Phase II study of the antiangiogenesis agent thalidomide in recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Thalidomide has been shown to have antiangiogenic effects in preclinical models as well as a significant antitumor effect in hematologic tumors such as multiple myeloma. The authors performed this Phase II study to determine the activity, toxicity profile, and antiangiogenic effect of thalidomide in patients with locoregionally recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: Twenty-one patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with single-agent thalidomide. All patients had received radiation therapy, and most had undergone surgery (95%) and/or chemotherapy (90%). Thalidomide was initiated at 200 mg;3>daily and increased to a target dose of 1000 mg daily. Patients continued treatment until disease progression, unacceptable toxicity, or death occurred. RESULTS: All 21 patients eventually developed progressive disease. Median time to progression was 50 days (95% confidence interval, 28-70), with median overall survival time of 194 days (95% lower confidence boundary, 151), similar to the progression and survival times reported for this patient group with other agents. Thalidomide was generally well tolerated, with few patients experiencing Grades 3 to 4 toxicities. Serum vascular endothelial growth factor and basic fibroblast growth factor levels increased in six of seven patients, for whom paired serum samples were available and all of whom had progressive disease. CONCLUSIONS: In this heavily pretreated population of patients with advanced squamous cell carcinoma of the head and neck, thalidomide does not appear to have single-agent antitumor activity. Further evaluation of the mechanism of action of thalidomide is indicated. Potentially, future evaluations of thalidomide may be performed in combination with other antiangiogenic or cytotoxic agents in patients with earlier stage disease or in patients with minimal residual disease.

Approaches to preclinical screening of antiangiogenic agents.

Angiogenesis, or new blood vessel growth, is essential for the growth, invasion, and metastasis of solid tumors. The inhibition of this process, or antiangiogenesis, is a promising new therapeutic anticancer strategy. Several antiangiogenic compounds are currently in preclinical or clinical development for the treatment of cancer. However, the challenge for the discovery and characterization of antiangiogenic targets remains in developing efficient in vitro or in vivo preclinical angiogenesis screening assays to assess and compare antiangiogenic activity. Several semiquantitative or quantitative angiogenesis assays exist, including in vitro endothelial cell systems and ex vivo or in vivo neovascularization models utilizing mouse, rat, or human tissues. We describe the more common and cost-effective angiogenesis assays currently in use, summarizing their unique advantages and disadvantages. Since angiogenesis inhibition is a novel therapeutic modality towards controlling solid tumors, antiangiogenic drug development underlines the importance in describing, standardizing, and developing quantitative screening assays for the next generation of antiangiogenic agents.

A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer.

PURPOSE: Thalidomide is a potent teratogen that causes dysmelia in humans. Recently, in vitro data suggested that it inhibits angiogenesis. Prostate cancer is dependent on the recruitment of new blood vessels to grow and metastasize. Based on those data, we initiated a Phase II trial of thalidomide in patients with metastatic androgen-independent prostate cancer. EXPERIMENTAL DESIGN: This was an open-label, randomized Phase II study. Thalidomide was administered either at a dose of 200 mg/day (low-dose arm) or at an initial dose of 200 mg/day that escalated to 1200 mg/day (high-dose arm). RESULTS: A total of 63 patients were enrolled onto the study (50 patients on the low-dose arm and 13 patients on the high-dose arm). Serum prostate-specific antigen (PSA) decline of > or = 50% was noted in 18% of patients on the low-dose arm and in none of the patients on the high-dose arm. Four patients were maintained for > 150 days. The most prevalent complications were constipation, fatigue, neurocortical, and neurosensory. CONCLUSION: Thalidomide, an antiangiogenesis agent, has some activity in patients with metastatic prostate cancer who have failed multiple therapies. A total of 27% of all patients had a decline in PSA of > or = 40%, often associated with an improvement of clinical symptoms. Because our preclinical studies had shown that thalidomide increases PSA secretion, we believe that the magnitude of PSA decline seen in our trial justifies further study.

