Purpose: The objectives of the analysis were to characterize the time course of neutropenia after pemetrexed administration using
an established semimechanistic-physiologic model, characterize the ...relationship between pemetrexed exposure and neutropenia,
and describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients.
Experimental Design: An eight-compartment population pharmacokinetic/pharmacodynamic model was used to describe the absolute neutrophil count
(ANC)-time profile (neutropenic response) following pemetrexed doses of 300 to 1,400 mg/m 2 administered every 21 days. The analyses pooled data from 13 studies including 279 patients (161 supplemented with oral folic
acid and intramuscular vitamin B 12 , and 118 unsupplemented; 248 Western and 31 Japanese) who received 857 treatment cycles.
Results: Vitamin supplementation status, ethnic origin, and drug exposure were the dominant predictors of neutropenic response. Vitamin
supplementation diminishes neutropenic response to pemetrexed. Model-predicted ANC nadirs for the “typical” Western patient
receiving 500 mg/m 2 pemetrexed ± vitamin supplementation were 2.74 × 10 9 /L and 1.70 × 10 9 /L, respectively. Japanese patients had a less pronounced neutropenic response to pemetrexed relative to Western patients.
The model-predicted ANC nadir for Japanese patients receiving 500 mg/m 2 pemetrexed with vitamin supplementation was 2.66 × 10 9 /L. Values for the 1,000 mg/m 2 dose with vitamin supplementation were 1.91 × 10 9 /L and 1.34 × 10 9 /L for Japanese and Western patients, respectively. Increased albumin, decreased cystathionine, and decreased body surface
area were also associated with increased neutropenic response.
Conclusions: The neutropenic response to higher pemetrexed doses administered with vitamin supplementation is tolerable. All other factors
equal, Japanese patients have a lesser neutropenic response to pemetrexed relative to Western patients.
Purpose: To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin)
in patients with advanced malignancies when administered in ...cycles of once weekly for 3 of 4 weeks.
Experimental Design: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was
available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status
of ≤2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts
receiving escalating doses from 800 to 4,300 mg/m 2 . The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics,
and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan
dose and pharmacokinetic variables.
Results: Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m 2 . Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m 2 . Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic
cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be
46 ± 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve
extrapolated to infinity (AUC 0-∞ ) > 20 ng h/mL and 0 of 10 patients with an AUC 0-∞ ≤ 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma
and the other with metastatic esophageal cancer.
Conclusions: The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m 2 . The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary
toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m 2 ). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in
phase 2 studies.
Purpose
To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient ...population.
Patients and Methods
Sixty-two adult cancer patients received intravenous bortezomib at 0.7–1.5 mg/m
2
on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m
2
into five cohorts: normal renal function (≥60 ml/min/1.73 m
2
); mild dysfunction (40–59 ml/min/1.73 m
2
); moderate dysfunction (20–39 ml/min/1.73 m
2
); severe dysfunction (<20 ml/min/1.73 m
2
); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed.
Results
Bortezomib escalation to the standard 1.3 mg/m
2
dose was well tolerated in all patients with CrCl ≥20 ml/min/1.73 m
2
; 0.7 mg/m
2
was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m
2
). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m
2
in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function.
Conclusion
Bortezomib 1.3 mg/m
2
is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.
In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and VEGFR-2, a comprehensive pharmacodynamic program was implemented in addition ...to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients.
Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD). A nonlinear model (Emax model) was used to describe the relationship between AEE788 exposure and target-pathway modulation in skin and tumor tissues.
Overall, 111 patients were treated (25 to 550 mg/day). DLTs included rash and diarrhea; MTD was 450 mg/day. Effects on biomarkers correlated to serum AEE788 concentrations. The concentration at 50% inhibition (IC(50)) for EGFR in skin (0.033 μmol/L) and tumor (0.0125 μmol/L) were similar to IC(50) in vitro suggesting skin may be surrogate tissue for estimating tumor EGFR inhibition. No inhibition of p-MAPK and Ki67 was observed in skin vessels at ≤ MTD. Hence, AEE788 inhibited EGFR, but not VEGFR, at doses ≤ MTD. A total of 16 of 96 evaluable patients showed a >10% shrinkage of tumor size; one partial response was observed.
