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PubMed2002

Alimta (pemetrexed disodium): a multitargeted antifolate for the treatment of mesothelioma.

Pemetrexed disodium is an antimetabolite with multiple sites of action. It inhibits dihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide formyl transferase (GARFT). As a single agent it is active against a variety of solid tumors. One phase II trial demonstrated a 14.5% response rate for single-agent pemetrexed disodium in patients with previously untreated mesothelioma. The combination of pemetrexed disodium and cisplatin was associated with very encouraging regression rates in mesothelioma patients treated as part of a phase I trial. A subsequent trial showed similarly encouraging activity (10 partial responses out of 25 evaluable patients [40%]) in mesothelioma patients treated with pemetrexed and carboplatin. A large, prospectively randomized, phase III trial of cisplatin alone versus cisplatin and pemetrexed with vitamin support has been completed. The findings will be presented at the 38th Annual Meeting of the American Society of Clinical Oncology in May 2002.

Antimetabolites, Antineoplastic↗

PubMed1997

Efficacy and safety of topotecan in the treatment of advanced ovarian carcinoma.

Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) has emerged as a promising new chemotherapy drug for patients with refractory and progressive stage III and IV epithelial ovarian carcinoma. A semisynthetic analog of camptothecin, topotecan exerts its antitumor effects through inhibition of the nuclear enzyme topoisomerase I. Phase I trials found antitumor activity in many topotecan dosing schedules, one of which involved the administration of topotecan daily as a 30-minute infusion for 5 consecutive days, with the cycle repeated every 21 days. With this schedule, the maximum tolerated dose was found to be 1.5 mg/m2/d. In a series of phase II investigations in platinum-resistant ovarian cancer patients, response rates have ranged from 13% to 25%. In addition, a number of patients exhibit prolonged disease stabilization, with overall rates of nonprogression ranging from 37% to 81%. Activity in paclitaxel-resistant patients is also seen, with a multicenter phase II trial showing a response rate of 13% among first-line paclitaxel failures and 14.3% among second-line failures. A phase III trial compared topotecan and paclitaxel as second-line therapies in 226 advanced ovarian cancer patients who had been previously treated with platinum-containing regimens. Preliminary data show that patients treated with topotecan evidenced a higher response rate (23% v 14%), longer response duration (32 weeks v 20 weeks), and significantly longer time to progression (23 weeks v 14 weeks; P = .002). Additional schedules are still being evaluated, with a phase II trial of prolonged infusion of relatively low-dose topotecan over 21 days demonstrating a 37% response rate in 16 patients. All phase II and III trials analyzed thus far indicate that topotecan is well tolerated with an acceptable toxicity profile, with myelosuppression as the dose-limiting toxicity. Hematologic toxicities are predictable, of short duration, and noncumulative. Mild to moderate nonhematologic toxicities are manageable. These findings demonstrate that topotecan is a viable new second-line or salvage treatment for patients with advanced ovarian cancer who are refractory or resistant to prior chemotherapy, including platinum-based agents and/or paclitaxel.

Antineoplastic Agents↗

PubMed1995

Risks and benefits of retinoids in the chemoprevention of cancer.

Chemoprevention of cancer is a new branch of clinical research; it may be defined as the reduction of cancer incidence by pharmacological means through the suppression of established malignant cell clones or through alteration in growth and progression of premalignant cell populations. In the last few years, this area of research has progressed dramatically from preclinical studies to phase I, II and III clinical trials. Among the various chemical or natural compounds used as chemopreventive agents, retinoids appear to be one of the most promising groups of agents. Analyses of preclinical and clinical studies have shown retinoids to be active in reversing skin and oral precancer, in preventing primary skin cancer, superficial bladder cancer, and second primary tumours associated with head and neck and lung cancers. Preclinical studies have shown evidence of the activity of fenretinide in breast cancer. Preliminary clinical data seem to show a protective effect of fenretinide against ovarian cancer. Current evidence therefore suggests that chemoprevention of cancer with retinoids is a promising path.

Antineoplastic Agents↗

PubMed2001

Cizolirtine. Laboratorios Dr Esteve.

