Dose escalation studies

However, several important studies have shown that intravenous thrombolysis may be beneficial more than 3 hours after stroke onset, provided that only patients with a significant diffusion-perfusion mismatch are treated. In one such smdy, Ribo et al. found that patients with a significant diffusion-perfusion mismatch could be treated safely and effectively in the 3-6-hour time period. In phase II of the desmo-teplase in acute stroke (DIAS) trial, patients with diffusion-perfusion mismatch were treated with desmoteplase up to 9 hours after stroke onset, and showed better outcomes than patients given placebo, with only a minimal incidence of symptomatic hemorrhage. Similar success was achieved in the same time window by the dose escalation study of desmoteplase in acute ischemic stroke (DEDAS). ... 

Abciximab in acute ischemic stroke a randomized, double-blind, placebo-controlled, dose-escalation study. The Abciximab in Ischemic Stroke Investigators. Stroke 2000 31 601-609. 

The abciximab in Acute Ischemic Stroke trial was a randomized, placebo-controlled dose-escalation study to examine the safety of abciximab in acute stroke. It randomized 74 patients within 24 hours of stroke onset to receive one of four doses of abciximab (by bolus with or without additional infusion, 54 patients) or placebo (20 patients). The median baseline National Institute of Health Stroke Scale (NIHSS) score was 15. The rates of asymptomatic ICH were 19% in the intervention group compared to 5% in the placebo group p = 0.07). Most (9 of 11) of the asymptomatic ICH patients had more severe stroke (NIHSS >14). No cases of symptomatic ICH or major systemic bleeding occurred. There was a trend toward a lower rate of stroke recurrence (2% vs. 5%) and a higher rate of functional recovery at 3 months in the group treated with abciximab than with placebo. 

Lazarus, H.M. et al. 2002. Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection A dose escalation study. J Clin Pharmacol. 42 395. 

Glund, K., Hoffmann, T., Demuth, H.-U., Banke-Bochita, J., Rost, K.-L. and Fuder, H. (2000) Single dose-escalation study to investigate the safety and tolerability of the DP IV inhibitor P32/98 in healthy volunteers. Experimental and Clinical Endocrinology and Diabetes, 108, 159. 

Sievenpiper, J. L., Arnason, J. T., Leiter, L. A., and Vuksan, V. (2003b). Null and opposing effects of Asian ginseng (Panax ginseng C. A. Meyer) on acute glycemia Results of two acute dose escalation studies. /. Am. Coll. Nutr. 22,524-532. 

Modi S, Stopeck AT, Gordon MS, Mendelson D, SoUt DB, BagateU R, Ma W, Wheler J, Rosen N, Norton L, Cropp GF, Johnson RG Hannah AL, Hudis CA. (2007) Combination of trastuzumab and tanespimycin (17-AAG KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer A phase I dose-escalation study. J Clin Oncol 25 5410-5417. 

In healthy male volunteers a dose-escalating study with iodine doses of 1-2 mL kg was performed. Liver enhancement, as measured by CT, reached values of 15-30 HU in a dose-dependent manner. The most common side-effects were headache, rhinitis, sore throat and bitter taste, which occurred at late time points (6 hours) after administration. 

Interim reviews of the data are an essential requirement to minimise risk during dose-escalation studies. After each study day, or certainly after a predefined number of volim-teers have received the next dose increment, the investigator, nurses, study physician and preferably one or two other experienced physicians who are not intimately involved with the study should meet to review the data. When the study is being conducted in a CRO, a sponsor company physician and a limited number of other personnel should participate by tele- or video-conference if not in person. A decision to stop, modify or continue dose escalation should be made jointly between the Principal Investigator at the CRO and the sponsor s physician. Such reviews should be conducted with maintenance of the double-blind and steps should be taken to avoid inadvertent unblinding, such as by coding of subject numbers. The data that should be reviewed are listed in Box 4.12. 

A preliminary assessment of the effect of food on pharmacokinetics can generally be studied in a single-dose, two-arm, randomised, crossover design. Preliminary information can often be obtained by including a fed occasion in the first, dose-escalating study. This will be insuffi-cent for registration purposes, which require an adequately powered study performed with the final formulation, but the information should be sufficient to indicate whether there is need for restrictions on dosing relative to meals in repeat-dose studies in healthy volunteers and patient clinical trials. 

J Biller, EW Massey, JR Marler, HP Adams, JN Davis, A Bruno, RA Henriksen, RJ Linhardt, LB Goldstein, M Alberts, CT Kisker, GJ Toffol, CS Greenberg, KG Banwart, C Bertels, DW Beck, M Walker, HN Maganani. A dose escalation study or org 10172 (low-molecular-weight heparinoid) in stroke. Neurology 39 262-265, 1989. 

Koukourakis MI, Bizakis JG, Skoulakis CE, et al. Combined irinotecan, docetaxel and conventionally fractionated radiotherapy in locally advanced head and neck cancer. A phase I dose escalation study. Anticancer Res 1999 19(3B) 2305-2309. 

