AEG-35156, an antisense oligonucleotide against X-linked inhibitor of apoptosis for the potential treatment of cancer

Aegera, under license from Idera Pharmaceuticals, is developing AEG-35156, a 19-mer phosphorothioate antisense oligonucleotide targeting the caspase inhibitor X-linked inhibitor of apoptosis protein (XIAP) messenger RNA, for the potential treatment of cancer. Several clinical trials are ongoing and include: two phase I monotherapy clinical trials for the potential treatment of cancer and in patients with solid tumors; a phase I combination clinical trial of AEG-35156 with docetaxel in locally advanced, metastatic, or recurrent solid tumors; four phase I/II combination clinical trials for the potential treatment of pancreatic cancer, advanced breast cancer, advanced NSCLC, and acute myeloid leukemia. Mild to moderate adverse effects were observed in early phase clinical trials. Aegera plans to initiate randomized phase III trials if tolerable side effects and evidence of activity are demonstrated in phase I/II clinical trials.     

BMS-247550 Bristol-Myers Squibb/GBF

Bristol-Myers Squibb and the German Research Centre for Biotechnology are developing BMS-247550 as one of a series of epothilones, for the potential treatment of various forms of cancer. BMS-247550 had successfully completed phase I trials by September 2000 and by February 2001, phase II trials had been initiated for a variety of tumor types in collaboration with the National Cancer Institute; at this time, DNA filing was expected in 2003, and commercialization in 2004. By April 2002, phase I trials in children had also been initiated. As of May 2002, phase II studies had been conducted in patients with non-small-cell lung cancer and breast cancer.     

KW-2170 (Kyowa Hakko Kogyo)

The pyrazoloacridone, KW-2170, an alkylating agent and topoisomerase II inhibitor, is being developed by Kyowa Hakko Kogyo as a potential treatment for cancer [273964], [409111], [422561]. By December 2001, KW-2170 had entered phase II trials in the US, following approval for the trial from the FDA, which was received in November 2001. At this time, the company planned to extend the phase II trials to Australia, Singapore, Taiwan and Costa Rica using data from US phase I trials. Accelerated Japanese trials were also planned, and an NDA was anticipated for 2006, with non-small-cell lung cancer, prostate cancer, colorectal cancer, ovarian cancer and breast cancer as the targets [434794], [444539]. By August 2002, Japanese phase I trials had been completed [460177].     

Tetrathiomolybdate, a copper chelator for the treatment of Wilson disease, pulmonary fibrosis and other indications

Tetrathiomolybdate (TTM) is a copper chelator that has also demonstrated antiangiogenic, antifibrogenic and anti-inflammatory actions in preclinical studies. The drug, from the University of Michigan was licensed to Pipex Pharmaceuticals Inc for development for several indications; development of the drug for cancer was later licensed to Attenuon LLC. In a phase III clinical trial, TTM stabilized neurological function in patients with Wilson disease, causing significant recovery in 81% of patients at 3 years post initiation of therapy; a second phase III trial was ongoing at the time of publication. A phase I/II clinical trial demonstrated the efficacy of TTM in patients with idiopathic pulmonary fibrosis, and led the FDA to grant TTM Orphan Drug status for this disease. Several phase II clinical trials had also been completed in patients with various cancers, and revealed mixed efficacy. TTM was also assessed in a phase I clinical trial for age-related macular degeneration, but the results reported from the trial were negative; no further development has occurred for this indication. TTM was assessed for the treatment of psoriasis in a phase II clinical trial, but no data have been reported. At the time of publication, phase II and phase III clinical trials were ongoing in patients with Alzheimer's disease and primary biliary cirrhosis, respectively. The most common clinical side effects observed for TTM over the range of indications have been anemia, neutropenia, leukopenia and transaminase elevations. These side effects were generally resolved with either a dose adjustment or temporary suspension of the dosing regimen. TTM is predicted to most likely find a niche in the therapy of Wilson disease, for which current treatment options are limited.     

