Download Metody rozpoznawania i leczenie chorób onkologicznych narządu

Postęp w onkologii - nowe techniki,
nowe leki
Radosław Mądry
Katedra i Klinika Onkologii Uniwersytety Medycznego
im. K. Marcinkowskiego w Poznaniu
Cancer Treatment Today
• Surgery
• Radiation
• Systemic treatment:
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Cytotoxic Chemotherapy
Hormone therapy
Immunotherapy
Non-cytotoxic therapy
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Stanley B. Kaye Progress in the treatment of ovarian cancer. Lessons from Homologous
Recombination
10th International Symposium Advanced Ovarian Cancer: Optimal Therapy. Update
Valencia, Hiszpania, 6 Marca 2015
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Long Term Survival (%)
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Leukemia in children
Leukemia in adults
Bone cancer
Testicular cancer
Breast cancer
Non-small cell lung cancer
Colon cancer
Hodgkin’s disease
1970
0
0
5
0
40
0
30
10
2008
80
45
60
80
85
15
60
85
From Lab….. To Clinical
Trials…. To Standard Practice
Laboratory data
Effective Therapy
Drug Development
• Identification of new agents
• Preclinical requirements:
efficacy, toxicology (ICH)
• Formulation, manufacturing
• Regulatory (government) review
(IND submission)
• Phase I, II, III clinical trials
• Regulatory (government) review
(NDS = new drug submission)
Anticancer Drug Discovery
• Mechanism based
– Rational synthesis or discovery of agents targeting
mechanisms of malignant behavior. Then test in
laboratory models
• Screening/Compound based
– Screen new chemical entities for activity in cancer
models in the laboratory. Then discover mechanisms
of action.
Screening/Compound
Based Discovery
• Majority of available anticancer drugs have been identified
by screening
• Sources: plants (vincas, taxanes)
microbes (doxorubicin)
chemicals (cisplatin)
• Most act by interfering with molecular process of cell
division. Therefore, many normal tissues will be affected.
Preclinical Requirements
A new drug must have completed the following prior to
patient testing:
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Demonstration of efficacy in tumor models
Toxicology testing: 2 species (rodent and non-rodent)
Formulation and manufacturing
Animal pharmacokinetics
Mechanism of action studies
Preclinical Evaluation of Cytotoxic
Agents
IN VITRO
Mechanism of action
IN VIVO
Stage I
Stage II
 Target level
 Maximum tolerated dose
 Spectrum of activity
 Cellular level
 Dose-limiting toxicities
 Schedule dependency
 Efficacy
 Route of administration
 Cross resistance
 Combination therapies
Human Tumor in Nude Mouse
Moving a New Therapy from
the Lab to the Clinic
Clinical
Evaluation
Laboratory
Experiments
River of Unknowns
Clinical Trials
• Phase I
• Phase II
• Phase III
Phase I Trials:
Important issues
What kind of purpose (goals)
To determine the appropriate dose for phase II evaluation
Dose Limiting toxicity (DLT)
Those toxic effects that by nature of their severity limit
further dose escalation
Maximum-tolerated dose (MTD)
That dose producing a certain frequency of DLT within the
treated population
Eisenhauer EA et al, J Clin Oncol 2000; 18: 684-692
Phase I Design:
Selection of Starting Dose
• Based on mouse toxicity:
– 0.1 Mouse Equivalent LD10 (MELD10)
• In instances where dog toxicity show this
dose to be toxic, 1/3 Toxic Dose Low (TDL)
in dogs is selected as starting dose
Phase I Trials
• Find highest safe dose (1 level below MTD)
• Identify side effects
Dose
Severe toxicity
Recommended dose
3 pts
3 pts
3 pts
3 pts
3 pts
3 pts
Dose escalating by modified Fibonacci
Modified Fibonacci
Escalation
Dose Level
Theory
Example
x
1
level 2
2 x level 1
2
level 3
1.67 x level 2
3.3
level 4
1.5 x level 3
5
level 5
1.4 x level 4
6.7
level 6
1.33 x level 5
8.8
level 7
1.33 x level n-1
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starting Dose
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Phase II Trials
• Screen drug for activity in cancer patients
• Use recommended dose
• Test it in 15-30 patients with same tumor type
• Look for objective tumor shrinkage: Partial or Complete
Response
RECIST Guidelines:
Response Criteria
• Target lesions ( LD /  LD baseline)
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CR
PR: 30%  (50% surf. area and 65% volume)
SD
PD: 20%  (44% surf. area and 73% volume)
• Non-target lesions
– CR (including markers)
– Non-CR
– PD
New Response Evaluation
Criteria in Solid Tumors: Revised
RECIST Guidelines (version 1.1)
E.A. Eisenhauer, et al.