The Kentucky group reported the results of their phase I/II dose escalation study. Gemcitabine was delivered at a dose of 50 mg/m2 over 24 h with radiation. The dose was increased in 50 mg/m2 increments. The radiation dose was 40 Gy plus a boost at 1.8 Gy fractions. The clinical tumor response was evaluable in 12 unresectable patients. Five patients had a cCR of (42%), four patients (33%) had cPR after being treated with gemcitabine and radiation concurrently (59). Other ongoing phase I studies also found the concomitant delivery of GEM and radiation to be feasible (60-63). 

In a phase I dose escalation study in locally advanced HNC patients, a concomitant regimen of weekly docetaxel and irinotecan and conventional radiotherapy was combined (47). Docetaxel was given over 20 min on d 1, irinotecan was administered as 30 min infusion on d 3. Three docetaxel/irinotecan dose levels were compared 20/25 mg/m2 (level 1), 20/40 mg/m2 (dose level 2), and 25/55 mg/m2 (dose level 3). Severe asthenia resulted in all patients at dose level 3. Myelosuppression was minimal. Complete responses were seen radiologically in 75% of patients and a partial response in 25% of patients. 

Chan AKP, Wong AO, Langevin J, et al. Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer a phase II dose escalation study. Int J Radiat Oncol Biol Phys 2000 48 845-856. 

Stopeck A. Results of a phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Proc Am Soc Clin Oncol 2000 19 206 (abst). 

Ad.TNF gene therapy is presently in clinical trials in patients receiving radiotherapy. An open-label, phase I, dose-escalation study of tumor necrosis factor-alpha (TNFerade) gene transfer with radiation therapy for locally advanced, recurrent, or metastatic solid tumors is currently accruing patients and has several endpoints (82), including toxicity and tolerable dose. Pharmacokinetics will be evaluated and biological correlates will determine the histologic response to therapy. 

Dyskinetic activity. A 4-week dose escalation study was performed to assess the safety and tolerability of cannabis in six patients with Parkinson s disease (PD) with levodopa (L-DOPA)-induced dyskinesia. 

Dose-escalation studies performed in an early phase of drug development provide preliminary information to explore pharmacodynamic parameters at different dose levels up to the MTD. If the focus of a study is on the relationship between the pharmacokinetic and pharmacodynamic parameters (rather than on dose response relationships), then the term PK PD studies is used. 

Cloughesy TF, et al. Intra-arterail Cereport (RMP-7) and Carboplatin a dose escalation study for recurrent malignant gliomas. Neurosurgery 1999 44(2) 270-278. 

Kemeny N, Brown K, Covey A, Kim T, et al. 2006. Phase I. Open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver. Hum Gene Ther. 17 1214-1224. 

Goldberg AC. Clinical trial experience with extended-release niacin (Niaspan) dose-escalation study. Am J Cardiol 1998 82 35U-38U. 

Individual members of the AG and SEFA family have been studied for their ability to promote the nasal and ocular absorption of peptide drugs in rats, mice, cats, dogs, and monkeys [1,6,10,53,54,84—90]. Dose-escalation studies were conducted in rats to determine the potencies of each of the AGs and SEFAs as enhancers for the ocular and nasal absorption of insulin and to determine the contribution of the alkyl chain and the sugar moiety. Insulin... 

An assumption concerning the number of compartments is, by nature, not required. For reliable results and precise parameter estimates, however, a relatively large number of data points per individual are required. Phase 1 studies of mAbs usually provide sufficient data for a noncompartmental analysis, but the assumption of linear pharmacokinetics is not valid for most mAbs. This prerequisite, however, was frequently neglected during the early years of therapeutic mAh development, and an overall estimate for CL, for example, was frequently reported in the literature. In dose-escalating studies, however, the concentration-time plots of the raw data clearly indicate that the slope of the terminal phase is not parallel for the different doses, but increases with increasing dose (Fig. 3.10). As a result, the listing of different clearance values for different doses can be found. For example, the clearance of trastuzumab was reported to be 88.3 mL/h for a 10-mg dose, 34.3 mL/h for a 50-mg dose, 25.0 mL/h for a 100-mg dose, 19.0 mL/h for a 250-mg dose, and 16.7 mL/h for a 300-mg dose. 

The PK of cetuximab were investigated after single IV doses ranging from 5 to 500 mg/m2. PK data obtained after administration of cetuximab monotherapy were available from 82 patients in five of the dose-escalation studies, and from 214 patients in four of the studies with the approved dosing regimen. In two studies, cetuximab was administered both as a monotherapy and in combination with irinotecan single- as well as multiple-dose cetuximab concentration data were available from 300 patients in these two studies. 

In the dose-escalation studies, PK data were obtained for patients with a variety of EGFR-expressing solid cancers, while the studies at the approved dosing regimen were conducted in the indications of colorectal carcinoma, squamous cell cancer of the head-and-neck, pancreatic cancer, and renal cell cancer. 

Johnston E, Crawford J, Blackwell S, etal. Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. /. Clin. Oncol. 2000 78 2522-2528. 

Laham RJ, Chronos NA, Pike M, et al. Intra-coronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease results of a phase I open-label dose escalation study, J Am Coll Cardiol 2000 36 2132-2139. 

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