CoFactor (Biokeys Pharmaceuticals)

BioKeys is developing CoFactor (methylenetetrahydrofolate), a thymidylate synthase inhibitor and modulator of 5-fluorouracil (5-FU), for the potential enhancement of cancer treatments using 5-FU [357795]. By March 2000, phase I/II trials had been completed and phase III trials were in preparation for the US and Scandinavia [357806,357795]. In November 2000, the company initiated a pharmacogenomic study of CoFactor [389157]. The company believes that genomic screening will be very useful for determining the most likely candidates for successful 5-FU/CoFactor therapy, therefore, Biokeys is undertaking a study on tissue samples from 62 patients who were previously treated in phase I/II trials. Analyses will be based upon a RT-PCR from paraffin-embedded tissues. This improved technology, which permits retrospective analyses from paraffin-fixed tissues, will enable BioKeys' scientists to better understand previous responses by the patients treated in the phase I/II trials [389157]. In phase I/II trials, CoFactor was administered to 62 cancer patients receiving 5-FU therapy and resulted in partial responses of 21 to 55% in colorectal, pancreas, stomach, gallbladder and breast cancer patients. Toxicity was milder than expected for 5-FU or 5-FU/leucovorin [357806,357795]. CoFactor has been shown to be 100-fold stronger than leucovorin in the promotion of thymidylate synthase inhibition [357795].     

Recombinant human keratinocyte growth factor palifermin reduces oral mucositis and improves patient outcomes after stem cell transplant

Oral mucositis, the breakdown of the mucosal lining of the oropharynx, occurs as a result of a toxic insult to the normal epithelium of the oral mucosa. Typically this is seen after exposure to a toxic agent such as radiation or chemotherapy; therefore, it is a frequent problem for patients undergoing treatment for cancer. In clinical trials, mucositis has been reported in up to 98% of patients receiving high-dose chemotherapy followed by hematological stem cell transplant. When mucositis develops it causes severe patient symptoms such as pain, but it is also associated with inferior clinical outcomes including increased infection, narcotic use and even mortality. In clinical trials, palifermin, a recombinant humanized keratinocyte growth factor (rHuKGF), has demonstrated an ability to decrease the incidence and duration of mucositis. In the registrational phase III trial in patients undergoing stem cell transplant for hematological malignancies, only 63% of patients who received palifermin developed World Health Organization grade 3 or 4 mucositis compared to 98% of patients on the placebo arm (1). The patients on the palifermin arm also had a shorter duration of mucositis with significantly decreased pain, use of narcotics, need for total parenteral nutrition and febrile neutropenia. Based on these results, palifermin became the first drug that has been approved by the U.S. Food and Drug Administration (FDA) to decrease the incidence and duration of severe oral mucositis in patients with hematological malignancies receiving high-dose chemotherapy requiring hematopoietic stem cell support. The development of mucositis is also a problem for patients receiving treatment for nonhematological tumors. In clinical trials, mucositis has been reported in over 75% of patients receiving combined chemo-/radiotherapy for head and neck cancer or fluorouracil for metastatic colon cancer. Initial phase I and II clinical trials of palifermin have demonstrated a benefit in patients receiving chemotherapy with or without radiation therapy for solid tumors; however, large phase III trials need to be completed before palifermin can gain FDA approval for this indication.     

AT-9283, a small-molecule multi-targeted kinase inhibitor for the potential treatment of cancer

AT-9283 has been identified and developed by Astex Therapeutics via structure-based optimization of a ligand-efficient pyrazole-benzimidazole fragment. AT-9283 inhibits several important kinases, including the Aurora kinase A, Aurora kinase B, Janus kinase (Jak)2, Jak3 and Abl kinase. Studies using multiple solid tumor and leukemia cell lines have demonstrated the ability of AT-9283 to inhibit growth and survival of tumor cells, and the direct inhibition of these kinases has been demonstrated in cell-based systems. The in vivo antitumor activity of AT-9283 has also been demonstrated in human tumor xenograft models. Based on these preclinical studies, several clinical trials have been conducted in patients with hematological malignancies, such as leukemias, myelodysplastic syndrome, myeloproliferative disease, chronic myeloid leukemia, lymphomas and multiple myeloma, and also in patients with solid tumors. Although phase II clinical trials have not been completed, AT-9283 demonstrated good safety and efficacy in phase I clinical trials. Thus, AT-9283 has potential as a therapeutic agent in several patient populations through its different inhibitory activities.     