Drug-induced lupus associated with COL-3: report of 3 cases.

BACKGROUND: Anti-angiogenesis is an exciting new approach to anticancer therapy. COL-3, a tetracycline derivative, is a novel anti-angiogenesis agent with potent preclinical anticancer activity. During the conduct of a phase 1 clinical trial for refractory metastatic cancer at the National Institutes of Health, we observed 3 individuals who developed phototoxicity followed by clinical and laboratory features of drug-induced lupus. OBSERVATIONS: Three of 35 patients treated with COL-3 developed sunburnlike eruptions accompanied by fever and a positive antinuclear antibody titer within 8 to 29 days of starting treatment. Two of 3 had positive antihistone antibody levels and arthralgia. One patient had marked systemic manifestations including pulmonary infiltrates and elevated erythrocyte sedimentation rate remittent for more than 1 year after discontinuing COL-3 treatment. The other 2 patients' symptoms and rash abated within 2 weeks of discontinuing therapy although the serologic markers remained abnormal for the duration of follow-up. CONCLUSIONS: COL-3 is the second tetracycline derivative to be implicated in the development of drug-induced lupus. A sunburnlike eruption immediately preceded or accompanied the systemic and serologic changes in these 3 patients. The rapid onset and the phototoxic appearance of the accompanying eruptions might suggest that damage to the keratinocytes caused the formation of neoantigens to which autoantibodies formed.

Reversible sideroblastic anemia associated with the tetracycline analogue COL-3.

Eight of 35 patients with cancer receiving COL-3, a tetracycline derivative with antiangiogenic properties, developed anemia while on treatment. All of these patients were enrolled on an approved Phase I clinical trial at the National Cancer Institute. Three of these patients had bone marrow examinations that revealed ringed sideroblasts. This paper describes these cases. Am. J. Hematol. 67:51-53, 2001. Published 2001 Wiley-Liss, Inc.

Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer.

PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.

Clinical trial designs for cytostatic agents: are new approaches needed?

Preclinical data suggest that some new anticancer agents directed at novel targets demonstrate tumor growth inhibition but not tumor shrinkage. Such cytostatic agents may offer clinical benefits for patients in the absence of tumor shrinkage. In addition, lower doses of some of these agents may be just as effective as higher doses, implying that toxicity may not be an ideal end point for dose finding. Because of these factors, the sequence and design of traditional phase I, II, and III trials used for cytotoxic agents (which typically shrink tumors and in a dose-dependent manner) may not be appropriate for cytostatic agents. This article discusses options for modifying trial designs to accommodate cytostatic agents. Examples are given where these options have been tried or are currently being tried. Recommendations given for choosing among the trial designs depend on what is known preclinically about the agents (eg, does one have a validated and reproducible biologic end point that can be used to guide a dose escalation?), what is known about the patient population being studied (eg, does one have a well-documented historical progression-free survival rate at 1 year for comparison with the experience of the new agent?), and the numbers of agents and patients available for participation in trials. Planned and ongoing trials will test the utility of some of these new approaches.

Phase II evaluation of thalidomide in patients with metastatic breast cancer.

PURPOSE: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. RESULTS: No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. CONCLUSION: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.

Activity of thalidomide in AIDS-related Kaposi's sarcoma.

PURPOSE: To assess the toxicity and activity of oral thalidomide in Kaposi's sarcoma (KS) in a phase II dose-escalation study. PATIENTS AND METHODS: Human immunodeficiency virus (HIV)-seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed. RESULTS: Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm(3) (range, 14 to 646 cells/mm(3)) were enrolled. All patients were assessable for toxicity, and 17 for response. Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease. Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response was 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months. CONCLUSION: Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.

High-performance liquid chromatography with mass spectrometry detection for quantitating COL-3, a chemically modified tetracycline, in human plasma.