Cizolirtine is a centrally-acting analgesic that is under development by Esteve for the potential treatment of pain [171179]. In March 2001, phase II and III trials in the US and Europe were ongoing [404223]. Its mechanism of action is based on the inhibition of substance P and calcitonin gene-related peptide release at the spinal cord level [404223] but this has not yet been fully confirmed. Cizolirtine does not produce gastrointestinal lesions or depress respiration [388894], however, it does exhibit antipyretic activity in animal models [260611], [388894]. The compound was disclosed in EP-00289380, published by Esteve in 1988. A method of resolving the racemic compound has also been claimed in WO-09902500.

Analgesics, Non-Narcotic↗

PubMed2006

Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs.

Many agents are being considered for treatment of Parkinson disease (PD). Given the large number of agents and the limited resources to evaluate new agents, it is essential to reduce the likelihood of advancing ineffective agents into large, long-term Phase III trials. Futility design methodology addresses this goal. The authors describe how a single-arm Phase II futility study uses a short-term outcome to compare a treatment group response to a predetermined hypothesized or historically based control response. The authors present advantages and limitations of futility designs along with examples derived from the data archive of a large Phase III efficacy study of treatments to delay PD progression, the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. Using the same control progression rate and treatment effect assumptions used to power the original DATATOP trial, the authors calculated the number of subjects needed to conduct two 12-month futility studies. DATATOP was designed to enroll 800 patients. Using data on 124 consecutive subjects randomized into each of the DATATOP treatment groups, the authors identified tocopherol as futile and deprenyl as worthy of further study. Using Phase II information, DATATOP could have been simplified from a 2 x 2 factorial design to a comparison of deprenyl vs placebo. While not testing efficacy, futility designs provide a strategy for discarding treatments unlikely to be effective in Phase III. A limitation is the dependence on historical data or hypothesized outcomes for untreated controls. Futility studies may decrease the time to identify treatments unworthy of further pursuit and reduce subjects' exposure to futile treatments.

Antiparkinson Agents↗

PubMed2004

[Association of taxanes and radiotherapy: preclinical and clinical studies].

Taxanes (paclitaxel and docetaxel) stabilized microtubules against depolymerization, and inhibit their function. Their radiosensitizing properties have been discovered more than 10 years ago; they synchronized tumor cells in G2/M phase, the most radiosensitive portion of the cell cycle. Other radiosensitizing mechanisms have been also discussed, as reoxygenation, promotion of radio-apoptosis and antiangiogenic cooperation. Many phase I and II studies have been performed, essentially in bronchus and head and neck carcinomas. In lung cancer, paclitaxel was delivered weekly at a dose of 60 mg/m2. Many studies combined cisplatin or carboplatin with paclitaxel, demonstrating that this combination is feasible and efficient. Only one phase III trial was reported; after two cycles of chemotherapy for inoperable lung cancers, radiotherapy was delivered, with or without paclitaxel radiosensitization: a benefit in disease-free survival was observed for the combination arm. In head and neck carcinomas, conomitant association of cisplatin, paclitaxel and radiation was feasible and showed promising results. Clinical trials with docetaxel are in progress.

Animals↗

PubMed2001

5-fluorouracil/leucovorin versus capecitabine in patients with stage III colon cancer.

Capecitabine is an orally administered fluoropyrimidine carbamate that is preferentially converted to 5-fluorouracil in tumors relative to normal tissue. Three different dosing regimens were investigated in phase I studies: continuous monotherapy, intermittent monotherapy, and intermittent therapy supplemented with leucovorin. These studies defined the maximum tolerated dose for each regimen. Dose-limiting toxicities were diarrhea, hand-foot syndrome, and leukopenia. Each phase I study recommended a dose; these were directly compared in a phase II study. This phase II study showed that the intermittent regimen of capecitabine monotherapy was the most favorable on the basis of tumor response rates, time to progression, dose intensity, and toxicities. The intermittent regimen of capecitabine has been compared with the Mayo Clinic regimen of 5-fluorouracil/leucovorin in two large, phase III studies of patients with advanced colorectal cancer. The combined data from the two studies showed that capecitabine was superior to 5-fluorouracil/leucovorin in terms of tumor response rate (22% v 13%; P < .0001) and similar in terms of time to disease progression and overall survival. Capecitabine is now being compared with the Mayo Clinic regimen as an adjuvant treatment for patients with Dukes' C colon cancer.