Rubitecan: 9-NC, 9-Nitro-20(S)-camptothecin, 9-nitro-camptothecin, 9-nitrocamptothecin, RFS 2000, RFS2000

Rubitecan [Orathecin, 9-nitrocamptothecin, 9NC, RFS 2000] is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree, which is native to China. Rubitecan is an oral compound being developed for the treatment of pancreatic cancer and other solid tumours by SuperGen. One of the major benefits of rubitecan is that it can be administered in an outpatient setting, so patients can be treated in their homes. Rubitecan was isolated by the Stehlin Foundation in the US. SuperGen is currently awaiting regulatory approval in the US and the EU for rubitecan in the treatment of pancreatic cancer. At the BIO-2004 conference, SuperGen announced it is seeking a partner for rubitecan for territories outside the US. SuperGen acquired exclusive worldwide rights to rubitecan from the Stehlin Foundation in 1997 except in Mexico, Canada, Spain, Japan, the UK, France, Italy and Germany. SuperGen has also received approval from the US FDA to use its own manufactured rubitecan in clinical trials. SuperGen and the Stehlin Foundation have an 8-year research agreement that secures global rights to other camptothecins and additional anticancer compounds for the former. In December 1999, SuperGen and Abbott signed a worldwide sales and marketing agreement for rubitecan. Under the terms of the agreement, Abbott had exclusive distribution and promotion rights for rubitecan outside the US, and co-promotion rights with SuperGen within the US. In return, Abbott made an initial equity investment in SuperGen. SuperGen and Abbott Laboratories ended their collaboration agreement in February 2002 by mutual consent with SuperGen stating that the dissolution of the agreement was based on commercial motivation rather than anything to do with rubitecan's safety or efficacy. Abbott no longer has rights or obligations to purchase shares of SuperGen stock or an option to purchase up to 49% of the company. For its part, SuperGen will no longer receive milestone payments worth up to $US57 million. SuperGen has formed a clinical and business alliance with US Oncology (created by the merger between American Oncology Resources and Physician Reliance Network in the US), and will collaborate on clinical trials of rubitecan. SuperGen believes that this relationship will increase the patient population available for trials and enable it to market the drug directly to Oncologists. SuperGen and Capital Research and Management Company have completed a $US16.6 million private placement transaction that will enable future funding for the rubitecan programme as well as other oncology programmes. In July 2004, SuperGen's European subsidiary, EuroGen Pharmaceuticals, submitted a Marketing Authorisation Application for rubitecan in the treatment of pancreatic cancer. The application will be reviewed under the EMEA Centralised Procedure. In June 2003, the EMEA granted SuperGen orphan drug status for rubitecan for the treatment of pancreatic cancer. The US FDA has also granted orphan drug status for rubitecan in the treatment of pancreatic cancer and fast-track status for rubitecan for the treatment of locally advanced or metastatic pancreatic cancer that is resistant or refractory to chemotherapy. SuperGen has conducted three phase III pivotal trials in patients with pancreatic cancer. A phase III randomised trial in chemotherapy-naive patients was conducted at 132 centres throughout the US. The trial enrolled approximately 994 patients who were randomised to receive rubitecan or gemcitabine. Enrollment was completed in October 2001. Another phase III trial has compared rubitecan with the most appropriate chemotherapy in chemotherapy-resistant patients. Enrollment of over 400 patients at 200 medical centres across the US was completed in June 2001. Results from the trial were presented at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003) [Chicago, US; 31 May - 3 June 2003], after they had been compiled, analysed and submitted to the FDA. The results of the study showed that rubitecan could not help all chemotherapy-resistant patients, but could increase survival in those that do respond. The other phase III pivotal trial was conducted in patients with pancreatic cancer who had failed treatment with gemcitabine. This trial completed enrollment in October 2001, and had enrolled approximately 448 patients. SuperGen is conducting phase II trials of rubitecan in patients with solid tumours in the UK, Italy, France, Germany, the Netherlands and Denmark. Each trial will enroll 100-150 patients with various tumour types, including colorectal, lung, breast, gastric, prostate, cervical and head and neck cancers. Phase I/II trials are underway to investigate rubitecan as a radiosensitiser in patients with lung cancer, and phase II trials in patients with breast cancer are also being conducted. A phase II study in ovarian cancer patients is also being conducted. Results from an ongoing phase II study in cancer patients have shown that rubitecan was effective against chordomas, a rare type of bone cancer. Phase II studies are also underway in haematological malignancies including myelodysplastic syndrome (preleukaemia) and chronic myelomonocytic leukaemia. In February 2000, SuperGen announced that its IND submission for rubitecan had been approved by the Therapeutics Products Programme of Canada. The company stated that it intended to begin clinical trials in Canada in the near future. In February 2004, SuperGen announced an offering of shares of its common stock to finance the commercialisation of rubitecan capsules. In July 2003, SuperGen was granted a US patent covering combination therapies with chemotherapeutic anthracycline agents and structural modifications that may one day lead to next-generation rubitecan compounds. In December 2002, SuperGen was granted US patent No. 6,482,830, covering its polymorphic formulations of rubitecan. The patent also covers a class of polymorphs that are similar to the one at the centre of rubitecan. In addition, SuperGen was also issued US patent No. 6,485,514 in December 2002, covering the local delivery of rubitecan via stents and/or catheters to sites of proliferating cells. Stent- or catheter-delivered rubitecan may be beneficial in certain types of cardiac procedures, such as ablation or angioplasty, as well as for direct injection into a certain number of solid tumours. SuperGen is also developing an inhaled, liposomal formulation of rubitecan. It acquired the worldwide rights to this formulation from the Clayton Foundation in December 1999. Inhaled rubitecan is in clinical trials in the US for the treatment of lung cancer and pulmonary metastatic cancer.     