European Journal of Cancer 2009; 45: 228-247
RECIST 1.1
• Measurable lesions defined by
unidimensional measurement
• Tumor burden based on sum of diameters
• Categories of response:
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CR
PR (30% decrease in sum from baseline)
SD
PD (20% increase in sum from nadir)
Courtesy of E.A. Eisenhauer
Summary
RECIST 1.0
RECIST 1.1
Measuring tumor
burden
10 targets
5 per organ
5 targets
2 per organ
Lymph node
Measure long axis as for other
lesions.
Silent on normal size
Measure short axis.
Define normal size.
Progression definition
20% increase in sum
20% increase
and at least 5 mm absolute increase
Non-measurable
disease PD
“must be unequivocal”
Expanded definition to convey impact on
overall burden of disease.
Confirmation
required
Required when response primary endpoint—
but not PFS
New lesions
--
New section which includes comment on
FDG PET interpretation
Maximum % Change in Tumor Shrinkage (Stage 1)
Investigator Assessment
Randomized set; adjusted mean change. Only patients with baseline and at least one post-baseline measurement are included.
Inhibitory PARP u chorych na raka jajnika
będących nosicielami mutacji BRCA1/2
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What is Efficacy?
• Response  Efficacy
• Efficacy is improved:
– Cure rates
– Survival
– Quality of life: i.e. meaningful symptom palliation
• “Response” is a measure of biologic effect
which may be a marker for efficacy
2014
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Phase III Trials
Once a new agent has shown activity in phase II, comparative trials are
usually designed.
New agent can be given alone or in combination
• Objectives: Compare “new” to
“standard”
• Endpoints: Survival, toxicity, quality
of life.
• Sample Size: 200-2000 patients
Phase III Trials:
Definitive Tests of Efficacy
• Large studies to detect “significant” differences in
outcomes of interest:
– Cure, survival, quality of life
• Randomized design:
– Allows unbiased assessment of treatment effect
• Sample Size:
– Determines power with which one can detect postulated
differences
How Much Improvement in
Efficacy?
• Critical question which drives:
– Trial design and sample size
– Eventual change in practice
• Patients and physicians (staff) differ on
degree of improvement which must be
seen to choose a more toxic therapy.
• If patients views are accepted: many
trials are too small (underpowered).
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!
Bez korzyści
Bez korzyści
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2014
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ORR = objective response rate; PD = progressive disease; PFS = progression-free survival;
aEpithelial ovarian, primary peritoneal or fallopian tube cancer
bStratification factors: selected chemotherapy; prior anti-angiogenic therapy; platinum-free interval (<3 vs 3–6 months)
cOr 10 mg/kg q2w. d15 mg/kg q3w, permitted on clear evidence of PD
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GOG 172
CISPLATYNA/PAKLITAKSEL IV vs. IP
PFS
+5,5 m
n = 415 FIGO III, < 1 cm
p=0,05
6x PC (like GOG111) vs.
6x Paclitaxel IV d1+Cisplatin IP d2
+ Paclitaxel IP d8
(100 mg)
Only 42% with 6 courses IP
+15,9 m
p=0,03
OS
IV
IP
PFS
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Survival
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Armstrong et al, N Engl J Med., 2006
JCO March 23, 2015
Survival
IV
IP
51,4
61,8
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Dziękuje
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