Administration, Oral↗

PubMed2002

Imatinib. Novartis.

Novartis has launched imatinib, an inhibitor of tyrosine kinases, including Bcr-Abl, for the treatment of chronic myeloid leukemia (CML). Imatinib selectively inhibits activation of target proteins involved in cellular proliferation. It also inhibits c-KIT tyrosine kinase activity and is equally effective against both wild-type and constitutively active enzyme. Close correlation between in vitro responses to IFNalpha and imatinib suggested that it may be an alternative to IFNalpha therapy for chronic-phase CML, and the compound has the advantage that it can be administered orally. Futhermore, Bcr-Abl-expressing cells treated with imatinib undergo apoptosis. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. In February 2002, the FDA approved imatinib for the treatment of inoperable and/or metastatic malignant gastrointestinal stromal tumors (GIST); in September 2001, launch for the indication was expected in 2002. In November 2000, imatinib was granted Orphan Drug status in Japan for the target indication of Philadelphia chromosome-positive leukemia. By May 2001, imatinib had entered phase II trials for small cell lung cancer, prostate cancer and glioma. Imatinib has been launched in more than 35 countries, including the US, Brazil, Switzerland, Australia and the UK. By December 2001, the drug had also been launched in Japan. The drug is marketed as Gleevec (imatinib mesilate) in the US, and Glivec (imatinib) outside the US. In August 2001, Deutsche Bank estimated sales of SFr 233 million in 2001, rising to SFr 850 million in 2005; while Bear Stearns & Co predicted sales of SFr 250 million in 2001, rising to SFr 800 million in 2005.

Animals↗

PubMed2001

ONYX-015. Onyx Pharmaceuticals.

ONYX-015 (CI-1042), an adenovirus modified selectively to replicate in and kill cells that harbor p53 mutations, is under development by Onyx Pharmaceuticals for the potential treatment of various solid tumors, including head and neck, gastrointestinal and pancreatic tumors. It is a recombinant adenovirus that carries a loss-of-function mutation at the E1B locus, the product of which is a 55 kDa protein that binds to and inactivates the p53 tumor suppressor protein. Wild-type adenoviruses must disable this gene before viral replication can occur. This, the ONYX-015 adenovirus will leave normal cells unaffected. Mutations in the p53 tumor suppressor gene are the most common type of genetic abnormality in cancer, occurring in more than half of all major cancer types. Thus, these cells are susceptible to the virus, which will readily replicate and cause cell death. ONYX-015 is in ongoing phase III trials for the treatment of recurrent head and neck cancer, phase II trials for colorectal, ovary, pancreas and mouth tumors, and phase I trials for digestive disease, esophagus and liver tumors. Onyx Pharmaceuticals was granted US-05677178 covering methods for the treatment of p53-related cancers in October 1997. The patent specifically covers the use of modified adenoviruses and other DNA viruses, which lack viral proteins that bind to p53, for the treatment of cancer patients whose tumors lack p53 function. The USPTO awarded Onyx Pharmaceuticals US-05846945 in December 1998, covering methods for treating cancer using replicating adenoviral therapy in combination with chemotherapy. In April 1999, the company also received EP-094910177.8 covering the technology in Europe.

Adenoviridae↗

PubMed2001

Cangrelor AstraZeneca.

AstraZeneca is developing the P2T (P2YADP) purinoceptor antagonist and platelet aggregation inhibitor, cangrelor, for the potential treatment of unstable angina and as an ultrafast-acting intravenous antithrombotic agent. It is in phase IIb clinical trials [315723]. NDA and MAA applications are planned for after 2003 [275466], [314472]. It superseded the earlier compound, ARL-67085, which also reached phase II trials [328760]. In ex vivo samples of angina patients' blood, cangrelor inhibits platelet/monocyte conjugate development, which indicate the drug has some degree of disease-modifying activity [377418]. AstraZeneca is also developing derivatives of cangrelor. Removal of the triphosphate side chain, modification of the ribose to a carbocycle and the purine to a triazolopyridine resulted in a potent (IC50 = 4 nM) orally-active P2T/P2Y12 receptor antagonist. A lead compound was scheduled to enter trials as an antithrombotic agent in July 2000 [377666]. In March 1999, Lehman Brothers predicted a 30% probability that the drug would reach world markets and would be launched in 2002 [336599].