Progress in the clinical development of new marine-derived anticancer compounds

Naturally derived anticancer agents continue to be instrumental in the systemic therapeutic intervention against solid tumors and hematological malignancies. Such compounds now have a relevant role in contemporary models of combination with targeted agents, thus providing a rationale to consider nature as a valid tool to discover new innovative anticancer agents. The marine ecosystem has increasingly been the focus of interest for new discoveries in the field that are expected to be of significant therapeutic impact in cancer patients. A critical review of the integrated data generated in our marine-derived anticancer program seems to confirm such expentancies. ET-743 (Yondelis) represents the first new agent developed against advanced pretreated soft tissue sarcoma in the past 25 years, and also harbors activity in women bearing pretreated ovarian cancer and a solid potential in combination therapy. The lack of cumulative toxicities makes this compound suitable for long-lasting therapies, reversible transaminitis being the most prevalent toxicity. Aplidin has shown a positive therapeutic index in phase I trials and phase II studies are ongoing. In contrast to the lack of bone marrow toxicity, a set of translational results anticipates a potential in leukemia. Kahalalide F has also successfully completed the phase I program in solid tumors with evidence of activity in resistant tumors and phase II studies are under way. Finally, the mechanistic data generated in parallel with the clinical program confirms the potential of the marine ecosystem in the discovery of new agents acting against new cellular targets of relevance in cancer cell biology.     

