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Nessun titolo diapositiva

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Title: Nessun titolo diapositiva


1
Rome, 28/3/2008
Clinical trials challenges with targeted
agents
Paolo Bruzzi Clinical Epidemiology, Dept. of
Epidemiology and Prevention, Istituto Nazionale
per la Ricerca sul Cancro Genoa - Italy
2
Trials Rationale of Phases
  • Any new drug, when first used in man, involves
    unknown risks, and has unknown pharmacological
    and toxic properties
  • PHASE I

3
Aims of of clinical trials
  • Phase I
  • Question (How much, often, etc.) can (should) I
    use the drug?

4
Aims of of clinical trials
  • Phase I
  • Question How (much, often, etc.) can (should) I
    use the drug?
  • Endpoints
  • Toxicity,
  • Pharmacology
  • MTD
  • (Dose-response?)

5
Rationale of Phases
  • Any new drug, when first used in man, involves
    unknown risks, and has unknown pharmacological
    and toxic properties PHASE I
  • Before starting a long and expensive efficacy
    trial, it is convenient to know if the drug has
    the effects (ACTIVITY) that make its efficacy
    plausible
  • PHASE II

6
Activity vs Efficacy
  • Efficacy The benefit desired by the patient
  • Usually, quantity and/or quality of life

7
Activity vs Efficacy
  • Efficacy The benefit desired by the patient
  • Activity The direct effects (mechanisms) by
    which the treatment is supposed to produce the
    benefit

8
Activity vs Efficacy
  • Efficacy The benefit desired by the patient
  • Activity
  • Antihypertensive
  • Diuretic
  • Lipid Lowering
  • Antibacterial
  • Antiarythmic

9
Aims of of clinical trials
  • Phase I
  • Phase II
  • Question Does the drug what it is supposed to
    do to the disease (the organism)?

10
Aims of of clinical trials
  • Phase I
  • Phase II
  • Question Does the drug what it is supposed to
    do to the disease (the organism)?
  • Endpoints Activity Endpoints (Changes in the
    disease or in physiopathological parameters)

11
Rationale of Phases
  1. Any new drug, when first used in man, involves
    unknown risks, and has unknown pharmacological
    and toxic properties PHASE I
  2. Before starting a long and expensive efficacy
    trial, it is necessary to know if the drug has
    the effects (ACTIVITY) that make its efficacy
    plausible PHASE II
  3. The EFFICACY of a treatment is not warranted by
    its Activity PHASE III

12
Activity Mechanisms of action
13
Activity Mechanisms of action
14
Aims of of clinical trials
  • Phase I
  • Phase II
  • Phase III
  • Question Does the drug do what the patient
    expects from it?

15
Aims of of clinical trials
  • Phase I
  • Phase II
  • Phase III
  • Question Does the drug do what the patient
    expects from it?
  • Endpoints Efficacy Endpoint(s)
  • Overall Survival - QoL
  • Surrogate endpoints

16
Note
  • The rationale of trial phases has no implications
    for their methodology
  • The methodology of phases is related to
  • Therapeutic paradigm
  • Characteristics of experimental therapy
  • Endpoints
  • Ethical Problems

17
Trials of Cytotoxic Drugs
  • Underlying Paradigm
  • Monotonic dose-effect relationship
  • (the more the better)

18
Trials of Cytotoxic Drugs
  • Underlying Paradigm
  • Monotonic dose-effect relationship
  • Direct cell killing

19
Trials of Cytotoxic Drugs
  • Underlying Paradigm
  • Monotonic dose-effect relationship
  • Direct cell killing
  • Constant proportion of tumor cells killed
    (independent of the number of cells)

20
Consequences
  • PHASE I trials
  • Aim (The more the better -gt) Finding the Maximum
    Tolerated Dose (MTD) of the drug (combination)
  • Note MTD? (single dose, total dose,
    dose-intensity, dose-density, mode of injection,
    etc.)

