Phase II studies

Moore J, Seiter K, Kolitz J et al (2006) A Phase II study of Bcl-2 antisense (oblimersen sodium) combined with gemtuzumab ozogamicin in older patients with acute myeloid leukemia in first relapse. Leuk Res 30(7) 777-783... 

More TKIs directed against other tyrosine kinases, like c-Met, IGF1R, Flt-3, FGFRs, Tie-2, Axl or Ron are at earlier stages of development with the most advanced candidates having entered phase II studies in different types of cancers. 

R. A., Comparative evaluation of the safety and contraceptive effectiveness of 65 mg and 100 mg of 90-day norethindrone microspheres for controlled release steroid contraception Phase II study, Fertil. Steril., 51. 803, 1989. 

Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, RothweU NJ, Tyrrell PJ. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 2005 76 1366-1372. 

Vinorelbine, a microtubule interactive agent, also has shown impressive response rates in metastatic breast cancer.60 Vinorelbine was approved by the FDA in 1994 for the treatment of non-small cell lung cancer. It is not approved for breast cancer, but response rates to vinorelbine range from 30% to 50%, with an overall 5% complete response rate in phase I and phase II studies in patients with advanced breast cancer. Importantly, paclitaxel, docetaxel, and vinorelbine do not appear to be cross-resistant with anthracyclines, which are arguably considered first-line treatment of metastatic breast cancer. 

Rose PG, Blessing fA, Ball HG, et al. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma a Gynecologic Oncology Group study. Gynecol Oncol 2003 88 130-135. 

A Phase II study was recently completed whereby Org-25935 was compared against placebo for the ability to improve negative symptoms in 246 subjects maintained on a stable dose of an atypical antipsychotic (data not disclosed) [46]. A second Phase II study in progress (200 patients) is designed to assess the efficacy of Org-25935 as a stand-alone therapy versus placebo, using olanzapine as the active control [46]. Org-25935 is also being investigated in separate Phase II studies as a treatment for panic disorder and for recidivism in subjects with alcohol dependence [46]. 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

The intravenous PARPi PF-1367338 has been investigated in the clinic for several years, and recently a Phase II study coupling PF-1367338 with cisplatin was initiated in TNBC patients [46]. A Phase II study with... 

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

The design of phase II trials is influenced by the phase I results. Phase II studies typically last for anything up to 2 years, with anywhere between a few dozen and a hundred or more patients participating, depending upon the trial size. 

Sleijfer, D.T. et al., Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis, J. Clin. Oncol., 10, 1119, 1992. 

Bukowski, R. et al. Phase II study of anguidine in gastrointestinal malignancies A Southwest Oncology Group study. Cancer Treat. Rep. 66, 381, 1982. 

Both enantiomers and the racemate of l-(3,4-dichlorophenyl)-3-azabicyclo [3.1.0]hexane, 27a-c, have been reported to be in development. The racemate, DOV 216,303, inhibits the reuptake of NE, 5-HT and DA with IC50 values of 20, 14 and 78 nM, respectively [85]. DOV 216,303 is active in tests predictive of antidepressant activity, including the mouse FST (minimum effective dose = lOmg/kg), reversal of tetrabenazine-induced ptosis and locomotor depression. DOV 216,303 was also reported to be well tolerated in phase I clinical trials [85,86], In a phase II study designed to explore safety and tolerability in depressed individuals, patients received either DOV 216,303 (50 mg, b.i.d.) or citalopram (20 mg, b.i.d.) for two weeks [85]. It was found that the side effect profile was not remarkably different between the two treatment groups. In addition, time-dependent reductions in Hamilton Depression Scores (HAM-D) were similar for both groups. 

A phase II study of EVT-201, a partial positive modulator of GABAa receptor, has recently been initiated in the US in elderly patients with chronic insomnia with the maintenance as primary endpoint (no structure disclosed). 

Currently the safety and efficacy of 20 is being evaluated in a Phase II study. The program is focused on the evaluation of the sleep induction and maintenance in insomnia patients but also will attempt to demonstrate orexin antagonists effects on improved sleep and side effect profiles compared to current GABAa receptor modulators. 

Eplivanserin (39) is a 5-HT2A antagonist initially developed for a broader spectrum of psychiatric disorders but that has been tested recently for insomnia. Within this latter indication, phase II studies showed benefits in sleep maintenance, but not in induction [9]. Compound 39 is currently in phase III, to assess the efficacy for the treatment of sleep maintenance insomnia, evaluating both sleep and daytime functioning [96]. 

Estimate efficacy information necessary to make sample size determinations for Phase II studies and establish adequate duration of treatment. 

The reported steps are critical, especially because only one of 50 molecules that reach phase II studies reaches the market. 

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... 

Phase II studies encompass a detailed assessment of the compound s safety and efficacy in a larger patient population (a few-to-several hundreds of patients). It is important that any formulation selected for these studies must be based on sound biopharmaceutical and pharmaceutical technology principles. Phase III clinical studies, also referred to as pivotal studies, involve several thousands of patients in multiple clinical centers, which are often in multiple countries. The aim of these studies is to demonstrate long-term efficacy and safety of the drug. Since these studies are vital in the approval of the drug, the dosage form plays a very critical role. 

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