Current status of pyrazoloacridine as an anticancer agent

Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. Recent studies suggest that PZA might be a dual inhibitor of DNA topoisomerase I and DNA topoisomerase II that exerts its effects by diminishing the formation of topoisomerase-DNA adducts. Consistent with this unique mechanism of action, PZA exhibits broad spectrum antitumor activity in preclinical models in vivo. In addition, this agent displays several unique properties including solid tumor selectivity, activity against hypoxic cells, and cytotoxicity in noncycling cells. PZA also retains full activity against cells that are resistant to other agents on the basis of overexpression of P-glycoprotein or the multidrug resistance-associated protein (MRP). PZA has been studied in phase I trials in adults and children, and is currently undergoing broad phase II trials in a number of tumor types. No significant anti-tumor activity has been seen in gastrointestinal malignancies and prostate cancer. Results from ongoing or recently completed trials are awaited before the utility of this agent in our current armamentarium can be defined. Because of its unique properties, combination studies with other antineoplastic agents are warranted.     

Plerixafor: AMD 3100, AMD3100, JM 3100, SDZ SID 791

Plerixafor [Mozobil, AMD 3100, JM 3100, SDZ SID 791] is a bicyclam derivative that acts as a stem cell mobiliser by blocking the CXCR4 chemokine receptor. Plerixafor was synthesised by Johnson Matthey (AnorMED) in collaboration with the Rega Institute of Leuven, Belgium. Plerixafor is in phase III clinical trials in stem cell transplantation among cancer patients. Plerixafor blocks CXCR4, which triggers the rapid movement of stem cells out of the bone marrow and into circulating blood. These cells can then be collected and used in stem cell transplant procedures. Plerixafor had been available for partnering in Europe. However, decisions concerning partnering arrangements were deferred by AnorMED until top-line clinical data became available (expected in 2007). In November 2006, Genzyme Corporation completed its acquisition of AnorMED. Genzyme intends to commercialise plerixafor in >50 countries throughout the world using its existing transplant business. Evotec OAI was selected by AnorMED to support it in the chemical development of plerixafor. Evotec OAI will use EVOdevelop, its integrated chemical and pharmaceutical development platform, to complete the full validation of the process to plerixafor, including process research and development, cGMP manufacturing and analytical work. Evotec OAI will also be responsible for producing the relevant Chemical Manufacturing Control (CMC) documentation for regulatory filings. Top line results from the phase III studies are expected in the second quarter of 2007 and, assuming these are successful, the marketing submissions are planned for the US in 2007 (launch in 2008), and for Canada and Europe in 2008. Plerixafor has orphan drug status for stem cell transplantation in cancer patients in the US and the EU. AnorMED (now Genzyme) decided to pursue a full Marketing Authorisation Application (MAA) in Europe for plerixafor in stem cell transplant. Previously, the company had been planning on filing a CMA (Conditional Marketing Authorisation) in this region. The change in strategy requires additional phase II trials in the five major EU markets. Multicentre phase II trials with plerixafor have begun in Canada and Germany in approximately 50 patients with non-Hodgkin's lymphoma and multiple myeloma (studies EU21 and C201). Enrolment has been completed in a US-based, multicentre, phase II trial (study 2105) of plerixafor plus G-CSF in patients with multiple myeloma and non-Hodgkin's lymphoma. This study is designed to optimise the administration schedule of this combination therapy regimen. Plerixafor has completed a phase II study (study 2104) in multiple myeloma and NHL patients in combination with chemotherapy. A US-based phase II pilot study (study 2108) with plerixafor as a single mobilising agent in multiple myeloma patients undergoing stem cell transplant is underway. Another US-based phase II pilot study (study 2106) is evaluating plerixafor in combination with the standard mobilisation regimen, G-CSF, in patients with Hodgkin's disease undergoing stem cell transplant. AnorMED completed a phase II study (study 2101) evaluating the potential of plerixafor in combination with G-CSF as a therapy for stem cell transplantation compared to G-CSF therapy alone. The study involved patients with multiple myeloma and patients with NHL. Results indicated that the combination regimen was significantly superior to G-CSF treatment alone in stem cell mobilisation. Further trials are planned for plerixafor, to expand its use in transplant and in other indications including one to investigate the potential of plerixafor to improve the effectiveness of chemotherapy in patients with leukaemia. Phase I trials have been completed.     

