant phase
PLD for 16 weeks vs. no adj. treatment
PLD for 16 weeks vs. CM for 16 weeks
= QL Assessments: QL Form, Mini-Cog, VES-13
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)
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?
Appetite
Good
None
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
Physical Functioning
• Vulnerable Elders Survey (VES-13)
– Screening tool to identify older persons at
risk for health deterioration
– Functioned-based considering age, selfrated 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
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)
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
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
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
In case of questions…
… you are very welcome to contact
the Quality of Life Office!
[email protected]
+ 41 31 389 93 88
IBCSG 32-05 / BIG 1-05 CASA
Investigator Meeting
How to participate
Gerda Egli, MD
Head Quality Assurance & Audits
IBCSG Coordinating Center, Berne
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
[email protected]
How to participate:
New member/Non-member
• Contact the CASA Trial coordinator at
[email protected]
• Return completed application form
• Prepare for Initial visit by QA team
• Receive approval for participation
How to participate:
As a Cooperative Group
• Contact the CASA trial coordinator at
[email protected]
• 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“
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
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)
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
Quality control / Quality
assurance
•
•
•
•
•
•
Initial site visits
Data manager review
Medical review
Quality control reports
Audits
No on-site monitoring
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…
IBCSG audits (2)
• Establish personal contacts
• Improve Communication and
Collaboration
• Exchange information
• Present new trials
• Receive feed-back from investigators
Audit intervals
•
•
•
•
Initial site visit
1-year audit
3-year audit
Special audits (rapid accrual/for cause)
Audit case selection
• Random selection
• At least 10% of cases
• Relapses included
Audit procedures
•
•
•
•
•
•
Evaluation of QC reports
Source data verification (10%)
Signed informed consents (100%)
Investigator folder
Drug accountability
Discussion with investigator/DM’s
Audit follow-up: QA-team
• General audit report
• Patient case reports
• Corrective action plan
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
IBCSG 32-05 / BIG 1-05 CASA
Investigator Meeting
Regulatory Issues
Barbara Ruepp
Head Safety & Regulatory Office
IBCSG Coordinating Center, Bern
How to participate:
Regulatory Issues
• Preparation of center-specific documents
• Regulatory procedures: obtaining Ethics
Committee (EC) and Health Authority
(HA) approvals
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
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
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
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
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)
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
Navigating Regulatory Hurdles
• Coordination of centers within one country
is crucial
• For specific requests and questions contact
us at [email protected]
competent and prompt assistance is our
goal
IBCSG 32-05 / BIG 1-05 CASA
Investigator Meeting
How to start participation:
Patient Entry
Regula Studer
Head Trial Coordination
IBCSG Coordinating Center, Berne
How to start participation:
Patient entry
• Selection of randomization option
• Randomization procedures
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)
Randomization options (2)
• Option 1 or 2 ?
 investigator's decision and/or
patient’s preference
Select option: Informed Consent
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
Randomization (2)
After successful randomization the
randomization system issues:
– Confirmation of randomization and
treatment arm
– Projected Idealized Schedule for visits and
CRF submission
Web-based Randomization
Randomization:
Select Treatment Option
Randomization: Confirmation /
Treatment Arm
Projected Idealized Schedule
Randomization: Useful Tools
• Registration/Randomization Procedures
Manual
• Test system:  try it out !
IBCSG 32-05 / 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
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
Patient CRF Packet
Patient CRF Packet
Baseline CRFs
CT and Follow-Up
CT and Follow-Up
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
IBCSG Circular Letter
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)
CASA CRFs: Chemotherapy
• Not required if randomized to Nil
• Total of 4 forms due at 4 timepoints
Form Name
Form 32-CT Week 4
Form 32-CT Week 8
Form 32-CT Week 12
Form 32-CT Week 16
Submission #
Treatment Period
Cycle
Weeks 1–2
1
Weeks 3–4
2
Weeks 5–6
3
Weeks 7–8
4
Weeks 9–10
5
Weeks 11–12
6
Weeks 13–14
7
Weeks 15–16
8
001
002
003
004
Chemotherapy Form
Chemotherapy Form
Chemotherapy Form
Data Submission
DataFax: Paperless System
DataFax Data Flow
Participating Center
1: Faxes
CRFs
3. E-mails
QCs
4. Faxes
QC ans
DataFax System
2. Data Entry Personnel verify data
System generates quality checks (QC)
Data Manager reviews CRFs & adds queries
DataFax: Character Recognition
DataFax: QC Report
• Forms request
• Quality Checks
– Logical checks
– Queries
• Sent via e-mail
QC Report Part 1
QC Report Part 2
QC Report Part 3
Fax/User Support
• Direct fax numbers
• Toll-free numbers (with country-specific
access codes)
• User support by phone or e-mail
– Business Hours: 7:30 – 18:00 US Eastern
Time
– Telephone: +1-716-898-7400
– E-mail: [email protected]
Useful DM Documents
•
•
•
•
•
•
•
•
•
Data Managers’ Manual for Trial 32-05
Patient Packets for Trial 32-05
Obvious Corrections for Trial 32-05
QL Manuel for Trial 32-05
Randomization Manual
Instructions for Using the DataFax System
Toll-Free Numbers
Test DataFax Forms
Printing PDF
www.ibcsg.org
IBCSG 32-05 / BIG 1-05 CASA
Investigator Meeting
Drug Supply &
SAE Reporting Procedures
Barbara Ruepp
Head Safety & Regulatory Office
IBCSG Coordinating Center, Bern
Trial Medication
• PLD: Doxorubicin encapsulated in
pegylated liposomes (Caelyx®, Doxil®)
→ provided (investigational treatment)
• CM: Cyclophosphamide, Methotrexate
→ not provided (standard chemotherapy)
Supply Chain of PLD
(Caelyx®/Doxil®)
Activities/Responsibilities
• Manufactering & Vial Filling
Who
Schering-Plough/Ben
Venue Laboratories
Ohio USA
• Labeling for Clinical Trial use
• Final release
Distributor: Fisher
• Shipment to Schering-Plough Clinical Services, UK
Country Offices
• Distribution to centers
SP Country Offices
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
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
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
Drug Accountability
• Drug accountability is mandatory for PLD
• Already existing forms at your institution
may be used
• Alternatively download Drug Accountability
Form from www.ibcsg.org
• File Drug Accountability Form in
Investigator‘s Folder
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: resupply will be provided
Coordination of Drug Supply
• All drug supply-related activities are
coordinated by IBCSG CC in Berne,
Switzerland
• Questions, requests?
[email protected]
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
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
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)
IBCSG 32-05 / BIG 1-05 CASA
Investigator Meeting
Administrative Issues
Anita Hiltbrunner
Executive Director
IBCSG Coordinating Center, Berne
Administrative Issues
• Insurance
• Funding
• Contracts
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)
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
Funding (1)
• Trial supported by ScheringPlough/ITGI
• Per patient fee 1’700 €
(700 € upon randomization, 500 € after
3 years, 500 € after 5 years, payment
twice a year)
Funding (2)
• Support available for coordinating
groups with ACTIVE involvement
• Up to 1’000 € per patient
• Payment upon randomization
Contracts (1)
• Main contract Schering-Plough/ITGI
with IBCSG
• Subcontracts IBCSG with
groups/centers
• Contract template is based on main
contract
Contracts (2)
• Contract discussions between lawyers
can cause serious delay  contract
discussions with your hospital
administration to start asap
• Signed contract needed for activation
Administrative Issues
• Bureaucracy – hopefully as much as
necessary and as few as possible !