Our pharmacodynamic-based study showed effective inhibition of EGFR, but not of VEGFR at tolerable AEE788 doses. Emax modeling integrated with biomarker data effectively guided real-time decision making in the early development of AEE788. Despite clinical activity, target inhibition of only EGFR led to discontinuation of further AEE788 development.
Anticancer drug discovery and development is a rapidly evolving field. Recent advances in molecular oncology and the effort to completely sequence the human genome has led to an explosion in our ...understanding of the mechanisms involved in the transformation and growth of malignant cells. This in turn has led to major changes in our approach to traditional drug discovery and development. A dynamic example of how genomics is affecting cancer developmental therapeutics is provided by the ongoing changes being implemented in the anticancer drug development program run by the US National Cancer Institute (NCI). This review summarizes the history of drug screening and development efforts at the NCI over the past five decades from its inception up to its current state emphasizing molecularly targeted therapies. These changes have not only had an impact on drug discovery, but they are also providing new paradigms for the design and conduct of preclinical and early clinical trials.
Purpose: Pemetrexed is an antimetabolite that is structurally similar to methotrexate. Because nonsteroidal anti-inflammatory drugs
(NSAID) impair methotrexate clearance and increase its toxicity, we ...evaluated the pharmacokinetics and toxicity of pemetrexed
when coadministered with aspirin or ibuprofen in advanced cancer patients.
Experimental Design: In two independent, randomized, crossover drug interaction studies, cancer patients with a creatinine clearance (CrCl) ≥60
mL/min received an NSAID (aspirin or ibuprofen) with either the first or the second dose of pemetrexed (cycle 1 or 2). Pemetrexed
(500 mg/m 2 ) was infused i.v. on day 1 of a 21-day cycle, and all patients were supplemented with oral folic acid and i.m. vitamin B 12 . Aspirin (325 mg) or ibuprofen (400 mg; 2 × 200 mg) was given orally every 6 hours, starting 2 days before pemetrexed administration,
with the ninth and final dose taken 1 hour before infusion. Pemetrexed pharmacokinetics with and without concomitant NSAID
treatment were compared for cycles 1 and 2.
Results: Data from 27 patients in each study were evaluable for the analysis of pemetrexed pharmacokinetics. Coadministration of aspirin
did not alter pemetrexed pharmacokinetics; however, ibuprofen coadministration was associated with a 16% reduction in clearance,
a 15% increase in maximum plasma concentration, and a 20% increase in area under the plasma concentration versus time curve
but no significant change in V ss compared with pemetrexed alone. No febrile neutropenia occurred in any patient, and no increase in pemetrexed-related toxicity
was associated with NSAID administration.
Conclusions: Pemetrexed (500 mg/m 2 ) with vitamin supplementation is well tolerated and requires no dosage adjustment when coadministered with aspirin (in patients
with CrCl ≥60 mL/min) or ibuprofen (in patients with CrCl ≥80 mL/min).
Patupilone is a novel microtubule-targeting cytotoxic agent, which exerts its antitumor effect through microtubule stabilization. Pharmacokinetics, pharmacodynamics, and safety of warfarin when ...administered concomitantly with patupilone were investigated, and antitumor activity was assessed. This was a phase I, two-center, drug-drug interaction study. In the core phase of the study, treatment consisted of warfarin 20 mg orally (days 1 and 29) and patupilone 10 mg/m(2) i.v. (days 8 and 29). Patients benefiting from patupilone treatment continued treatment every 3 weeks (extension phase) until progression of disease, death, or unacceptable toxicity. Seventeen patients were treated (core phase, 17; extension, 9). The geometric mean ratios (comedication/monotherapy) for C(max) and area under the curve(0-168) of warfarin were near unity and their 90% confidence intervals were within the equivalence limits of 0.80 and 1.25. The half-life, plasma clearance, and International Normalized Ratio (INR) of warfarin were not affected by patupilone coadministration. The most common adverse events were diarrhea, nausea, vomiting, abdominal pain, anorexia, dehydration, asthenia, and peripheral neuropathy. Five (29.4%) patients experienced grade 3 study drug-related adverse events (diarrhea, 17.6%; increased INR, 11.8%; dehydration, 5.9%; and neutropenia, 5.9%). One patient with triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2/neu negative) had a partial response (35% decrease in tumor measurements by Response Evaluation Criteria in Solid Tumors), and 11 had stable disease for 6 weeks or more (≥12 weeks, 6 patients). The pharmacokinetics and pharmacodynamics of warfarin were not affected by patupilone coadministration, suggesting that patupilone has no clinically relevant effect on CYP2C9 metabolism. Patupilone showed antitumor activity in triple-negative breast cancer.