COL-3, 6-deoxy-6-demethyl-4-dedimethylamino-tetracycline, is a matrix metalloproteinase inhibitor. A specific and sensitive analytical method was necessary to quantitate the analyte in human plasma. High-performance liquid chromatography with atmospheric pressure chemical ionization mass spectrometry detection was utilized to quantitate COL-3 from 30 to 10,000 ng/ml in two calibration curves: 30-1,500 and 400-10,000 ng/ml. The sample preparation consisted of acetonitrile precipitation for all plasma samples. COL-3 is separated on a Waters Symmetry C-18 (2.1 x 150 mm) column with oxalic acid (0.01 M, pH 2.2)-acetonitrile mobile phase. The total run time was 23 min. Identification of COL-3 and the internal standard was through positive chemical ionization and selective ion monitoring. A quantifying and qualifying ion for COL-3 is used to verify the presence of COL-3 in patient samples. Inter- and intra-run mean percent errors for all of the quality controls were less than 18.3', and relative standard deviations were all less than 14.9'% Recovery of COL-3 and the internal standard was approximately 55 and 72', respectively. Freeze thaw stability of COL-3 was variable. This method is suitable for quantifying COL-3 in patient samples and to further characterize the clinical pharmacology of this compound.

Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.

PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.

A pharmacokinetically guided Phase II study of carboxyamido-triazole in androgen-independent prostate cancer.

We conducted a Phase II clinical trial of the antiproliferative, antimetastatic, and antiangiogenic agent carboxyamido-triazole (CAI), using pharmacokinetic assessment to guide drug dosing. Fifteen patients who had stage D2 androgen-independent prostate cancer with soft tissue metastases were enrolled. Because CAI previously had been shown to decrease prostate-specific antigen secretion in vitro, this marker was not used to assess disease status. The dose of CAI used in this study was calculated so that plasma steady-state maximum concentrations between 2.0 and 5.0 microg/ml would be maintained. Following the initial dosage adjustment, 93% (14 of 15) of patients were within the predicted range. Fourteen of 15 patients were evaluable for response. All of the 14 evaluable patients demonstrated progressive disease at approximately 2 months. Twelve patients progressed by computed tomography and or bone scan at 2 months, whereas two patients demonstrated clinical progression at 1.5 and 2 months. One patient was removed from study at 6 weeks due to grade II peripheral neuropathy lasting >1 month. Although no clinical responses were noted, a 27.7% decrease in serum vascular endothelial growth factor concentration was observed. CAI does not possess clinical activity in patients with androgen-independent prostate cancer and soft tissue metastases. Pharmacokinetically guided dosing, although found to be feasible using a Bayesian approach, was not found to be of practical benefit. Although plasma CAI concentrations were maintained within the designated range, grade III toxicity requiring drug discontinuation was still observed.

O6-benzylguanine: a clinical trial establishing the biochemical modulatory dose in tumor tissue for alkyltransferase-directed DNA repair.

Early phase evaluation of anticancer drugs has traditionally used toxicity (usually hematological) rather than efficacy end points to establish appropriate dosing schedules. To establish a biochemical efficacy end point for overcoming alkylguanine DNA alkyltransferase (AGT)-mediated tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea, we performed a novel dose escalation clinical trial for the AGT-depleting agent O6-benzylguanine (BG). The dose of BG required to deplete AGT to undetectable levels (BMD(T)) in sequential computed tomography-guided tumor tissue biopsies before BG and 18 h after BG was determined. Thirty patients received doses of BG ranging from 10 to 120 mg/m2. In tumor tissue, AGT depletion >86% of baseline was demonstrated at all doses tested. Residual tumor AGT activity, present 18 h after BG doses of 10-80 mg/m2, was eliminated at the 120 mg/m2 dose and is thus the BMD(T) of BG. BG pharmacokinetics are characterized by the rapid, dose-independent clearance of BG from plasma Metabolism of BG to its biologically active metabolite, 8-oxo-benzylguanine (8-oxo-BG), was found. The t(1/2) of 8-oxo-BG is longer than BG. Plasma concentrations of 8-oxo-BG well above 200 ng/ml 18 h after the end of the BG infusion were observed at the highest dose levels tested and appeared to correlate with depletion of AGT activity to undetectable levels in tumor tissue. AGT activity in peripheral blood mononuclear cells at baseline did not correlate with tumor tissue AGT activity. Depletion of AGT activity to undetectable levels in peripheral blood mononuclear cells occurred at lower doses and was not a reliable predictor for tumor tissue depletion. No serious side effects were observed with administration of BG alone or in combination with 13 mg/m2 1,3-bis(2-chloroethyl)-1-nitrosourea. This is the first clinical study in which biochemical analyses from pre- and posttreatment tumor biopsies have been used as an efficacy end point for the clinical development of an anticancer agent. From our tumor tissue biopsy data, we have established that a BG dose of 120 mg/m2 infused over 1 h should be used in Phase II clinical trials.

