Transcript Clinical trials of the nanocell

Clinical trials of the nanocell
B.Ichinkhorloo
Master student, AIT
Outlines
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Introduction
Phase I
Phase II
Phase III
Phase IV
Conclusion
Introduction
Phase I
 n=30-50
 Patient with any type of tumor
 Tumor size I-II
 Vary dose
 Duration (about 2-3cycles)
Phase II
 n=50-100
 Patient with solid liver tumor
 Dose based on phase I
 Duration longer than phase I
Introduction (cont.)
Phase III
 n=150-300
 Patients with HCC
 Fixed dose
 Long time- about 1 year
 Appropriate schedule
Phase IV
 involve the post-launch safety surveillance and ongoing
technical support of a drug
detect any rare or long-term adverse effects
over a much larger patient population and timescale
 mandated by regulatory authorities
Objectives on each phase of
clinical trials
Phase I
Define MTD
Phase II
Response rate,
survival, quality of
life
Describe common
side effects
Expand toxicity data
base
Describe
pharmacokinetics/
pharmacodynamics
Possibly
pharmacodynamic
relationships
Phase III
Survival, quality
of life
compared to
standard
treatment
MTD- Maximum Tolerated Dose
Pharmacokinetic
Doxorubicin (Adriamycin)
– Rapid tissue uptake: initial half-life 5 minutes
– Slow elimination from tissue-terminal half-life 2048 hours
– Steady state distribution volume ranges -809-1214
L/m2
– Extensive drug uptake into tissues
– Does not cross the blood brain barrier.
– Approximately 40% of the dose appears in the bile
in 5 days,
– 5 to 12% of the drug and its metabolites appear in
the urine during the same time period
Phamacokinetic (cont.)
5 Fluorouracil (5FU)
– Rapid distribution
– Disappears from the blood within 4 hour
– Preferentially taken up by actively dividing
tissues and tumours after conversion to its
nucleotide.
– Readily crosses the blood-brain barrier and
distributes into the cerebrospinal fluid
– About 20% excreted unchanged in the urine
within 6 hours
– The remainder is mostly metabolised in the liver
by the usual body mechanisms for uracil
Side effects: Doxorubicin and 5FU
Chemotherapeutics
Side effects
Common
Less common
Doxorubicin
pain along the side where treatment
was given
Fatigue, tired
nausea, vomiting
Feeling or being sick (usually mind)
low blood count
Mouth sores and ulcers
mouth sores
Diarrhea
hair loss
low blood count
eyes watering
Hair thinning , sensitivity of the skin to sunlight
urine may appear red, red-brown,
orange or pink
Rashes the skin, eyes watering and blurring
vision
darkening of the nail beds
problems with fertility
Uncommon
5FU
interference with the pumping action of
the heart
Loss of appetite,
soreness and redness of palms of the hands
and feed
loss of fertility
Total hair loss
Darkened skin
Angina or heart attack
Confusion or unsteadiness
Nanocell- antiangiogenic agent
FTY720
• Low overall toxicity
• Adverse effects in higher dose
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Bradycardia with the first few doses
Gastrointestinal disorder - diarrhea and nausea
Nervous system disorder -headache
Respiratory disorders -short breath and cough
• Pharmacokinetic
– Long terminal phase - half-life
– High volume of distribution
– Low clearance rate
Patient selection criterion
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Histologically or cytologically proven liver cancer
No effective therapy was available
Age >18 years
Adequate performance status 80-100 (WHO scale
scores)
• Life expectancy ≥ 3 months
• > 4 weeks since previous treatment with
chemotherapy or >3 weeks since previous
radiotherapy
Patients selection criterion (cont.)