Adenosine Monophosphate↗

PubMed1997

[Current status of the clinical development of MR contrast media].

The paramagnetic extracellular Gd contrast media (Gd-CM) Magnevist, Dotarem, Omniscan, and ProHance are on the market, whereas Gadovist, Optimark, and MultiHance (also used as a hepatobiliary CM) are undergoing clinical trials (phase III). Among other indications, Gd-CM are applied in tumours, inflammation, vascular pathologies, and MR-angiography. The paramagnetic hepatobiliary CM Teslascan, Eovist and MultiHance are in clinical trials (phase II and III). They improve tumour detection and characterisation. The Mn-CM Teslascan is also suited for pancreatic imaging, the Gd-CM MultiHance for imaging of myocardial infarction and the brain, and the Gd-CM Eovist has been used in liver CT. The superparamagnetic reticuloendothelial CM Endorem is on the market whereas Resovist is undergoing phase-III trials. Both agents have the same indications as the hepatobiliary CM. Sinerem is another superparamagnetic CM. However, it acts as a blood pool agent and accumulates in lymph nodes (MR lymphography). Gastrointestinal CM are divided into paramagnetic, superparamagnetic and diamagnetic agents acting either as positive or negative CM. Some are on the market, but their clinical value is limited.

Adult↗

PubMed2005

[Imatinib therapy for patients with chronic myelogenous leukemia].

Chronic myelogenous leukemia (CML) is a clonal hematopoietic disorder caused by the reciprocal translocation between chromosome 9 and 22. As a result of this translocation, a novel fusion gene, BCR-ABL, is created on Philadelphia (Ph) chromosome, and the constitutive activity of the BCR-ABL protein tyrosine kinase plays a critical role in the disease pathogenesis. Imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, was first given to a patient with CML in June 1998. Since then, it has continued to demonstrate remarkable efficacy in treating patients with CML. Based upon the results of early phase I and II studies, a phase III study (IRIS Study) that was randomized to first-line imatinib (400 mg/day) or to standard treatment with interferon+low-dose Ara-C, was conducted on 1,106 patients newly diagnosed (within 6 months) with chronic-phase CML. After median follow-up of 30 months, imatinib showed significantly superior tolerability, hematologic and cytogenetic responses (major cytogenetic response, 90%; complete cytogenetic response, 82%), and overall survival (95% without censoring allo-HSCT). Although imatinib is the first-line therapy and has changed the paradigm of CML treatment strategy, questions remain as to the meaning of cytogenetic and molecular response, curability, optimal dose, and relation with allo-HSCT.

Antineoplastic Agents↗

PubMed2002

Docetaxel in combination with platinums (cisplatin or carboplatin) in advanced and metastatic non-small cell lung cancer.

In a large, multinational, randomized phase III trial, 1,220 patients with advanced and/or metastatic non-small cell lung cancer were randomized to receive one of three treatments: docetaxel 75 mg/m(2) plus cisplatin 75 mg/m(2) every 3 weeks; docetaxel 75 mg/m(2) plus carboplatin to an AUC of 6 every 3 weeks; or a standard reference arm of vinorelbine given at 25 mg/m(2) on days 1, 8, 15, and 22 plus cisplatin 100 mg/m(2) on day 1 every 4 weeks. The choice of treatment and dose was based on a series of four phase II studies that indicated the combination of docetaxel (75 to 100 mg/m(2)) and cisplatin (75 to 100 mg/m(2)) was active and feasible; carboplatin may have a more favorable therapeutic index than cisplatin, particularly with regard to nonhematologic toxicities, and had proven activity in combination with docetaxel in phase II study; and randomized studies had shown the combination of vinorelbine plus cisplatin was superior to either vinorelbine alone or cisplatin alone and was considered as a reference study regimen in the clinical setting upon initiation of this phase III study. Preliminary results of the phase III trial showed that the overall survival among patients randomized to receive docetaxel plus cisplatin was significantly better than that among patients treated with vinorelbine/cisplatin and similar between the docetaxel plus carboplatin versus control arm. The three arms were similar for toxicity data, except the use of vinorelbine plus cisplatin was associated with a significantly greater incidence of grade (3/4) anemia and nausea and vomiting than use of docetaxel plus either cisplatin or carboplatin.