Tezacitabine Hoechst Marion Roussel

Tezacitabine (MDL-101731, KW-2331, FMdC), an antimetabolite deoxycytidine analog, is an irreversible ribonucleotide reductase inhibitor and DNA chain terminator discovered by Hoechst Marion Roussel, now Aventis Pharma, and under development by Matrix and Kyowa as a potential treatment for solid tumors [117987,153697]. It is in phase II trials for colorectal and hematological cancer [333949,343071,353481] and was evaluated in a phase II trial for non-small cell lung cancer, for which enrollment was reported to have stopped [342009]; however, tezacitabine continues to be explored for this indication [378351]. In February 1999, the first phase II trial patient was treated with tezacitabine. A total of 30 patients with non-small cell lung cancer were expected to be enrolled by Matrix [316463]; however, in October 1999, Matrix closed enrollment in this trial (after 28 patients were enrolled); preliminary analysis of the evaluable patients did not show meaningful clinical activity with tezacitabine as a stand-alone therapy in this indication at the dose and regimen tested [342009]. In May 1999, Matrix announced it would enroll up to 30 colorectal cancer patients for treatment in a phase II study [326017]. Despite closing enrollment for the NSCLC trial, as of October 1999, the phase II trial of tezacitabine in colorectal cancer was continuing to accrue patients [342009]. In March 2000, a clinical trial was initiated at the University of Pennsylvania to study tezacitabine administered intravenously in combination with cisplatin; a phase I trial studying the drug in combination with 5-FU at the Dana Farber Cancer Institute also commenced at that time [360590]. In May 1999, the results of four phase I trials were presented at the 35th Annual Meeting of the American Society of Clinical Oncology (ASCO). The studies enrolled 70 patients, 97% of whom had had previous chemotherapy and 46% of whom had failed three or more prior regimens. Groups of patients were given i.v. infusions of tezacitabine in schedules ranging from once every 3 weeks to twice a week for 3 weeks at doses ranging from 16 to 630 mg/m2. The dose-escalation studies showed the compound to be well tolerated and indications of efficacy were observed in patients with various advanced solid tumors [325070,327102]. In September 1998, Matrix Pharmaceutical acquired worldwide rights to tezacitabine except in Japan [299373]. Kyowa Hakko Kogyo has a license from HMR to develop tezacitabine in Japan [195494]; in 1995, the company began phase I clinical trials in Japan for tezacitabine administered orally [195494]. In 1996, this product was designated one of HMR's nine top priority products, serving an unmet medical need and addressing a potential market in excess of US $500 million per year [221118].     

Hsp90 inhibitors in the clinic

Specific inhibitors of Hsp90 have recently entered human clinical trials. At the time of writing, trials have been initiated only in metastatic cancer, although a rationale exists for using these agents in a variety of human diseases where protein (mis)folding is involved in the disease pathophysiology. Hsp90 inhibitors offer a unique anti-cancer opportunity because they provide simultaneous combinatorial blockade of multiple oncogenic pathways. The first compound in this class, 17-AAG, has completed phase I trials and phase II trials are in progress. The toxicity has been manageable and evidence of possible clinical activity has been seen in metastatic melanoma, prostate cancer and multiple myeloma. Other inhibitors with improved properties are approaching clinical trials. This chapter presents an update of the current clinical trials using Hsp90 inhibitors, focussing on the areas that will be increasingly relevant in the next 5 years.     

Tipifarnib (Janssen Pharmaceutica)

Janssen is developing tipifarnib (formerly known as R-1 15777), an inhibitor of RAS farnesylation, for the potential treatment of neoplasia [287030], [289610]. Janssen commenced clinical trials in the US, in conjunction with the National Cancer Institute, in April 1997 [287030], [289610], and by May 1999, phase II trials in patients with advanced non-small cell lung cancer were being planned [325960]. By February 2001, phase III trials for the potential treatment of pancreatic cancer and leukemia had been initiated [399065], and by June 2001, it was in phase II trials for RAS-dependent solid tumors [412618]. In November 2001, Credit Lyonnais Securities predicted NDAfilings in 2002 and 2003 for pancreatic cancer and other cancers, respectively, and projected US introductions for these indications in 2004 and 2005, respectively [436939].     

