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Early Clinical Trials’ Designs and their Challenges

Early Clinical Trials’ Designs and their Challenges. Pamela N Munster, MD TICR 4-14-2011. Historical Drug Development Snapshot. Molecular Screens. Cell culture, signaling studies, combinations, xenografts and animal models . Animal Tox . IND granted. Phase 0. Phase I

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Early Clinical Trials’ Designs and their Challenges

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  1. Early Clinical Trials’ Designsand their Challenges Pamela N Munster, MD TICR 4-14-2011.

  2. Historical Drug Development Snapshot Molecular Screens Cell culture, signaling studies, combinations, xenografts and animal models Animal Tox IND granted Phase 0 Phase I Safety/Phase II dose 2554 Phase I trials currently accruing 3908 NCI listed Phase II Efficacy/Tox 1872 NCI listed Phase III Compare new vs. standard FDA Approval Phase IV long term safety

  3. Types of Treatments in Phase I Clinical Trials (I) Testing of a novel strategy/compound • New single agent • First in Man, Proof of Concept • New formulations, schedules or doses • Combinations of novel agents with existing agents • X combined with chemotherapy • X combined with hormonal therapies • Novel agent as biological response modifier • Inhibition of Histone deacetylase, • Inhibition of DNA repair (e.g. PARP, Chk1, wee1) • Inhibition of chaperone proteins, (e.g. HSP90)

  4. Testing of a novel strategy/compound Different Modalities Electroporation of inhibitory genes, siRNA, anti-sense Immune modifiers Types of Treatments in Phase I Clinical Trials (II)

  5. Early Phase Clinical Trials’ Design Terms and Definitions • Safety, Toxicity and Tolerability • Dose limiting toxicities (DLT) • Maximally Administered Dose (MAD) • Maximally Tolerated Dose (MTD) • Recommended Phase II dose (RPTD) • Dose Escalation Rules • Pharmacokinetics and Pharmacodynamics

  6. Early Phase Clinical Trials’ Design Terms and Definitions • Safety, Toxicity and Tolerability • Standard toxicity assessment by Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0 or more recently 4.0 • Grading • 0-5 • Causality determination: • treatment-emergent vs treatment-related

  7. Example: Toxicity Assessment Presentation: A 47 year old Caucasian male starts an investigational agent on 4-1-11, Four days later he presents with a new rash over his entire right arm with itching. He continues to have mild fatigue, but now has an unquenchable thirst. He is able to do his daily chores. His fasting blood glucose is 271 mg/dL. Baseline criteria included Grade I fatigue, but otherwise no symptoms. Assessment: Grading and Relatedness (CTCAE IPhone App, or (ctep.cancer.gov/protocoldevelopment/electronic.../ctcaev3.pdf) Fatigue: Rash: Fasting Blood Glucose:

  8. Example: Toxicity Assessment Presentation: A 47 year old Caucasian male starts an investigational agent on 4-1-11, Four days later he presents with lightheadedness, fatigue, unquenchable thirst. He is able to do his daily chores and has otherwise no symptoms. His fasting blood glucose is 271. Baseline criteria included Grade I fatigue, but otherwise no symptoms. Assessment: Fatigue: Grade 1, not related Rash: Grade 2, related Fasting Blood Glucose: Grade 3, related

  9. Classical Phase I Clinical Trials’ Design Terms and Definitions Dose limiting toxicities (DLT) within window (usually 3-4 weeks) • Grade 3 non-hematological toxicities • Grade 4 hematological • Protocol-specific definitions • E.g. allow for grade 3 • Diarrhea despite optimal care, • Nausea despite optimal care • Hyperglycemia (with treatment for more than 14 days) (PI3k, mTOR) • Hypertension (VEGF inhibitors, VEGFR inhibitors)

  10. Classical Phase I Clinical Trials’ Design Terms and Definitions • Maximally Administered Dose (MAD) • Highest administered dose (>2/6 pts with DLT) • Maximally Tolerated Dose (MTD) • Highest tested dose where 0/6 or 1/6 patients experienced DLT • Recommended Phase II dose (RPTD) • The dose to be tested in phase II

  11. Dose escalation designs Leonardo di Pisa (ca.1202) (Fibonacci) First mentioned in Pingala (200 BC)

  12. Early Phase Clinical Trials’ Design Dose escalation designs • Fibonacci (0, 1, 1, 2, 3, 5, 8, 13, 21, …) • Modified Fibonacci • Dose doubling Designs • Adaptive Designs • real time pharmacokinetics, • statistical adaptations • Combinations of designs

  13. Fibonacci and modified Fibonacci Dose escalations Dose escalation

  14. Dose doubling Dose escalation

  15. Other Dose Escalation schemes Dose escalation with fixed tablets: e.g. 100 mg tablets

  16. Adaptive Designs (Example) Adaptive Dose escalation with fixed tablets: e.g. 100 mg tablets

  17. Cohorts and Sample Size Cohort Size Patient Escalation 1+1 (occ. used for lowest doses) 3+3 (most common) 6+6

  18. Early Phase Clinical Trials’ Design Terms and Definitions • Dose Escalation Rules • PRE-DEFINED CONDITIONS FOR DOSE ESCALATION • (standard and specific to the individual protocol)