21
Consequences
  • PHASE I trials
  • Toxicity Specific
  • Uncontrolled phase I trials

22
Consequences
  • PHASE II trials
  • Aim (Direct cell killing -gt) Assessing the
    antitumor activity (ability to differentially
    kill tumor cells)
  • Antitumor activity Reduction of volume of tumor
    mass
  • Primary Objective Response ()

23
Phase II Implications
  • Spontaneous tumor reduction (gt50) is rare
    (lt1)?No need for control groups

24
Phase II Implications
  • Uncontrolled Phase II trials

25
Phase II Implications
  • Uncontrolled Phase II trials
  • Need to assess tumor reduction
  • Patients with measurable lesions
  • Unresectable cancers
  • (Preoperative (primary) chemotherapy)

26
Phase II Implications
  • Uncontrolled Phase II trials
  • Phase II trials in metastatic pts

27
Phase II Implications
  • Uncontrolled Phase II trials
  • Phase II trials in metastatic pts
  • Proportional reduction Effects in metastatic
    cancer ? Micrometastatic disease

28
Phase II Implications
  • Uncontrolled Phase II trials
  • Phase II trials in metastatic pts
  • Phase III trials in disease-free (and metastatic)
    patients

29
Development of cytotoxic drugs
  • Phase I Uncontrolled, dose-escalation in heavily
    pretreated pts
  • Phase II Uncontrolled, response rate with MTD in
    pts with measurable disease
  • Phase III Large RCTs, OS (RFS/PFS) in
    unselected, resected/metastatic pts

30
Development of cytotoxic drugs
  • Other peculiarities of phase III trials
  • Unselected patients
  • Site- and stage-specific

31
Development of cytotoxic drugs
  • Other peculiarities of phase III trials
  • Unselected patients
  • Site- and stage-specific
  • Histology-specific? (e.g. NSCLC)

32
Development of cytotoxic drugs
  • Other peculiarities of phase III trials
  • Unselected patients
  • Pragmatic (EFFECTIVENESS)

33
Development of cytotoxic drugs
  • Other peculiarities of phase III trials
  • Unselected patients
  • Pragmatic (EFFECTIVENESS)
  • Classical Frequentist Statistics
  • Test of significance, power
  • Adjustment of p values for multiple looks
  • Frequentist 95 CI

34
Development of a new cytotoxic drug
35
New Anticancer Therapies
  • Targeted Therapies
  • Biological Response Modifiers (e.g.IL-2)
  • Cancer Vaccines
  • Cell Therapy
  • Gene Therapy
  • Anti-angiogenetic drugs
  • Others
  • Associations?

36
Targeted therapies
  • Definition (NCI Dictionary)
  • targeted therapy (...THAYR-uh-pee)  A type of
    treatment that uses drugs or other substances,
    such as monoclonal antibodies, to identify and
    attack specific cancer cells without harming
    normal cells.

37
Targeted therapies
  • G. Sledge (JCO, 2005) A targeted therapy
    should attack a biologically important process
    (usually, though not necessarily, a single
    molecule), preferably one central to a hallmark
    of cancer. The target should be measurable in the
    clinic, and measurement of the target (in either
    quantitative or qualitative terms) should
    correlate with clinical outcome when the targeted
    therapy is administered.

38
Targeted therapies
  • Working definition
  • Drugs aimed at specific (functional) targets of
    (some) cancer cells

39
Targeted therapies
  • Working definition
  • Drugs aimed at specific targets of (some) cancer
    cell
  • 1 example Tamoxifen?Estrogen receptors in
    breast cancer cells

40
Recent examples (Targets)
  • Epidermal Growth Factor Receptor (Anti-EGFR)
  • Vascular Endothelial Growth factor (anti-VEGF)
  • Human epidermal growth factor receptor
    (anti-HER2)
  • Protein products of oncogenes (e.g. BRC/Abl)
  • Multitargeted agents
  • Other pathways/receptors

41
Recent examples (drugs)
  • Monoclonal Antibodies (xxxxab)
  • Tyrosine kinase inhibitors (xxxib)
  • Other Inhibitors (mTOR, FTI,etc) (xxxx.ib)
  • Others

42
Recent examples
  • Epidermal Growth Factor Receptor (Anti-EGFR)
  • Vascular Endothelial Growth factor (anti-VEGF)
  • Human epidermal growth factor receptor
    (anti-HER2)
  • Protein products of oncogenes (e.g. BRC/Abl)
  • Multitargeted agents
  • Other pathways/receptors
  • Monoclonal Antibodies (xxxxab)
  • Tyrosine kinase inhibitors (xxxib)
  • Other inhibitors
  • (xxxx.ib)
  • Others