BMS-184476 Bristol-Myers Squibb

BMS-184476 is a taxane analog under development by Bristol-Myers Squibb for the potential treatment of solid tumors. By February 2001, it had entered phase II trials and, as of May 2002, phase II studies had been carried out in patients with a number of tumor types, including breast, ovarian and non-small-cell lung cancer.     

Motexafin gadolinium: gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120

Motexafin gadolinium [gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120] is a radiosensitising agent developed for use in cancer therapy. It is cytotoxic in haematological malignancies by selectively localising in cancer cells that have high rates of metabolism. Motexafin gadolinium inhibits cellular respiration resulting in the production of reactive oxygen species and inducing apoptosis. It is being developed by Pharmacyclics in the US. Bulk motexafin gadolinium is supplied to Pharmacyclics by the US company, Celanese, through a manufacturing and supply agreement between the two companies. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), the importance of having an agent for the treatment of brain metastases from lung cancer was highlighted. Results of a phase III study were presented that showed that motexafin gadolinium treatment was associated with a delay in time to neurological and neurocognitive progression in lung cancer patients. This was an important finding, as 46.6% of lung cancer patients already have brain metastases at the time of initial diagnosis, compared with only 2.7% of breast cancer patients. Brain metastases are also often the only site of metastatic disease in patients with lung cancer. In December 2002, Pharmacyclics began a phase III trial of motexafin gadolinium in patients with brain metastases (brain cancer in phase table) from lung cancer in the US, Europe, Canada and Australia. The trial is known as the Study of neurologic progression with Motexafin gadolinium And Radiation Therapy (SMART) and will compare whole-brain irradiation with whole-brain irradiation plus motexafin gadolinium in 550 patients. The primary efficacy endpoint is time to neurological progression and the secondary endpoints are survival and neurocognitive function. In January 2003, the US FDA completed its Special Protocol Assessment (SPA) of the SMART trial with a positive result and by June 2003, enrollment had begun. In addition, phase I trials are underway in children with intrinsic pontine glioma and adults with head and neck, lung and pancreatic cancers. A phase II trial is also being conducted in the US in patients with glioblastoma multiforme. Enrollment in this trial has been completed and preliminary results have been reported. Pharmacyclics has completed enrollment and follow-up of adults in its pivotal phase III trial of motexafin gadolinium as a radiation sensitiser for the treatment of brain metastases. The trial was conducted at 35 centres in Europe, Canada and the US. Full results from this initial phase III trial were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida, USA, held in May 2002. Pharmacyclics also announced in October 2002, at the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), that motexafin gadolinium significantly prolonged time to neurological progression when added to whole brain radiation therapy and reduced the number of deaths in patients with brain tumour. Pharmacyclics announced in September 2000 that it has initiated two NCI-sponsored phase I trials conducted under a Cooperative Research and Development Agreement (CRADA) between Pharmacyclics and the NCI. The first trial, conducted in patients with stage IIIA non-small cell lung cancer, was designed to determine the safety of two different dosing regimens of motexafin gadolinium during preoperative radiotherapy after induction chemotherapy. The second study was designed to examine the use of motexafin gadolinium in combination with stereotactic Gamma Knife radiosurgery in patients with primary glioblastoma mutiforme. Two phase I clinical trials have also been conducted for the treatment of newly diagnosed glioblastoma multiforme at the UCLA Jonsson Comprehensive Cancer Center, USA. These phase I studies were sponsored by the NCI and were conducted under a CRADA with the NCI. Pharmacyclics has also completed multicentre US phase II clinical trials of motexafin gadolinium fin gadolinium in patients with metastatic tumours of the brain who require whole brain radiotherapy. Motexafin gadolinium is in a phase II trial in patients with lymphomas and multiple myeloma in the US.     