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Early stage of cancer
Recovered from any treatment-related toxicities
Recovered from previous surgery
With adequate hepatic, renal, and bone marrow
function
• Excluded pregnant and nursing women
• Understand participation
Prestudy of patients
• Patient history (drug sensitivity)
• Blood profile examination
– Blood
– Complete blood counts
– Electrolytes
– Liver function tests
– Kidney function tests
• Urine analysis
• ECG (Electrocardiography)
• CT (Computed tomography) of the chest, abdomen,
pelvis and brain
Dose estimation
• Animal dose
Interspecies UF=10
F= 50mg/kg
•Human dose
500µg/kg
F=5mg/kg
Intraspecies UF=10
•Human dose
D+5
50µg/kg
F=0.5mg/kg
D+5
5µg/kg
D+5
Dose estimation
100µL/nanocell/kg = 0.5mg/kg (F)+5µg/kg (D+5)
70kg
700µL/nanocell/70kg = 35mg (F)+350µg (D+5)
1 cycle=1day every 3 weeks
Total 8 cycles
5.6ml/nanocell/70kg/8cycles = 280mg(F) + 2800µg(D+5)
(F) - FTY720,
(D+5) – Doxorubicin + 5FU
Study design-Phase I
Control
Group I
(nanocell)
Group II
(D+5FU)
Group III
(FTY720)
MTD
Common side effects
Pharmacokinetics
n=25
n=25
n=25
Single dose intermittent schedule
D- Doxorubicin
5FU-5Flourouracil
Evaluation of phase I
• Toxicity assessment
• Response assessment
• Pharmacokinetic studies
• Statistic analysis
Toxicity assessment
• Weekly
– Blood cells count
• White blood cells
• Red blood cells
• Platelets
– Biochemistry
• Liver function (alanine aminotransferase (ALT), aspartate
aminotransferase (AST), lactate dehydrogenase (LDH), creatinin,blood
urea nitrogen (BUN))
• Kidney function
– Side effect observation
Response assessment and
evaluation
• Every 2 cycles
– CT and MRI
• Evaluation
– Tumor size
Patient (n)
Variable
No
Complete
response
Partial response
Minor response
Stable disease
CT-computed Tomography
MRI-magnetic resonance imaging
nanocell
group
Progressive
disease
%
control
group
No
%
Pharmacokinetic studies
– Blood sample
• Before start
• 5, 10, 20, 35 minutes
• 2, 4, 6, 24 hours from the start of infusion
– Urine sample
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before start
0 to 4
4 to 7
7 to 24 hours after the start of infusion.
– Liquid chromatography/mass spectrometry/mass
spectrometry method
Pharmacokinetic evaluation
• ADME (Absorption, Distribution, Metabolism and
Elimination)
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Initial distribution half life
Volume distribution
Steady state distribution
Terminal half life
Renal Clearance
• Statistic analysis
– SPSS
Study design-Phase II
Control
Goal
Group II
(D+5)
Group I
Group III
(FTY720)
Response rate,
survival,
quality of life
Possibly
Expand toxicity pharmacodynamic
data base
relationship
Nanocell
n=50
n=50/each group
t=8 cycles
(D+5) - Doxorubicin +5FU
Study design - Phase III
Group I
nanocell
Group II
(TACE)
Survival,
quality of life
compared to
standard treatment
n > 150
t-about 1 year
TACE –Transcatheter Arterial Chemo-Embolization
n>150
Conclusion
We expect that our nanocell will be
• Less toxic
• More effective
• No side effects
• Higher liver cancer recovery
Summary
• Our nanocell represents a very promising novel
approach of drug delivery system in liver cancer
therapy
• Nanocell has advantages in liver tumor specificity,
higher therapeutic index, lower toxicity, reduce drug
resistance
• Our proposed nanocell process can be further
developed by doing experiment
Performance Status Scale of WHO
Score
Performance Status
100
Normal, no complaints, no evidence of disease
90
Able to carry on normal activity, minor signs or symptoms of disease
80
Normal activity with effort, some sings of symptoms of disease
70
Cared for self; unable to carry on normal activity or to do active work
60
Requires occasional assistance, but is able to carry on normal activity or to care
for most of his or her needs
50
Requires considerable assistance and frequent medical care
40
Disabled, requires special care and assistance
30
Severely disabled; hospitalization is indicated although death not imminent
20
Hospitalization necessary, very sick, active supportive treatment necessary
10
Moribund, fatal processes progressing rapidly
0
Dead
Response criteria
Complete response
(CR)
Complete disappearance of all clinical evidence of
active tumor all objective disease for all least 4 wk
Partial response (PR)
50% reduction in size from baseline of all clinically
measurable lesions without tumor or the
appearance of any new lesions for at least 4 wk
Minor response (MR)
A decrease of <50% but >25% in tumor size for at
least 4 wk
Stable disease (SD)
A <25% decrease in tumor size or a <25% increase for
at least 4 wk
Progressive disease
(PD)
The unequivocal appearance of any new lesions or an
increase of >=25% in the sum of the perpendicular
diameters of any measurable lesion, or in the
estimated size of a non-measurable lesion