1 / 26

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

dclayton
Download Presentation

Clinical trials of the nanocell

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

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 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

More Related