Phase I studies

Identification of Risk Susceptible Flood Areas was performed in the Phase I study using information from a plant visit and from NUREG-1150 and the IPE. 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

Qureshi Al, Harris-Lane P, Kirmani IF, Janjua N, Divani AA, Mohammad YM, Suarez Jl, Montgomery MO. Intra-arterial reteplase and intravenous abciximab in patients with acute ischemic stroke an open-label, dose-ranging, phase I study. Neurosurgery 2006 59 789-796 [discussion 796-787]. 

The Phase I study explored i.v. administration of BB-83698 at single dose-escalating levels up to 475 mg and systemic exposures were reportedly linear in both animals and humans [84]. While dose-limiting CNS effects... 

Hartinger, C. G., Jakupec, M. A., Zorbas-Seifried, S., Groessl, M., Egger, A. Bergar, W. KP1019, A New Redox-Active Anticancer Agent - Preclinical Development and Results of a Clinical Phase I Study in Tumor Patients. Chem. Biodiversity, 5, 2140-2155 (2008). 

Phase I The preliminary studies in humans are designed to evaluate the pharmacokinetics and the acute toxicity/tolerability of the potential dmg. Usually, phase I studies are carried out in a very small population [15—40] of healthy male volunteers. Thus, the nature of the population tested and the small number of individuals involved limits the scope of pharmacogenomics to the study of genetic variability in drug metabolism. 

Ratain MJ, Mick R, Berezin F et al. Phase I study of amonafide dosing based on acetylator phenotype. Cancer Res 1993 53 2304-2308. 

Several patent applications claiming variations represented by scaffold 42 have been published [81]. A developed PET ligand from this scaffold class, [11C]-GSK931145 (43) [82], was used in a Phase I study designed to evaluate the relationship between plasma concentrations and brain occupancy of GSK1018921 in healthy individuals (structure and data not disclosed) [46],... 

Preliminary Phase I data for PCI-32765 in refractory B-cell lymphoma indicates a partial response in 5/16 patients [40]. The irreversibility of the binding interaction enables a direct assessment of target occupancy with a fluorescent probe [42]. In the Phase I study, target occupancy was essentially complete and downstream biomarkers (CD63, pERK) were significantly inhibited at 2.5 mg/kg/ day. 

Based on these findings and toxicology studies [233], human clinical phase I studies have been initiated [234]. In tumor biopsies from melanoma patients obtained after treatment, a reduction was found in both the specific mRNA (M2 subunit of ribonucleotide reductase, RRM2) and in the protein (RRM2) levels when compared to pre-dosed tissue. The presence of an mRNA fragment that... 

Pollack IF, DaRosso RC, Robertson PL, Jakacki RL, Mirro JR, Blatt J, Nicholson S, Packer RJ, Allen JC, Cisneros A, Jordan VC (1997) A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood. Clin Cancer Res 3 1109-1115... 

Coombes RC, Haynes BP, Dowsett M, Quigley M, English J, Judson IR, Griggs LJ, Potter GA, McCague R, Jarman M (1995) Idoxifene report of a phase I study in patients with metastatic breast cancer. Cancer Res 55 1070-1074... 

In a double-blind, placebo-controlled phase I study, ospemifene exerted a very weak estrogenic effect on endometrial histology, and no clinically significant changes were seen in endometrial thickness at any dose level (Voipio et al. 2002). In another double-blind study, ospemifene at daily doses of 30 to 90 mg did not stimulate growth of endometrial thickness (Rutanen et al. 2003). 

Unfortunately, to date, no formal clinical studies have been conducted to specifically evaluate the effects of green tea, green tea extracts, or EGCG on immune function. However, based on several Phase I studies that have evaluated EGCG and/or Polyphenon E (a defined, decaffeinated green tea polyphenol mixture) and found them to be safe and tolerable at relatively high doses, it is likely that future clinical studies may follow [66-69],... 

Clinical results with 20 have been recently reported from a phase I study that enrolled 70 healthy male human subjects. In this study, morning administration of the drug (200 mg and above) reduced alertness and latency to sleep stage 2 and increased time spent in sleep stage 2 with an overall improvement of sleep efficiency and total sleep time. These effects disappeared 6.5 h after drug administration [57],... 

Sometimes investigators say that Phase I studies are not clinical trials because there is no treatment comparison being made (except that frequently a placebo is employed). Such treatment comparisons are not a prerequisite for experiments. Because Phase I trials rely on investigator controlled treatment administration and subsequent structured observations, they are clinical trials. 

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