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Clinical trials of the nanocell

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

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Clinical trials of the nanocell

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  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 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/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

  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

  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. Interspecies UF=10 F= 50mg/kg • Human dose 500µg/kg Intraspecies UF=10 F=5mg/kg D+5 • Human dose 50µg/kg 5µg/kg F=0.5mg/kg D+5 D+5 Dose estimation • Animal dose

  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. Group I (nanocell) Group II (D+5FU) Group III (FTY720) n=25 n=25 n=25 D- Doxorubicin 5FU-5Flourouracil Study design-Phase I Control MTD Common side effects Pharmacokinetics 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. Response assessment and evaluation • Every 2 cycles • CT and MRI • Evaluation • Tumor size CT-computed Tomography MRI-magnetic resonance imaging

  19. 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

  20. 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

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

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

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

  24. 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

  25. Performance Status Scale of WHO

  26. Response criteria

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