43
Common Issues
  • Low toxicity? (interactions with CTX?)

44
Common Issues
  • Low toxicity (interactions with CTX?)
  • Direct cell killing??Reduction in tumor size??
    Objective Response plausible?
  • Marginal effects

45
Common Issues
  • Low toxicity (interactions with CTX?)
  • Moderate/low anticancer activity (response rate)

46
Common Issues
  • Low toxicity (interactions with CTX?)
  • Moderate/low anticancer activity (response rate)
  • Dose-Response? Often Unlikely

47
Common Issues
  • Low toxicity (interactions with CTX?)
  • Moderate/low anticancer activity (response rate)
  • Dose-Response? Often Unlikely
  • Transient effect
  • Treatment duration
  • Resistance (partial, reversible)

48
Common Issues
  • Low toxicity (interactions with CTX?)
  • Moderate/low anticancer activity (response rate)
  • Dose-Response? Often Unlikely
  • Transient effect
  • Effect only in the presence of the target?

49
Common Issues
  • Low toxicity (interactions with CTX?)
  • Moderate/low anticancer activity (response rate)
  • Dose-Response? Often Unlikely
  • Transient effect
  • Effect only in the presence of the target?
  • Positive interaction with CTX/RTX?

50
Common Issues
  • Low toxicity (interactions with CTX?)
  • Moderate/low anticancer activity (response rate)
  • Dose-Response? Often Unlikely
  • Transient effect
  • Effect only in the presence of the target?
  • Positive interaction with CTX/RTX?
  • Activity independent of tumor size? (Yes?)

51
Consequences
  • Trials of novel therapies
  • Phase I Dose?
  • Phase II Activity?
  • Phase III Effectiveness?
  • New Methodology

52
Phase I trials of targeted therapies
  • MTD-Optimal Dose -Lowest effective Dose?
  • Safety
  • Dose-toxicity
  • Pharmacokinetics (e.g. saturation)
  • (MTD)?
  • Biologically Effective Dose
  • (Biologic endpoints from animal/human models)
  • Dose/Activity (Phase I-II)

53
Phase I-II trials of targeted therapies
  • Study design (for dose-activity)
  • Larger size
  • Randomization? (e.g. different doses)
  • Patients?
  • Duration of treatment?
  • Single agent or CTX?
  • Endpoint?

54
Phase II (or I-II) trials
  • Main Challenge
  • How to assess the activity of novel therapies?
  • Design and conduct of phase II studies of
    targeted anticancer therapy Recommendations from
    the task force on methodology for the development
    of innovative cancer therapies (MDICT) - Boot et
    al, Eur J Cancer 2007

55
Approach used in the development of some novel
anticancer therapies
  • Phase IA Safety, Toxicity
  • Biological Marker ?
  • Phase III Efficacy

56
Phase II (or I-II) trials
  • Reasons for phase II trials (Simon, JCO 2001)
  • Economy Insufficient resources to test all drugs
    in all tumor types by phase III trials

57
Phase II (or I-II) trials
  • Reasons for phase II trials (Simon, JCO 2001)
  • Economy
  • Ethics inappropriate to expose large numbers of
    pts in a phase III trial to an agent with no
    demonstrated activity.

58
Phase II (or I-II) trials
  • Reasons for phase II trials (Simon, JCO 2001)
  • Economy
  • Ethics
  • Opportunity chance to modify dose of the agent
    or to better select the target population for
    the phase III trials

59
Phase II (or I-II) trials
  • Reasons for phase II trials (Simon, JCO 2001)
  • Economy
  • Ethics
  • Opportunity
  • Science, i.e. statistics Results of subsequent
    phase III trial
  • Positive More convincing
  • Negative Can be interpreted

60
Phase II (or I-II) trials of targeted therapies
  1. Endpoint
  2. Design
  3. Selection of patients

61
Phase II (or I-II) trials
  • Activity
  • Endpoint
  • Design Selection of pts

62
a) Endpoints of Phase II (or I-II) trials
  • Activity endpoints
  • vs
  • Surrogate endpoints

