Phase I clinical studies

Research on an hCG vaccine has been conducted over the past 15 years. WHO has conducted a phase I clinical study in AustraUa, using a vaccine based on a synthetic C-terminal peptide (109—141) of P-hCG conjugated to Diptheria Toxoid (CTP-DT), that showed potentially effective contraceptive levels of antibodies were produced in vaccinated women without any adverse side effects. Phase II clinical studies are under consideration to determine if the immune response, raised to its prototype anti-hCG vaccine, is capable of preventing pregnancy in fertile women volunteers (115). While research on the C-terminal peptide from the P-subunit of hCG has been carried out under the auspices of WHO, research supported by the Population Council and the National Institutes of Health has involved two alternative vaccine candidates (109,116,118). 

Where the drug studied is a racemate, the pharmacokinetics, including potential interconversion, of the individual enantiomers should be investigated in Phase I clinical studies. Phase I or II data in the target population should indicate whether an achiral assay, or monitoring of only one optical isomer where a fixed ratio is confirmed, will be adequate for pharmacokinetic evaluation. If the racemate has already been marketed and the sponsor wishes to develop the single enantiomer, additional studies should include determination of any conversion to the other isomer and whether there is any difference in pharmacokinetics between the single enantiomer administered alone or as part of the racemate. 

Phase II clinical development — Phase II involves a greater number of patients (usually 100 to 300) than phase I clinical studies. At this stage more emphasis is placed on activity, dosing, and efficacy than in phase I, and thus, only patients are used for phase II studies and beyond. Sometimes, reevaluation... 

Aubry, A.F., Sebastian, D., Hobson, T., Xu, J.Q., Rabel, S., Xie, M., and Gray, V., In-use testing of extemporaneously prepared suspension of second generation non-nucleoside reversed transcriptase inhibitors in support of Phase I clinical studies, /. Pharm. Biomed. Anal., 23,535,2000. 

Figure 1.3. Structure of PKl (HPMA copolymer doxorubicin), a 28-kDa polymeric carrier-drug conjugate investigated for its anti-tumour activity in a phase I clinical study. Adapted from reference [15].

Reproductive toxicity tests are not required to support Phase I clinical studies in men. Detailed histological evaluations of the male reproductive organs should be performed in the repeated-dose toxicity studies. Male fertility studies in the rodent, however, would be expected to support Phase III studies. 

Agus DB, Gordon MS, Taylor C et al (2005) Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 23 2534-2543... 

Siminiak T, Kalawski R, Fiszer D, Jerzykowska O, Rzezniczak J, Rozwadowska N, Kurpisz M. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury phase I clinical study with 12 months of follow-up. Am Heart J 2004 148 531-537. 

Giantonio, W.M. Linehan, M. Walther, H. A. Fisher, E. Messing, et al.. Phase I clinical study of the recombinant oncotoxin TP40 in superficial bladder cancer. Clin Cancer Res, 1995.1(1) 57-61. 

The cost of drug development continues to spiral upward. Inflation and increased regulatory requirements, however, only account for a small portion of this increase. At this time, productivity is a major issue. A review of 198 new drug candidates that reached phase I clinical studies indicates a 60% failure rate due to poor pharmacokinetic properties or toxicity [23]. On the average, less than 2% of the drug failures could be attributed to drug interactions that resulted in adverse reactions [24], In elderly patients, however, drug interactions could contribute... 

Dolastatin 10 has been evaluated with promising results in a phase I clinical study in patients with solid tumors. Subsequently, its noticeable antitumor activity was well documented in various in vitro and in vivo tumor models (Madden et al., 2000). More than a dozen dolastatin peptides have been isolated to date. Recent studies have shown, for example, that the depsipeptide dolastatin 11 arrests cells at cytokinesis by causing a rapid and massive rearrangement of the cellular actin filament network and induces the hyperpolymerization of purified actin (Bai et al., 2001). The effects of dolastatin 11 were similar to those of the sponge-derived depsipeptide jasplakinolide however, dolastatin 11 exhibited threefold more cytotoxicity than jasplakinolide in the cells studied. 

A Phase I clinical study was carried out in four ovarian cancer patients to exploit the drug targeting ability of cholesterol-rich emulsions to LDL receptors of tumor cells. UptakiHjf [ etoposide oleate and fc] cholesterol oleate were 4.1 times and 4.9 times, respectively, greater than that in contralateral normal ovaries. This indicates that most ofthe etoposide is retained in the emulsion before its internalization by the tumor cells and shows the ability of ofthe cholesterol-rich emulsions to concentrate in ovarian carcinomas (Azevedo et al., 2005). 

Numerous structural modification studies of ellipticine have been conducted. It is found that side-chain substitution has considerable influence on the biological activity to compounds of this type. A pyridopyrrolo[2,3-g]iso-quinoline derivative, BD-40 (48) [235, 236], has demonstrated potent activity against many different experimental tumours including leukaemia L1210 and the Friend virus leukaemia. It is also active against the Moloney strain of murine sarcoma virus [237]. Phase I clinical study of (48) has been conducted [238, 239]. 

If the scope of work is a precursor to a phase I clinical study, enhanced monitoring may be required. The sponsor may want to visit the vendor to ensure that the company is capable of performing to the contract. 

BsAb 2B1 recognizes both HER2 and CD 16, the low-affinity type III Fc receptor (FcyRIII) expressed by mononuclear phagocytes and natural killer cells. In a phase I clinical study, 2B1 was shown to induce cytokine release, and several minor antitumor responses were observed (255). 

Bums, C. P., Halabi, S., Qamon, G. H., Hars, V., Wagner, B. A., Hohl, R. J., Lester, E., Kirshner, J. J., Vinciguerra, V., and Paskett, E., 1999, Phase I clinical study offish oil fatty acid capsules for patients with cancer cachexia cancer and leukemia group B study 9473, Clin. CancerRes. 5 3942-3947. 

Phase I clinical studies have recently been completed with Epo D, and phase II trials with the compound are now ongoing together with an additional phase I smdy [sponsored by Kosan Biosciences (as KOS-862)]. As for BMS-247550, KOS-862 was demonstrated to induce microtubule bundling in patient PBMCs, and several tumor responses have been noted in the phase I studies. ... 

Pharmacyclics, Inc. Press Release January 29, 1996 Pharmacyclics Initiates Phase Ib/II Trial of GdTex for Use in Treatment of Cancer Patients Receiving Radiation Therapy Phase I Clinical Study Confirms Tumor Selective Localization. 

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