Antineoplastic Agents, Phytogenic↗

PubMed2006

Methodology of clinical trials with new molecular-targeted agents: where do we stand?

In recent years, we have witnessed growing interest in the methodology of clinical trials with molecular-targeted agents. In phase I studies, alternative end points to toxicity have been proposed to define the optimal biological dose: the identification of a 'target effect', the measurement of 'surrogates' for biological activity and the assessment of drug plasma levels. However, these end points are not routinely incorporated into the study design and have rarely formed the primary basis for dose selection. In phase II studies, response rate remains the preferred end point in the early evaluation of new drugs. However, this approach might lead to rejection of potentially useful drugs when significant tumor shrinkage cannot be demonstrated. Therefore, a number of alternative end points have been proposed for agents that are not expected to cause a major tumor regression: time to progression, progression-free survival, overall survival, early progression rate and growth modulation index. In phase III trials, where efficacy in terms of survival remains the most important goal of the research, the major issues are the adequate selection of patients and the optimal clinical setting of evaluation of drugs. In conclusion, many important questions regarding the methodology of clinical research with target-based agents remain open and need to be defined by research in the near future.

Antineoplastic Agents↗

PubMed1994

Investigational drug tracking: phases I-III and NDA submissions--Part II.

The author catalogs over 800 investigational drugs/biologicals currently in Phase I, II or III clinical trials or drugs/biologicals submitted to the FDA as new drug applications. Part I of this article appeared in the September issue of Hospital Pharmacy. The list assists in predicting when new drugs will be marketed. The entries include generic/chemical name, investigational drug number, synonyms, trade names, manufacturers, clinical trial status, predicted approval year, indications or drug class, whether the drug has been developed through biotechnology, and references. Entries were gleaned from medical journals, stock market analysis publications, and the Pharmaceutical Manufacturers Association's Medicines in Development Series. The list is alphabetized by the generic/chemical name or investigational drug number and cross-indexed by the trade name and synonyms. The list reflects those drugs which were not FDA approved as of April 15, 1994. Part I concludes with the remaining alphabetical listing by generic/chemical name or investigational drug number.

Clinical Trials, Phase I as Topic↗

PubMed1997

Drug research: from the idea to the product.

The path of a new drug from the idea to product may be divided into 2 phases, namely drug discovery and drug development. In drug discovery a dramatic change is taking place. Due to a remarkable progress in understanding and explaining the underlying cause of many diseases by identifying and sequencing the genes encoded within DNA, it has become possible with new methods, like molecular biology or gene technology, to develop simple test assays by which a large number of compounds may be tested in regard to their biological efficacy. Automation of these test systems utilizing computer-controlled robotic systems has made it possible to evaluate up to 1 million substances per robot per year on their biological effect. While the classical medicinal chemistry cannot produce such a large number of new compounds, combinatorial chemistry may offer the opportunity to screen large numbers of novel compounds rapidly and to reduce the time taken to identify drug candidates substantially. Overall, it is estimated that combinatorial chemistry techniques have resulted in a reduction in the time taken to identify drug candidates of between 18-24 months. In drug development 2 partly overlapping phases can be differentiated, namely the preclinical and clinical phase. During the first part of drug development necessary requirements for first use in man are met by performing preclinical pharmacological, toxicological, and pharmacokinetic investigations in the animal and in in vitro testing. These investigations are playing a central part for the benefit/risk evaluation of new drugs. Only if the risks connected to the clinical study are medically justifiable in relation to the likely therapeutic benefit of the compound, the clinical trial may basically take place under consideration of the legal requirements of the country in which the study is carried out. In drug research clinical pharmacology is the connecting link between preclinical and clinical research. Clinical pharmacology produces the necessary basis for the clinical trial of a new substance in the patient with the target indication. After a first clinical-pharmacological profile of the new substance has been established during phase I on the basis of which a decision for the continuation of the clinical trial and the probable effective dose range and dosing interval is made, the aim of phase II-IV is now to answer the important questions of the therapeutic efficacy and tolerability in a large number of patients with the target indication. Only with a very careful drug investigation during phase I-IV it is really possible to register the therapeutic risk and benefit of a new drug and to control resulting serious problems. An analysis of registered drugs during the last years shows that despite enhanced efforts and dramatically rising development costs the innovation potential of the classical approach is steadily decreasing. Therefore, it is absolutely necessary to develop new innovative drugs with the help of new technologies like molecular and cell biology, gene technology, or immunology as well as combinatorial chemistry and robot supported substance screening.