63
Endpoints in phase II trials
  • Activity Endpoints
  • Assess mechanisms, direct effects on the
    disease/organism

64
Endpoints in phase II trials
  • Activity Endpoints
  • Surrogate endpoints
  • Intermediate events/markers/ parameters that (are
    assumed to) reflect the effects of the treatment
    on the true endpoint

65
Endpoints
  • Surrogate endpoints
  • Activity Endpoints

66
  • Activity endpoints may not be valid surrogate
    endpoints
  • Antiarythmic drugs
  • Effects on arythmia ? Effects on sudden deaths
  • Cast trial active antiarythmic drugs increased
    SD mortality

67
  • Activity endpoints may not be valid surrogate
    endpoints
  • Screening tests
  • Earlier diagnosis ? Reduction in mortality?
  • Mayo clinic lung project earlier diagnosis but
    no decrease in mortality

68
  • Activity endpoints may not be valid surrogate
    endpoints
  • (Chemo)prevention
  • Incidence ? Mortality?
  • Tamoxifen in BC?

69
Plausible surrogate endpoints may not be
activity endpoints
Endpoint Surrogate Activity
Obj. response yes ? For cytotoxic drugs
RFS yes ? No
PFS yes ? No
70
Endpoints in phase II trials
  • Phase II trials, if possible, should use Activity
    endpoints
  • Stronger rationale for phase III trials
  • Smaller size
  • Negative Phase III can be interpreted

71
Endpoints in phase II trials
  • Phase II trials, if possible, should use Activity
    endpoints
  • If not possible, plausible (validated?) surrogate
    endpoints are acceptable

72
Endpoints in Phase II (I-II) trials
  • Biological Activity
  • Tumor tissue markers, circ. tum. cells,
    plasma/serum markers, metabolic imaging, etc.

73
Endpoints in Phase II (I-II) trials
  • Biological
  • Example The smallest dose that inhibited the
    phosphorylation of CRKL, an adapter protein that
    is a major substrate of the deregulated BCR/ABL
    tyrosine kinase and is aberrantly
    tyrosine-phosphorylated in chromosome
    Philadelphia-positive leukemia cells, was 400 mg.
  • (Rosa DD et al., Molecular-targeted therapies
    Lessons from ..., Cancer Treat Rev (2007),
    doi10.1016/j.ctrv.2007.07.019)

74
Endpoints in Phase II (I-II) trials
  • Biological
  • Example Results from a phase I study evaluating
    cetuximab in patients with advanced solid tumours
    expressing EGFR showed that it effectively
    abrogated EGFR-mediated cell signalling, with no
    alteration in total EGFR protein.
  • (Rosa DD et al., Molecular-targeted therapies
    Lessons from ..., Cancer Treat Rev (2007),
    doi10.1016/j.ctrv.2007.07.019)

75
Biological endpoints
  • Sensitivity and Specificity of the Endpoint
  • Sensitive Representative of the mode of action
    of the treatment
  • Specific Does not show spontaneous modifications

76
Biological Endpoints
  • Specific Target
  • Eligibility restricted
  • Stronger effect (Smaller sample size)
  • More convincing evidence

77
Biological Endpoints
  • Specific Target
  • Not specific (e.g. TLI)
  • Weaker effect (large sample size)
  • Need for a randomised control group
  • Less convincing evidence

78
Biological Endpoints
  • Sensitivity and Specificity of the Endpoint?
  • (preclin. studies, studies in other cancers, with
    similar treatments)
  • Wrong endpoint ? effective treatment discarded

79
Biological Endpoints
  • Sensitivity and Specificity of the Endpoint?
  • Eligible patients
  • Measurable target
  • Patients amenable to multiple biopsies
  • Organizational and clinical burden

80
Biological Endpoints
  • Sensitivity and Specificity of the Endpoint?
  • Eligible patients
  • Sufficient evidence to start a phase III trial?

81
Endpoints in Phase II (I-II) trials
  • 2. Clinical (surrogate) Endpoints

82
Endpoints in Phase II (I-II) trials
  • 2. Clinical (surrogate) Endpoints
  • Objective response
  • Plausible?
  • Specific (gt50 reduction in tumor mass within few
    months)
  • Sensitive? If not observed, the treatment can be
    discarded as inactive?

83
Endpoints in Phase II (I-II) trials
  • 2. Clinical (surrogate) Endpoints
  • Objective response
  • Time to progression/relapse (median TTP,
    Progression- free at 6 months, etc.)

