Phase 2 trial

Phase 1 trials are the first in man studies of a new drug in humans. These studies are usually carried out on small samples of subjects. The idea here is to determine the safety of the drug in a small and usually healthy volunteer study population. 

Second, we described the successful outcomes of Ap immunotherapy in mutant mice with Ap amyloidosis. Unfortunately, in humans, although Phase 1 trials with Ap peptide and adjuvant vaccination were not associated with any adverse events, Phase 2 trials were suspended because of severe adverse reactions (meningoencephalitis) in a subset of patients [79,90]. The pathology in a single case, consistent with T-cell meningitis [90], was interpreted to show some clearance of Ap deposits, yet these regions... 

Phase 1 trials are designed to identify the early tolerability of new medicines, usually in healthy volunteers. At this time, the pharmacokinetics and pharmacodynamics of a medicine are determined in humans, thus forming the base of knowledge on how medicines should be dosed. 

Other clinical trials with CCR2 antagonists are underway [1], but no reports have been forthcoming. Both MLN-1202, a humanized anti-CCR2 antibody, and MK-0812, a small molecule antagonist, were examined in rheumatoid arthritis (vide supra) and are also being examined in multiple sclerosis. Two additional small molecules - CCX-915 and INCB-8696 - have entered phase 1 trials with multiple sclerosis as a projected phase 2 trial. An intention to study INCB-8696 in systemic lupus erythematosus has also been declared. Finally, phase 2 clinical... 

Discovery > Phase 1 Trials > Phase II Trials Phase III Trials FDA Approval ... 

Discovery (20) Phase 1 Trials (12) Phase II Trials (10) Phase III Trials (4) FDA Approval (2) ... 

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Depsipeptide is the leading compound in the cychc peptide class, and is currently in Phase 11 trials in CTCL, with a response rate (RR) of 38% in this disease. MS-275 and tacedinahne (CI-994) have undergone Phase I trials and are now in Phase 11 trials. Other drugs hke MGCD0103, a class-I isotype selective HDACi are in Phase 1 trials [123]. 

Data on phase 1 trial in 34 patients with imresectable hepatocellular cancer were presented at the 41st ASCO meeting. May 2005. Patients received 750-1250 mg Vatalanib orally, once daily in a 28-day cycle. The most common... 

In phase 1 trials, a total of 49 patients with mahgnant soHd tumors were treated with a single daily oral dose of Vandetanib (50-600 mg/kg) followed... 

In June 2005, Chiron began US and UK phase 1 trials in MM. Data from this trial were presented at the 42nd ASCO meeting, Jime 2006. A total of 35 patients were treated in four intermittent dosing cohorts (25, 50, 75, and 100 mg/day) and three continuous dosing cohorts (100,125, and 175 mg/day) all once daily. Treatment was 7 days on, 7 days off with a subsequent protocol amendment to daily dosing. The plasma PK values were hnear between 25 and 175 mg doses with respect to Cmax and AUC. DLTs occurred at 175 mg and the MTD was 125 mg. Treatment was associated with stable disease. 

VX-680 is being developed by Vertex in collaboration with Merck. In Jime 2005 it was announced that a Phase 1 trial of VX-680 in hematological cancers had started [164]. This trial will include CML patients in blast crisis. These trials are in addition to the initial clinical trials in sohd tumors. 

Ward, S., Brett, S.J., Castello-Cortes, A., Brunner, M.D. and Panoskaltsis, N. (2006) Cytokine storm in a phase 1 trial of the Anti-CD28 monoclonal antibody TGN1412. New England Journal of Medicine, 355, 1-11. 

A phase 1 trial of dasatinib in IM-resistant Ph+ leukemias was reported last year and dosed over a range of 15-240 mg per day in once- or twice-daily doses. Complete hematologic responses were seen in 37 of 40 patients with chronic phase CML while major hematologic responses were noted in 31 of 44 patients with Ph+ ALL and blast crisis or accelerated-phase CML. 

Done at hospitals and research centers around the country, clinical trials are conducted in phases. Phase 1 trials try to determine dosing, document how a drug is metabolized and excreted, and identify acute side effects. Usually, a small number of healthy volunteers (between 20 and 80) are used in Phase 1 trials. 

Schoffski P, Riggert S, Fumoleau P, et al. Phase 1 trial of intravenous Aviscumine (rViscumin) in patients with solid tumors. A study of the European Organization for Research and Treatment of Cancer (EORTC) New Drug Development Group (NDDG). Ann Oncol 2004 15(12) 1816-1824. 

Transgenic mice that overexpress Ab have been used to determine whether vaccines could be produced to reduce the concentration of the peptide in patients with AD. Experimental studies have shown that Ab peptide immunization reduces the cognitive impairments and the formation of plaques in rodent models of AD. This finding led to the development of vaccines for human use and while the phase 1 trials in the UK suggested that the vaccine was safe, more extensive studies in Europe led to the termination of the clinical trials because 5% of the patients develop meningioencephalitis. More studies are presently underway to induce an immune response against Ab without initiating T-cell activation which underlies the inflammatory process in the brain. 

Fox E et al (2010) A phase 1 trial and pharmacokinetic study of cediranib, an orally bioavail-able pan-vascular endothelial growth factor receptor inhibitor, in children and adolescents with refractory solid tumors. J Clin Oncol 28 5174-5181... 

There is a phase 1 trial (trials that examine the toxicity of the proposed treatment and determine an appropriate dose of the treatment) of an intramuscularly delivered O x-antitryp sin gene in a modified adeno-associated virus vector. It will be some time before efficacy data are available ... 

TABLE 4.7 Standard questions requiring response prior to conduct of phase 1 trials with high-risk pharmaceuticals in the United Kingdom... 

For these reasons, determining the nature, predictability, and reversibility of immune system effects become a critical factor in weighing the risk-benefit ration of an phase 1 trial in healthy volunteers, as well as the determining a safe starting dose, safe maximum dose, and methods for monitoring potential immunotoxicity in these subjects. Over the past decade single-dose PK and safety trials of biopharmaceuticals in healthy volunteers have often preceded initial patient studies, even for products with known immunomodulatory effects at the anticipated therapeutic chronic dose exposure. 

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