Clinical trials of the nanocell

B.IchinkhorlooMaster student, AIT

Outlines

• Introduction• Phase I • Phase II• Phase III • Phase IV • Conclusion

Introduction

Phase In=30-50Patient with any type of tumorTumor size I-IIVary doseDuration (about 2-3cycles)

Phase IIn=50-100Patient with solid liver tumorDose based on phase IDuration longer than phase I

Introduction (cont.)Phase IIIn=150-300Patients with HCCFixed 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 Phase II Phase III

Define MTDResponse rate,

survival, quality of life Survival, quality

of life compared to standard treatment

Describe common side effects

Expand toxicity data base

Describepharmacokinetics/pharmacodynamics

Possibly pharmacodynamic relationships

MTD- Maximum Tolerated Dose

PharmacokineticDoxorubicin (Adriamycin)

– Rapid tissue uptake: initial half-life 5 minutes – Slow elimination from tissue-terminal half-life 20-

48 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 5FUSide effects

Chemotherapeutics

Doxorubicin 5FU

Common

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

Less common

eyes wateringHair 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 Loss of appetite,

soreness and redness of palms of the hands and feed

problems with fertility loss of fertility

Uncommon interference with the pumping action of

the heart

Total hair loss Darkened skin Angina or heart attack Confusion or unsteadiness

Nanocell- antiangiogenic agentFTY720• Low overall toxicity • Adverse effects in higher dose

– 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

• 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.)

• 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

F= 50mg/kg

500µg/kg

D+5

•Human dose

Interspecies UF=10

•Human dose

Intraspecies UF=10

50µg/kg

F=5mg/kg

D+5

5µg/kg

F=0.5mg/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)

Total 8 cycles1 cycle=1day every 3 weeks

5.6ml/nanocell/70kg/8cycles = 280mg(F) + 2800µg(D+5)

(F) - FTY720, (D+5) – Doxorubicin + 5FU

Study design-Phase I

MTDCommon side effects

Pharmacokinetics

Group I(nanocell)

Group II(D+5FU)

n=25

D- Doxorubicin 5FU-5Flourouracil

Group III(FTY720)

n=25 n=25

Control

Single dose intermittent schedule

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

CT-computed TomographyMRI-magnetic resonance imaging

Variable

Patient (n)

nanocell group

control group

No % No %

Complete response        

Partial response        

Minor response        

Stable disease        

Progressive disease        

• Every 2 cycles– CT and MRI

• Evaluation – Tumor size

Pharmacokinetic studies– Blood sample

• Before start

• 5, 10, 20, 35 minutes

• 2, 4, 6, 24 hours from the start of infusion

– Urine sample • 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)

– Initial distribution half life– Volume distribution– Steady state distribution– Terminal half life– Renal Clearance

• Statistic analysis

– SPSS

Study design-Phase II

Group I Group II(D+5)

Response rate,survival,quality of life

Expand toxicity data base

Possibly pharmacodynamic

relationship

Goal

Nanocelln=50

n=50/each group

t=8 cycles

Control

Group III(FTY720)

(D+5) - Doxorubicin +5FU

Study design - Phase III

Survival, quality of life compared to

standard treatment

n > n>150150t-about 1 year

Group Inanocell

Group II (TACE)

TACE –Transcatheter Arterial Chemo-Embolization

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 criteriaComplete 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