Animals↗

PubMed2004

Discovery, Development, and clinical applications of bortezomib.

Proteasome inhibition is a novel, targeted approach in cancer therapy. Both natural and synthetic proteasome inhibitors selectively penetrate cancer cells, disrupting the orderly destruction of key regulatory proteins involved in tumorigenesis and metastasis. Disrupting the orderly destruction of regulatory proteins causes an imbalance of these proteins within the cell, which interferes with the systematic activation of signaling pathways required to maintain tumor cell growth and survival; therefore, cellular replication is inhibited and apoptosis ensues. Bortezomib (PS-341, Velcade), the first proteasome inhibitor evaluated in human clinical trials, has been approved by the US Food and Drug Administration for use in patients with refractory or relapsed multiple myeloma. Preclinical study results show that bortezomib suppresses tumor cell growth, induces apoptosis, overcomes resistance to standard chemotherapy agents and radiation therapy, and inhibits angiogenesis. Phase I study results established the antitumor activity of bortezomib, administered alone or in combination with standard chemotherapy agents, in patients with advanced hematologic malignancies or solid tumors, usually without additive toxicities. The results of phase II studies further supported the antitumor activity of bortezomib in patients with refractory or relapsed multiple myeloma and non-Hodgkin's lymphoma; less impressive results were observed in patients with stage IV renal cell cancer. Studies evaluating bortezomib in earlier stages of multiple myeloma, including first-line therapy, are under way. Evidence suggests that certain prognostic factors, such as older age and bone marrow containing more than 50% plasma cells, may be useful in predicting response and survival time in multiple myeloma patients receiving bortezomib. Further studies of bortezomib are needed to establish its full spectrum of activity, the ideal regimens for various tumor types, and clinically useful prognostic indicators that predict successful outcomes.

Animals↗

PubMed2005

Gefitinib (ZD1839, Iressa) in non-small-cell lung cancer: a review of clinical trials from a daily practice perspective.

Gefitinib (ZD1839) is the most widely studied targeting agent in the area of non-small-cell lung cancer (NSCLC). Gefitinib is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor. In order to assess the role of gefitinib in the management of NSCLC patients, we systematically reviewed published clinical trials from a daily practice perspective. A systematic research was made in the international medical literature. Gefitinib demonstrated a good tolerance and an encouraging efficacy in pretreated NSCLC patients in preclinical studies. These results were then confirmed in two phase II trials (IDEAL 1 and 2) involving more than 400 patients mostly pretreated with a platinum-containing regimen and docetaxel. All these results were reinforced by those of retrospective studies on patients enrolled in a compassionate use programme. Thus, two phase III trials in chemo-naive patients were initiated (INTACT 1 and 2). Unfortunately, the use of gefitinib with standard combination chemotherapy provided no survival benefit nor response rate or progression-free survival improvement over placebo. Furthermore, we also reviewed the results of studies interested in the characterization of predictive clinical or biological markers for response to gefitinib and discussed the results obtained with other EGFR inhibitors. The efficacy of gefitinib in the first-line setting of each stage of NSCLC has to be further studied through clinical trials. Furthermore, translational studies characterizing the molecular features involved in the response to anti-EGFR-targeted therapies are needed.

Adult↗