Phase I Studies - PDF

Phase I studies Robert Wieder, MD, PhD Division of Medical Oncology/Hematology Rutgers New Jersey Medical School  Elements of Phase I trials in oncology  It is the first time that a drug is introduced into human subjects  Primary objective is to identify the safe dose to be tested i...

Phase I studies Robert Wieder, MD, PhD Division of Medical Oncology/Hematology Rutgers New Jersey Medical School  Elements of Phase I trials in oncology  It is the first time that a drug is introduced into human subjects  Primary objective is to identify the safe dose to be tested in Phase II studies – target dose  The primary concern is the safety of the study subjects  Patients: advanced disease resistant to standard therapies: good functional status - all tumor types - other fields can use normal volunteers; oncology studies use patients  There are several types of phase I studies; most common are single drugs but combinations of licensed drugs with novel agents are also common Elements of Phase I trials in Oncology (cont.)  Dose escalation study with doses defined ahead of time  typically start at 1/10 LD10 in mice which is likely to be safe  Increase dose in groups of patients called cohorts where all patients in the group are treated simultaneously – size determined by progression model  use a variety of progression models – most common: 1) Fibonacci, 2) continual reassessment method (CRM) and 3) Bayesian approach  Also determine pharmacokinetics and pharmacodynamics  Starting dose  Use of 1/10 mouse LD10 provides an acceptable starting dose 83% of the time while using 2 or 3 species increases the rate to 97% of the time  The use of 1/10 mouse LD10 sometimes exceeds the MTD and sometimes results in having to de-escalate doses. Using more sensitive species like rat and dog as well eliminates the need for dose de-escalation Arbuck SG. Annals of Oncology. 7:567-73, 1996.  Dose escalation methods in Oncology  Dose escalation based on toxicity is simpler in Oncology than in normal patients  Therapy is considered tolerable if there is no unacceptable toxicity, usually grade 3 toxicity – therefore response is binary: toxicity v. no toxicity  NCI toxicity criteria are published for every organ system and all elements of each organ system form 0-4 Example of NCI toxicity grades for inner ear hearing 0 1 2 3 4 hearing normal hearing loss tinnitus/hearing tinnitus/hearing severe unilateral on audiometry loss not requiring correctible with or bilateral hearing only hearing aid or hearing aid or loss (deafness), treatment treatment not correctible by hearing aid or treatment  Traditional dose escalation by Fibonacci progression of the 3+3 design  3 patients per dose levels  if one patient suffers grade 3 toxicity, enter another 3. If