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author:("zannis, Peter")
1.  Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma 
Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses.
Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m2, days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected.
Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102–112 L/h for first dose; 15–32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m2 group.
Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m2 doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.
PMCID: PMC3951913  PMID: 20306195
Pharmacodynamics; Pharmacokinetics; Bortezomib; Multiple myeloma; Proteasome inhibition
2.  A Phase I Trial and Pharmacokinetic Study of a 24-hour Infusion of Trabectedin (Yondelis®, ET-743) in Children and Adolescents with Relapsed or Refractory Solid Tumors 
Pediatric blood & cancer  2012;59(5):865-869.
The objectives of this phase I study were to determine the maximum tolerated dose (MTD), toxicity profile and pharmacokinetics of a 24-hour continuous intravenous infusion of trabectedin administered to children and adolescents with refractory or relapsed solid tumors.
Patients between the ages of 4 and 16 years old with refractory solid tumors received trabectedin as a 24-hour infusion every 21 days. Dexamethasone and prophylactic growth factor support were administered with each cycle. Pharmacokinetic studies were conducted during cycle 1.
Patients (n=12) median (range) age 14.5 (8–16) years received trabectedin at 1.1 (n=3), 1.5 (n=6) or 1.7 (n=3) mg/m2. At the 1.5 mg/m2 dose level, one patient had dose limiting anorexia and fatigue. At 1.7 mg/m2, 2 patients experienced dose limiting toxicity, dehydration and gamma-glutamyl transpeptidase (GGT) elevation. Non-dose limiting toxicities included elevated serum transaminases, myelosuppression, nausea, emesis and fatigue. Plasma pharmacokinetic parameters were similar to historical data in adults. One partial response (PR) was observed in a patient with neuroendocrine carcinoma. Stable disease (SD) (≥6 cycles) was achieved in 3 patients (osteosarcoma n=2, desmoplastic small round cell tumor n=1).
The MTD of trabectedin in pediatric patients with refractory solid tumors is 1.5 mg/m2 IV over 24 hours every 21 days. Dexamethasone to ameliorate hepatic toxicity and prophylactic growth factor support are required.
PMCID: PMC3442122  PMID: 22847981
trabectedin; phase I clinical trial; pediatrics; pharmacokinetics
3.  Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors 
To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors.
Patients with ECOG performance status 0–1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m2) followed by trabectedin (starting dose, 0.3 mg/m2). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses.
Fifteen patients received ≥1 dose, with a median of two treatment cycles (range 1–10). The most common drug-related toxicity was hepatic. Dose reductions were required for trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m2 and gemcitabine 1,000 mg/m2, which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration.
Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.
PMCID: PMC3556988  PMID: 18379785
Dose-finding; Phase I; Gemcitabine; Pharmacokinetics; Trabectedin
4.  Phase 1 Trial and Pharmacokinetic Study of the Farnesyl Transferase Inhibitor Tipifarnib in Children and Adolescents with Refractory Leukemias: A Report from the Children's Oncology Group 
Pediatric blood & cancer  2010;56(2):226-233.
The objectives of this trial were to define the toxicity profile, dose, pharmacokinetics and pharmacodynamics of the farnesyl transferase (FTase) inhibitor, tipifarnib, in children and adolescents with hematological malignancies.
Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at a dose of 300 mg/m2/dose. Pharmacokinetic sampling was performed for 36 hours after the first dose and leukemic blasts were collected pre-treatment and at steady state for determination of FTase activity.
Of 29 patients enrolled, 18 were fully evaluable for toxicity, and 23 for response; 26 had pharmacokinetic and pharmacodynamic sampling. The recommended dose is 300 mg/m2/dose and toxicities included skin rash, mucositis, nausea, vomiting, and diarrhea. Neurotoxicity, which was dose-limiting in adults at doses exceeding 600 mg/dose, was infrequent and mild. The plasma pharmacokinetics of tipifarnib were highly variable but comparable to adults with acute leukemia and children with solid tumors. The median apparent clearance of tipifarnib was 630 mL/min/m2 and the median half-life was 4.7 hours. At steady state on 300 mg/m2/dose, FTase activity was inhibited by 82% in leukemic blasts. No objective responses were observed.
Oral tipifarnib is well tolerated in children with leukemia on a twice daily for 21days schedule at 300 mg/m2/dose.
PMCID: PMC3271115  PMID: 20860038
refractory childhood leukemia; phase I trial; pharmacokinetics; pharmacodynamics; toxicity
5.  A Phase I Study of the Safety and Pharmacokinetics of Trabectedin in Combination With Pegylated Liposomal Doxorubicin in Patients With Advanced Malignancies 
To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and Methods
Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-hour PLD (30 mg/m2) infusion was followed immediately by 1 of 6 trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 hours, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable txicity. Plasma samples were obtained to assess PK profiles.
The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxicities were neutropenia (31%) and elevated transaminases (31%). Six patients responded (1 CR, 5 partial responses), with an overall response rate of 16.7%, and 14 had stable disease >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared to trabectedin and PLD each given as a single agent.
Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types, and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
PMCID: PMC2598415  PMID: 18497430
trabectedin; ET-743; pegylated liposomal doxorubicin (PLD); sarcomas; ovarian cancer

Results 1-5 (5)