Purpose: The purpose of this study was to assess the feasibility and characterize the pharmacokinetics of squalamine administered
as a continuous i.v. infusion daily for 5 days every 3 weeks.
...Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of squalamine as a 5-day continuous i.v. infusion
every 3 weeks. Doses were initially escalated in 100% increments from a starting dose of 6 mg/m 2 /day, with a single patient treated at each dose level until moderate toxicity was observed, at which time additional patients
were treated.
Results: Thirty-three patients were treated with 73 courses of squalamine at 13 dose levels ranging from 6 to 700 mg/m 2 /day. Hepatotoxicity, characterized by brief, asymptomatic elevations in transaminases and hyperbilirubinemia, was the principal
dose-limiting toxicity of squalamine. At 700 mg/m 2 /day, two of three patients developed grade 4 hyperbilirubinemia, which precluded further dose escalation. At 500 mg/m 2 /day, one of seven patients experienced dose-limiting grade 4 hyperbilirubinemia and grade 3 neurosensory changes, which resolved
soon after treatment. Squalamine pharmacokinetics were dose-proportional. At 500 mg/m 2 /day, the mean (percentage coefficient of variation) clearance, half-life, and volume of distribution of squalamine were 2.67
liters/h/m 2 (85%), 9.46 h (81%), and 36.84 liters/m 2 (124%), respectively, and steady-state concentrations 20.08 μg/ml (13%) were well above those that inhibit angiogenesis
in preclinical models.
Conclusions: At the recommended Phase II dose of 500 mg/m 2 /day, squalamine is well tolerated and results in plasma concentrations at least an order of magnitude higher than those required
for prominent antiangiogenic effects in preclinical studies.
Background
Paclitaxel poliglumex (PPX, also called Xyotax
®
or CT-2103) is a water soluble macromolecular drug conjugate that links paclitaxel with a biodegradable polymer, poly-
l
-glutamic acid. ...The recommended phase II dose of PPX every 3 week is 235 mg/m
2
administered over a 10-min infusion without premedication. This study was designed to determine the MTD and pharmacology of PPX administered weekly to patients with solid malignancies.
Methods
The starting dose of weekly PPX was 20 mg/m
2
. Each cycle consists of 6 weekly treatments with pharmacokinetics of PPX (the conjugated paclitaxel) and unconjugated paclitaxel obtained after the first and sixth dose. Three to six patients were enrolled at each dose level. Toxicity and response were assessed by the NCI Common Toxicity criteria version 2 and RECIST criteria, respectively.
Results
Twenty-six patients were treated with PPX at the following dose levels: 20 mg/m
2
(five patients), 40 mg/m
2
(four patients), 60 mg/m
2
(four patients), 70 mg/m
2
(eight patients) and 80 mg/m
2
(five patients). Dose-limiting toxicities, consisting of grade 3 neutropenia, occurred in the 80 mg/m
2
cohort during cycle 1. Therefore, the dose recommended for phase II studies was 70 mg/m
2
. In this cohort, a single dose-limiting event, consisting of diarrhea, was seen. Neuropathy and fatigue were the most common toxicities. No objective responses were noted. Pharmacokinetics was dose-proportional, and the degree of neutropenia related to drug exposure, but not to peak plasma concentration. There was no significant accumulation of conjugated or unconjugated paclitaxel with this dosing schedule.
Conclusions
The recommended dose of PPX for subsequent disease-directed studies is 70 mg/m
2
weekly.
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