84
Endpoints in Phase II (I-II) trials
  • 2. Clinical (surrogate) Endpoints
  • Objective response
  • Time to progression/relapse
  • Historical data unreliable (control group?)
  • Randomised?
  • 2 stage designs?
  • Sample Size? (close to phase III trials)

85
Time to Progression/Relapse
  • Surrogate endpoint!
  • If a relevant effect on TTP is seen in a phase II
    trial, is the randomised Phase III trial still
    ethical?

86
Endpoints in Phase II (I-II) trials
  • 2. Clinical Endpoints
  • Objective response
  • Time to progression/relapse
  • Clinical Benefit (QoL, improvement in symtoms,
    combined endpoints)
  • Validated?
  • Same problems of TTP

87
b) Designs in Phase II (I-II) trials
  • Single-arm designs
  • Absolute values (e.g. 50 resp. Rate)
  • Relative to Historical Controls
  • Before-after designs
  • Regression to the mean?
  • Natural history of the tumor?
  • Bias?

88
Designs in Phase II (I-II) trials
  • Single-arm designs Can be used if
  • a) The endpoint is very specific
  • or
  • b) Historical data are very solid and stable
  • and
  • c) The endpoint can be assessed
    objectively/unbiasedly

89
Designs in Phase II (I-II) trials
  • Single-arm designs
  • Non-comparative randomised trials
  • Used to select the most active drug(s) among a
    series of drugs/combinations
  • Problems in the interpretation of results
  • Seldom used with novel therapies

90
Designs in Phase II (I-II) trials
  • Single-arm designs
  • Non-comparative randomised trials
  • Randomised comparative Phase II trials
  • Necessary for non specific endpoints
  • Sample Size lt than in Phase III trials
  • Various designs (e.g. random discontinuation)

91
Randomised Phase II (I-II) trials
  • Control arm
  • Untreated ?
  • Responding/Stable pts after standard therapy
  • Patients not candidate to further therapies
  • To encourage pts to participate
  • If endpoint is TTP, cross-over after progression
  • If biological endpoint, cross over after its
    assessment

92
Randomised Phase II (I-II) trials
  • Control arm
  • Untreated ?
  • Standard (chemo)therapy?
  • Same chemotherapy also in exp. arm
  • Negative/positive interactions?

93
Randomised Phase II (I-II) trials
  • Reduced Sample Size
  • Large Effect (esp. for biological endpoints)
  • Relaxed significance level
  • 0.10 (-23)
  • 0.20 (- 47)
  • Stopping rules for evidence of futility (clearly
    inactive treatment)

94
c) Selection of patients for Phase II trials
  • Bearing the (presumed) target
  • Increased power

95
Trial in Unselected patients - Response rate
from 20 to 40 (in pts with the target)
?0.05 ?0-2
96
Target?
  • Not always a yes/no phenomenon (e.g. number of
    copies of HER2)
  • Reliability of assessement (technique,
    inter-intra-laboratory variability)
  • Necessary but not sufficient (e.g. EGFR and K-ras
    mutation)
  • Sufficient but not necessary (e.g. multitargeted
    agents)

97
c) Selection of patients for Phase II trials
  • Bearing the (presumed) target
  • Increased power
  • Only if strong biologic rationale
  • Risk if wrong target

98
Phase II (I-II) trials
  • Selection of patients
  • With the (presumed) target
  • All patients
  • Identification a posteriori of markers of
    susceptibility (targets)
  • Much larger sample size (if true target)

99
Unselected patients
182 pts
300 pts
600 pts
900 pts
100
Phase II (I-II) trials
  • Selection of patients
  • With the (presumed) target
  • All patients
  • Enriched populations (unbalanced sampling of
    pts with the target)

101
Enriched populations
3-400 pts 50 with the mutation
182 pts
300 pts
600 pts
900 pts
102
Efficacy Trials of Novel Therapies
  • Standard RCTs Overall Survival (or
    surrogates)
  • Peculiarities
  • Selected patients (target present)
  • Organizational burden
  • Costs
  • Long-term toxicity
  • (smaller size/larger effect)?

