title: Pharmacodynamic-guided modified continuous reassessment method-based, dose-finding study of rapamycin in adult patients with solid tumors.
abstract: OBJECTIVE
  Pharmacodynamic studies are frequently incorporated into phase I trials, but it is uncommon that they guide dose selection. We conducted a dose selection study with daily rapamycin (sirolimus) in patients with solid tumors employing a modified continuous reassessment method (mCRM) using real-time pharmacodynamic data as primary dose-estimation parameter.
  
  
  METHODS
  We adapted the mCRM logit function from its classic toxicity-based input data to a pharmacodynamic-based input. The pharmacodynamic end point was skin phospho-P70 change after 28 days. Pharmacodynamic effect was defined as at least 80% inhibition from baseline. The first two dose levels (2 and 3 mg) were evaluated before implementing the mCRM, and the data used to estimate the next dose level based on statistical modeling. Toxicity-based boundaries limited the escalation steps. Other correlates analyzed were positron emission tomography (PET) and computed tomography, pharmacokinetics, phospho-P70 in peripheral-blood mononuclear cells, and tumor biopsies in patients at the maximum-tolerated dose (MTD).
  
  
  RESULTS
  Twenty-one patients were enrolled at doses between 2 and 9 mg. Pharmacodynamic effect occurred across dose levels, and toxicity boundaries ultimately drove dose selection. The MTD of daily oral rapamycin was 6 mg. Toxicities in at least 20% were hyperglycemia, hyperlipidemia, elevated transaminases, anemia, leucopenia, neutropenia, and mucositis. Pharmacokinetics were consistent with prior data, and exposure increased with dose. No objective responses occurred, but five previously progressing patients received at least 12 cycles. PET showed generalized stable or decreased glucose uptake unrelated to antitumor effect.
  
  
  CONCLUSIONS
  mCRM-based dose escalation using real-time pharmacodynamic assessment was feasible. However, the selected pharmacodynamic end point did not correlate with dose. Toxicity ultimately drove dose selection. Rapamycin is a well-tolerated and active oral anticancer agent.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Peter
authors.initials: P
authors.lastname: Kulesza
authors.forename: Wen Wee
authors.initials: WW
authors.lastname: Ma
authors.forename: Jenna
authors.initials: J
authors.lastname: Wheelhouse
authors.forename: Anna
authors.initials: A
authors.lastname: Howard
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Khan
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Heather
authors.initials: H
authors.lastname: Jacene
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.forename: Ross C
authors.initials: RC
authors.lastname: Donehower
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo