Phase I clinical trial

Another dideoxypyrimidine nucleoside active against human immunodeficiency vims is 3 -azido-2/3 -dideoxyuridine [84472-85-5] (AZDU or CS-87, 64) C H N O. Since its synthesis, (167) CS-87 has been identified as a promising antiHIV agent (168) and is currentiy undergoing phase I clinical trials in patients with AIDS and AIDS-related complex. It appears to be less potent than AZT against HIV in a peripheral blood mononuclear (PBM) cell screening system and in MT-4 cell lines. This lower activity in PBM cells appears to be related to a lower affinity of CS-87 for the enzyme responsible for its initial phosphorylation (169). However, CS-87 has significantly lower toxicity on bone marrow cells than AZT (170) and penetration of the CNS as a 5 -dihydropyridine derivative. 

The novel agent sulofenur (69) has entered clinical trials based on its broad spectmm antitumor activity in tumor models, its unusual mechanism of action, and its lack of cross-resistance to other agents (33). In Phase I clinical trials, the dmg was well tolerated and some clinical responses were noted. 

Clinical trials are usually divided into three phases. In phase I clinical trials, the new drug is tested in a small (20-80) group of healthy volunteers to evaluate its... 

The antisense oligonucleotide LErafAON against the serine/threonine kinase c-Raf has been tested in phase I clinical trials. The antisense oligonucleotides ISIS-5132, which also inhibits c-Raf, and ISIS-3521, which inhibits PKC, went through different phase clinical trials with solid tumour patients. Unfortunately, no objective responses occurred with these PKI. GEM-231, an oligonucleotide targeting the RIa subunit of protein kinase A is currently undergoing phase I/II clinical trials alone or in combination with traditional therapy for the treatment of solid cancers [3]. 

Proof of safety for non-FcR-binding CD3-antibodies (phase I clinical trials)... 

The importance of CD28 came out when the phase I clinical trial with the humanized monoclonal superagonist of the CD28, TGN1412, resulted in an unexpected cytokine storm with multiorgan failure in 2006 in the UK [71],... 

Two PDF inhibitors, BB-83698 (8) and LBM-415 (12), have been investigated in Phase I clinical trials, and these studies represent the most advanced status that any PDF inhibitor has attained. BB-83968 was investigated for intravenous administration, while LBM-415 was studied following oral administration. 

Investigation of the differences in crystal packing between (431) and (426) from comparison of their respective X-ray structures, revealed that (431) was more tightly packed than (442), reflected in their respective melting points of 235 and 170 °C. It was postulated that the absence of in vivo activity for (431) may be explained by the resultant reduction in water solubility and dissolution rate compared with (426). The comparatively high calculated polar surface area of (431) (122.5A ) compared with (426) (89.3 A ) was also proposed as a factor influencing the marked difference in bioavailability between the two related compounds. Compound (426) (SLV-319) is currently being developed with Bristol-Myers Squibb for the potential treatment of obesity and other metabolic disorders. Phase I trials for obesity were started in April 2004. Earlier Phase I clinical trials for the treatment of schizophrenia and psychosis, which commenced in April 2002, appear to have been abandoned. 

The safety of the cocaine vaccine TC-CD in former cocaine abusers has been evaluated in a Phase I clinical trial, and it was determined that the vaccine was well tolerated with dose-related increases in antibody levels.65 Two Phase II clinical trials have now been conducted.66,67 The vaccine was again well tolerated and subjects reported a reduction in cocaine s reinforcing effects. The antibody levels were detectable after the second dose, peaked at 8 to 12 weeks, and remained elevated for up to 6 months preliminary findings indicated a negative association between antibody level and cocaine use. Other anti-cocaine vaccines in development include a blocking antibody (ITAC-cocaine) and a monoclonal catalytic antibody (15A10). 

Since then, several potent and selective sarcosine-based inhibitors have been reported in the literature. Representative examples include 5 (LY2365109) [37,38], 6 ((R)-N[3-phenyl-3-(4 -(4-toluoyl)phenoxy)-propyl] sarcosine or (R)-NPTS) [39,40], 7 [41], 8 [42], 9 (JNJ-17305600) [43], and 10 [44]. Members of these series have demonstrated efficacy in several psychosis models [38,40] and JNJ-17305600 is reportedly in Phase I clinical trials for schizophrenia (data not available) [23]. 

At least four clinical candidates including GSK-256073 [112], MK-0354 [102], MK-1903 [113], and INCB-19062 [91], and one preclinical candidate MK-6892 [77] have been reported. Neither the structure of GSK-256073, nor the clinical data, has been reported. In Phase II clinical trials, neither GPR109A partial agonist MK-0354, nor the full agonist MK-1903 showed substantial lipoprotein effects, and both candidates were discontinued. INCB-19062 is targeted to a type II diabetes indication based upon the related role of FFA to insulin sensitization in type II diabetes, and the robust FFA lowering effect observed in a Phase I clinical trial devoid of FFA rebound. 

A series of indeno[l,2-c]isoquinolines have been described [27] and INO-lOOl has been investigated in the clinic. Although the structure of INO-lOOl has not been reported, sulfonamide 28 is a representative structure (IC50 = lnM, EC5O = 10nM). CEP-9722 is in Phase I clinical trials, while its exact structure has not been disclosed, it is a prodrug of CEP-8983 (29) and patent applications highlight 30. Preclinical efficacy in combination with TMZ and camptothecin have been... 

In 2008, a Phase I clinical trial using MK-4827 was initiated, with a cohort expansion planned in BRCA-1- and BRCA-2-mutant ovarian cancer patients [45]. 

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. 

Anwer K, Barnes MN, Fewell J, Lewis DH, Alvarez RD (2010) Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer. Gene Ther 17 360-369... 

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