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Clinical trials of the nanocell B.Ichinkhorloo Master student, AIT.

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Presentation on theme: "Clinical trials of the nanocell B.Ichinkhorloo Master student, AIT."— Presentation transcript:

1 Clinical trials of the nanocell B.Ichinkhorloo Master student, AIT

2 Outlines Introduction Phase I Phase II Phase III Phase IV Conclusion

3 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

4 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

5 Objectives on each phase of clinical trials Phase IPhase IIPhase III Define MTD Response rate, survival, quality of life Survival, quality of life compared to standard treatment Describe common side effects Expand toxicity data base Describe pharmacokinetics/ pharmacodynamics Possibly pharmacodynamic relationships MTD- Maximum Tolerated Dose

6 Pharmacokinetic Doxorubicin (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/m 2 –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

7 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

8 Side effects: Doxorubicin and 5FU Side effects Chemotherapeutics Doxorubicin5FU Common pain along the side where treatment was given Fatigue, tired nausea, vomitingFeeling or being sick (usually mind) low blood countMouth sores and ulcers mouth soresDiarrhea hair losslow 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 fertilityloss of fertility Uncommon interference with the pumping action of the heart Total hair loss Darkened skin Angina or heart attack Confusion or unsteadiness

9 Nanocell- antiangiogenic agent FTY720 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

10 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

11 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

12 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

13 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

14 Dose estimation 100µL/nanocell/kg = 0.5mg/kg (F)+5µg/kg (D+5) 70kg 700µL/nanocell/70kg = 35mg (F)+350µg (D+5) Total 8 cycles 1 cycle=1day every 3 weeks 5.6ml/nanocell/70kg/8cycles = 280mg(F) + 2800µg(D+5) (F) - FTY720, (D+5) – Doxorubicin + 5FU

15 Study design-Phase I MTD Common side effects Pharmacokinetics Group I (nanocell) Group II (D+5FU) n=25 D- Doxorubicin 5FU-5Flourouracil Group III (FTY720) n=25 Control Single dose intermittent schedule

16 Evaluation of phase I Toxicity assessment Response assessment Pharmacokinetic studies Statistic analysis

17 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

18 Toxic effect Patient (n) nanocell groupcontrol group No% % Hematologic neutropenia Grade I-II (AGC 1.0-1.9x10 3 µL Grade III-IV(AGC ≤ 0.9x10 3 µL Thrombocytopenia Grade I-II (PLT 50-75x10 3 µL) Grade II-IV (PLT ≤ 49x10 3 µL) Anemia Grade I-II (Hgb 8.0-9.0g/dl) Grade III-IV (Hgb<=7.9g/dl) Diarrhea Grade I-II Grade III-IV Nausea and vomiting Grade I-II Grade III-IV Fatique Grade I-II Grade III-IV Cardiotoxity Grade I-II Grade III-IV Toxicity analyses

19 Response assessment and evaluation CT-computed Tomography MRI-magnetic resonance imaging Variable Patient (n) nanocell group control group No% % Complete response Partial response Minor response Stable disease Progressive disease Every 2 cycles –CT and MRI Evaluation –Tumor size

20 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

21 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

22 Study design-Phase II Group I Group II (D+5) Response rate, survival, quality of life Expand toxicity data base Possibly pharmacodynamic relationship Goal Nanocell n=50 n=50/each group t=8 cycles Control Group III (FTY720) (D+5) - Doxorubicin +5FU

23 Study design - Phase III Survival, quality of life compared to standard treatment n > n>150 150 t-about 1 year Group I nanocell Group II (TACE) TACE –Transcatheter Arterial Chemo-Embolization

24 Conclusion We expect that our nanocell will be Less toxic More effective No side effects Higher liver cancer recovery

25 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

26 Performance Status Scale of WHO ScorePerformance Status 100Normal, no complaints, no evidence of disease 90Able to carry on normal activity, minor signs or symptoms of disease 80Normal activity with effort, some sings of symptoms of disease 70Cared for self; unable to carry on normal activity or to do active work 60Requires occasional assistance, but is able to carry on normal activity or to care for most of his or her needs 50Requires considerable assistance and frequent medical care 40Disabled, requires special care and assistance 30Severely disabled; hospitalization is indicated although death not imminent 20Hospitalization necessary, very sick, active supportive treatment necessary 10Moribund, fatal processes progressing rapidly 0Dead

27 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 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

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