  19. Dose Escalation Rules (3+3 design)

  20. Cohorts and Sample Size Patient Escalation 3+3

  21. Cohorts and Sample Size Patient Escalation 3+3

  22. Cohorts and Sample Size Patient Escalation 3+3

  23. Cohorts and Sample Size Patient Escalation 3+3

  24. Cohorts and Sample Size Patient Escalation 3+3

  25. Cohorts and Sample Size Patient Escalation 3+3

  26. Dose expansion • Purpose: • Estimation of toxicities in larger sample set • Estimation of PK and PD markers • Preliminary Efficacy • Sample size • Minimum 6 • General 12-15

  27. Dose expansion • Purpose: • Estimation of toxicities in larger sample set • Estimation of PK and PD markers • Preliminary Efficacy • Sample size • Minimum 6 • General 12-15

  28. Pharmacokinetics and Pharmacodynamics

  29. Pharmacokinetics • “Drug Behavior in the Subject”

  30. Pharmacokinetics Pharmacokinetics Absorption Metabolism Polymorphism Free Drug Plasma ↕ Metabolites Bound Drug TARGET SITE (Receptor) Free Drug ↕ Bound Drug TISSUE SITE Free Drug ↕ Bound Drug Elimination Excretion P. Munster

  31. Pharmacokinetics • Measurables • Routinely done: albeit often limited • Half-life (t1/2) • Distribution volume • Peak concentrations (Cmax) • Time to peak concentration (Tmax) • Area under the curve • Food effects • Not routinely done • Polymorphisms • Drug-drug interactions • PK-PD interactions

  32. Example of PK sampling in Phase I trial Heparinized blood samples (10 mL) will be collected on Day1 at 0, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hours after the first dose of LY335562 Day 15 at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after that day’s dose Day 57 at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after that day’s dose. Single blood samples for pharmacokinetic studies for the desmethyl metabolite were also collected on days 8, 15, 22, 29, 43, 71, and 85.

  33. Example: Plasma concentration: dose escalations ASCO 2008, J Infante

  34. Example: Plasma concentrations: Drug accumulations Fig 1. Mean plasma concentrations of LY353381.HCl versus time following a single dose at visit 1 and multiple doses of LY353381.HCl at visit 3 Munster, P. N. et al. J Clin Oncol; 19:2002-2009 2001

  35. Example: Plasma bioavailability: IV versus oral dosing Fig 2. Peak and day 3 plasma levels of valproic acid (VPA) Munster, P. et al. J Clin Oncol; 25:1979-1985 2007

  36. Example: Plasma Concentrations (Free and Total Drug) 450 70% 350 38% 400 45% 300 43% 350 35% 31% 250 300 39% 250 200 19% Total VPA plasma level (µg/ml) Free VPA plasma level (μg/ml) 200 150 20% 150 21% 100 100 50 50 0 0 0 15 30 45 60 75 90 100 120 140 160 0 15 30 45 60 75 90 100 120 140 160 VPA dose level (mg/kg/day) VPA dose level (mg/kg/day) Dose Escalation: n=41 Dose Expansion: n=15 Munster et al CCR 2009

  37. Example: Plasma Concentrations – Drug Interactions 10000 1000 100 10 1 0.1 0.01 0 50 100 150 200 250 300 VPA dose level (mg/kg/day) C 0.25 h 24 h 48 h 168 h Epirubicin level (ng/ml) VPA level (μg/ml) Munster et al CCR 2009

  38. Metabolism and Polymorphism

  39. Polymorphisms in the CYP2D6 gene changes Metabolizers status PM: Poor metabolizersIM: Intermediate metabolizerEM: Extensive metabolizerUM: Uebermetabolizer [Kirchheiner, 2003]

  40. Pharmacodynamics

  41. Pharmacodynamics • “Drug Effects on the subjects and tumors” • Symptoms • Signs • Changes in lab values • Molecular and Biological effects

  42. Pharmacodynamics: signs and symptoms Munster et al JCO 2007

  43. Pharmacodynamics: Effects on Lab Parameters DIRECT EFFECTS Munster P et al. Clin Cancer Res 2009;15:2488-2496 ©2009 by American Association for Cancer Research

  44. Pharmacodynamics: Effects on Lab Parameters INDIRECT EFFECTS Fig 1. Valproic acid (VPA) effects on epirubicin-associated toxicities Indirect effects Munster, P. et al. J Clin Oncol; 25:1979-1985 2007

  45. Pharmacodynamics: PD effects (histone acetylation) and Responses

  46. H4 acetylation occurred only in 58% of treated patients Acetyl-H4 Day 1 Day 8 % change in histone acetylation

  47. H3 and H4 acetylation more commonly seen in patients with clinical benefits % change in histone acetylation

  48. Correlative studies for the clinical trial (II)H3 and H4 acetylation more commonly seen in patients with clinical benefits * P=0.04, n=36 50 P=0.022, n=36 * 40 30 % change in acetyl-H4 Relative HDAC2 Expression * 20 10 0 ALL R NR ALL R NR NR R C % change in acetyl-H4

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