Necitumumab, a fully human IgG1 mAb directed against the EGFR for the potential treatment of cancer

Necitumumab (IMC-11F8), under development by ImClone Systems in collaboration with Bristol-Myers Squibb, is a fully human IgG1 mAb targeting the epidermal growth factor receptor (EGFR), for the potential intravenous treatment of cancer, in particular NSCLC. In vitro studies demonstrate that necitumumab inhibits downstream targets in the EGFR pathway (eg, MAPK), which are important for cellular proliferation, differentiation, invasion and metastasis. Furthermore, because necitumumab is an IgG1 construct, it has the potential to induce antibody-dependent cell-mediated cytotoxicity against tumor cells. Preclinical studies indicated that the antitumor activity of necitumumab is either comparable with or superior to that of ImClone's chimeric anti-EGFR mAb cetuximab. In a phase I clinical trial in patients with advanced solid malignancies, necitumumab displayed nonlinear pharmacokinetic behavior. The toxicity profile of necitumumab is acceptable, with skin toxicity being the most frequently reported adverse event in the phase I and II clinical trials conducted to date. Preliminary data from a phase II clinical trial of necitumumab in combination with chemotherapy for the first-line treatment of advanced colon cancer are promising. Success in the ongoing phase III clinical trials in patients with advanced NSCLC would lead to necitumumab becoming a valuable addition to future therapeutic strategies in oncology.     

Lerisetron. FAES

Lerisetron is a 5-hydroxytryptamine3 receptor antagonist under development by FAES Farma for the potential treatment of emesis resulting from chemotherapy. Phase I trials of lerisetron were underway in Spain by 1994, and as of June 2000, the compound was in phase II trials in the UK. By the end of 2001, phase II trials had been completed and phase III trials had commenced.     

Talarozole, a selective inhibitor of P450-mediated all-trans retinoic acid for the treatment of psoriasis and acne

Talarozole, being developed by Barrier Therapeutics Inc under license from Johnson & Johnson, is a potent and selective inhibitor of cytochrome P450 26-mediated breakdown of endogenous all-trans retinoic acid for the treatment of psoriasis and acne. Phase II clinical trials of an oral formulation of talarozole in patients with psoriasis and with acne, and a phase I clinical trial of a topical formulation have been completed. At the time of publication, Barrier Therapeutics had suspended the development of talarozole as part of a series of cost-cutting initiatives; the company had also been acquired by Stiefel Laboratories Inc. No formal announcement had been made regarding the further development of talarozole.     

Su-6668. SUGEN

SUGEN is developing SU-6668, a tyrosine kinase inhibitor that inhibits three distinct growth factor receptor targets, for the potential treatment of cancer [304530]. The compound is in phase I trials in the UK and US [321260], [374505]. A report in January 2001 stated that phase I/II trials for hematological and solid tumors were expected to commence shortly thereafter [395657]. In May 2001, phase I data from a dose-escalation study conducted at UCLA were presented at the 37th ASCO meeting in San Francisco, CA. By that time, 74 patients had been enrolled in this study which aimed to determine the toxicities of SU-6668 when delivered to fed and fasting patients. SU-6668 was administered orally either once or twice-daily at doses of 100 to 2400 mg/m2 to patients diagnosed as having advanced malignancies. Accrual in phase I is continuing to define the toxicities of doses > 200 mg/m2 twice-daily [409984], [411418]. In December 1998, SUGEN filed an IND with the FDA for the clinical testing of this compound with oral and iv formulations [310237]. In November 1998, SUGEN entered into a collaboration with the Cancer Research Campaign (CRC) to conduct a phase I trial of SU-6668 at the Royal Marsden Hospital, UK using an iv formulation [304530]. After the first six patients had been treated, the trial was halted owing to problems with the iv formulation. Some toxicities, including nausea, vomiting, fatigue and tumor pain were observed [413538]. No licensing agreement as involved between the CRC and SUGEN for this trial [408572].