103
Development of a novel therapy
Strong preclinical evidence of activity on the
target
104
Development of a novel therapy
Strong preclinical evidence of activity
Phase IA Safety
105
Development of a novel therapy
Strong preclinical evidence of activity
Phase IA Safety
Randomised Comparison
Biological endopint Stop if no activity
Unselected pts
Phase I-II Dose-response
106
Development of a novel therapy
Strong preclinical evidence of activity
Phase IA Safety
Randomised Comparison
Biological endopint Stop if no activity
Unselected pts
Phase I-II Dose-response
Surrogate endpoint (sel. Pts?)
Phase IIB
107
Development of a novel therapy
Strong preclinical evidence of activity
Phase IA Safety
Randomised Comparison
Biological endopint Stop if no activity
Unselected pts
Phase I-II Dose-response
Surrogate endpoint (sel. Pts)
Phase IIB
Efficacy (OS, PFS, RFS)
108
Development of a novel therapy
Strong preclinical evidence of activity
Phase IA Safety
Randomised Comparison
Biological endopint Stop if no activity
Unselected pts
Phase I-II Dose-response
Surrogate endpoint (sel. Pts)
Phase IIB
Stop if no difference with control arm (futility)
or toxicity
Efficacy (OS, PFS, RFS)
109
Development of a novel therapy
Strong preclinical evidence of activity
Phase IA Safety
Randomised Comparison
Biological endopint Stop if no activity
Unselected pts
Phase I-II Dose-response
Surrogate endpoint (sel. Pts)
Phase IIB
Stop if no difference with control arm (futility)
or toxicity
Stop random if suff. evid. of efficacy
Efficacy (OS, PFS, RFS)
110
Development of targeted therapies
  • Bayesian Statistics
  • To monitor study results for early stop
  • To use validated surrogate endpoints
  • To extrapolate results across cancers of
    different sites bearing the same target

111
  • A therapy targeted at a specific mutation in gene
    X has been demonstrated in RCTs to improve
    survival in resected pts with the mutation (20),
    (lung c. , colon c., prostate c. and breast
    c.), with reductions in mortality of 20-40

112
  • A therapy targeted at a specific mutation in gene
    X has been demonstrated in RCTs to improve
    survival in resected pts with the mutation (10),
    (lung c. , colon c., prostate c. and breast
    c.), with reductions in mortality of 20-40
  • We want to show its efficacy (phase III trial) in
    osteosarcomas with the same mutation

113
  • A therapy targeted at a specific mutation in gene
    X has been demonstrated in RCTs to improve
    survival in reseted pts with the mutation (10),
    (lung c. , colon c., prostate c. and breast c.),
    with reductions in mortality of 20-40
  • We want to show its efficacy (phase III trial) in
    osteosarcomas with the same mutation
  • Null Hypothesis? - Evidence needed to accept the
    efficacy of the new treatment in osteosarcomas?

114
Test of significance?
Mortality Other Tumors Nil vs B 15 vs
12.5 N12000 P
0.0007 Osteosarcoma Nil vs B 15 vs
8.3 N 240 P 0.11
115
Summary
  • The assessment of the activity of a treatment is
    critical in its development
  • The methodology of trials derives from the
    therapeutic paradygm
  • A priority of modern cancer research is the
    identification of efficient (sensitive and
    specific) markers of activity for phase II
    trials of novel drugs

116
Conclusions
  • Development of cytotoxic drugs
  • Fixed Standard Methodologies
  • Roles
  • Phase I - Pharmacologist
  • Phase II Oncologist (Statistician/Simons
    tables)
  • Phase III Oncologist Statistician (sample
    size and analysis)

117
Conclusions
  • Development of novel drugs
  • Specific (original) methodology developed,
    monitored and re-adjusted for each new drug
  • Roles
  • Multidisciplinary teams (Basic
    ResearcherOncologistStatistician) working
    together in the design, conduct and
    interpretation of all phases of development

118
Traditional Role of the Statistician
119
Tell me, Paolo, how many patients do I need
for..?
120
..back to the PC.and
121
for alfa0.0001 and power 99.999 you need
806,913.8 patients!
122
New duties of the statistician
Learn about biology!
123
New duties of the statistician
Think!
124
New duties of the statistician
Listen, propose and discuss!
125
Think again!
126
Until you find a rational solution
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