The challenge of designing clinical trials for AIDS-related Kaposi's sarcoma.

Kaposi's sarcoma (KS) is a frequent cause of morbidity and mortality in patients with human immunodeficiency virus (HIV) infection. Several characteristics of KS pose challenges for the conduct of clinical trials. Kaposi's sarcoma patients often have multiple, irregularly shaped lesions, making accurate assessment of tumor size difficult. The lesions may have varying degrees of nodularity. Involvement of the lung or other visceral organs often consists of multiple irregular lesions. Conventional oncology staging systems cannot be applied effectively to KS because there is no clear primary lesion. Kaposi's sarcoma is affected by the status of the underlying HIV infection, and there are reports of KS lesions regressing in response to effective antiretroviral therapy. A system for staging and response assessment in KS, developed by the AIDS Clinical Trials Group (ACTG), has proven to be a useful tool for the conduct of trials in KS. A newer system that also attempts to assess patient benefit in response to therapy is now being developed by the National Cancer Institute, FDA, and AIDS Malignancy Consortium. These tools, as well as careful methodology in the conduct of clinical trials, should help optimize the clinical development and evaluation of new therapies for KS.

Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi's sarcoma.

PURPOSE: To investigate the antitumor activity and safety of paclitaxel in patients with advanced human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS). PATIENTS AND METHODS: Twenty-nine patients with advanced HIV-associated KS were enrolled. The patients were overall quite immunosuppressed (median CD4 count, 15 cells/microL). Paclitaxel was initially administered at 135 mg/m2 over 3 hours every 3 weeks without filgrastim support; the dose was increased as tolerated to a maximum of 175 mg/m2. Patients who failed to respond or progressed could then receive filgrastim support or paclitaxel administered over 96 hours. RESULTS: Of 28 assessable patients, 20 had major responses (18 partial responses [PRs], one clinical complete response [CR], and one CR), for a major response rate of 71.4% (95% confidence interval [CI], 51.3% to 86.8%). Each of the five patients with pulmonary KS responded, as did all four assessable patients who had previously received anthracycline therapy for KS. Of six patients who went on to receive a 96-hour infusion of paclitaxel, five had major responses. Neutropenia was the most frequent dose-limiting toxicity; possible novel toxicities included late fevers, late rash, and eosinophilia. Two patients developed an elevated creatinine concentration and one cardiomyopathy. CONCLUSION: Paclitaxel has substantial activity against advanced HIV-associated KS as a single agent, even in patients with pulmonary involvement or who had previously received anthracyclines. Further research is needed to define the optimal treatment schedule and its role vis-a-vis the other available therapies for this disease.

Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

PURPOSE: To define, in a phase I study in relapsed non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), the maximum-tolerated dose (MTD), major toxicities, and possible antitumor activity of bryostatin 1, a macrocyclic lactone. PATIENTS AND METHODS: Bryostatin 1 was delivered by 72-hour continuous infusion every 2 weeks to patients with relapsed NHL or CLL, at doses that ranged from 12 microg/m2 to 180 microg/m2 per course. Correlative investigations included evaluations of total protein kinase C (PKC) in peripheral blood and lymphoid differentiation in patient tumor tissue. RESULTS: Twenty-nine patients were treated, including three patients with CLL and 26 with NHL. Generalized myalgia was the dose-limiting toxicity (DLT) and occurred in two of three patients treated with bryostatin 1 at 180 microg/m2 per course. Myalgias were dose-related and cumulative, and often started in the thighs and calves, improved with activity, were somewhat responsive to analgesics, and often took weeks to resolve once taken off study. Six patients were treated at the MTD of 120 microg/m2 per course. Myalgia, headache, and fatigue were common. Hematologic toxicity was uncommon. Total cumulative doses of bryostatin 1 up to 1,134 microg/m2 have been administered without untoward toxicity. Eleven patients achieved stable disease for 2 to 19 months. An in vitro assay for total PKC evaluation in patient peripheral-blood samples demonstrated activation within the first 2 hours with subsequent downregulation by 24 hours, which was maintained throughout the duration of the 72-hour infusion. CONCLUSION: This phase I study defined the MTD and recommended phase II dose of bryostatin 1, when administered over 72 hours every 2 weeks, to be 120 microg/m2 (40 microg/m2/d for 3 days). Generalized myalgia was the DLT. Future studies will define the precise activity of bryostatin 1 in subsets of patients with lymphoproliferative malignancies and its efficacy in combination with other agents.

Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies.

Compelling data implicate angiogenesis and tumor-associated neovascularization as a central pathogenic step in the process of tumor growth, invasion, and metastasis. These complex processes involve multiple steps and pathways dependent on the local balance between positive and negative regulatory factors, as well as interactions among the tumor, its vasculature, and the surrounding extracellular tissue matrix. A tumor remains in a dormant state, the cellular proliferation rate balanced by the apoptotic rate, unable to grow in size beyond a few millimeters in the absence of the acquired angiogenic phenotype. The mechanism by which tumors switch to the angiogenic phenotype is unknown. Therapeutic agents and strategies are being devised either to interrupt or inhibit one or more of the pathogenic steps involved in the process of tumor neovascularization or to directly target and destroy the tumor vasculature. Therapies affecting an end target or pathway that cannot be circumvented by alternate mechanisms may significantly enhance efficacy and broaden applicability. These approaches may result in small, avascular tumors maintained in a dormant state or, perhaps in combination with cytotoxic therapies, they may potentiate shrinkage of tumors to, and maintain them, in a dormant state. As more powerful antiangiogenic agents are developed, perhaps even these dormant microscopic foci may be eradicated. Antiangiogenesis agents and strategies differ from the usual cancer therapeutic approaches; therefore, investigators must devise new paradigms for the clinical development of agents that may only have a static effect on tumors and require prolonged, chronic administration. Methods to assess the in vivo biologic activity of these compounds in patients are needed. Ultimately, antiangiogenic therapy may provide an additional novel cancer treatment suitable for combination with standard therapies.

Promising new agents under development by the Division of Cancer Treatment, Diagnosis, and Centers of the National Cancer Institute.

The Division of Cancer Treatment, Diagnosis and Centers of the National Cancer Institute (NCI) has a large program in clinical cancer therapeutics development. It currently holds investigational new drug applications for nearly 200 agents with which it sponsors clinical trials. In addition, it has a major preclinical development program. With the tremendous advances in our understanding of molecular and tumor biology during the past decade, the NCI's portfolio of agents has expanded beyond classical cytotoxic agents to include a wide variety of new molecular and therapeutic targets. In addition to agents with more conventional mechanisms of action, the NCI has targeted therapeutics programs that focus on tumor vasculature, cell cycle control and cell signaling, mechanisms of apoptosis, invasion and metastasis, and immunological recognition and response. Each of these focused areas includes agents of different classes and modes of action that are all directed at the target of interest. The scope of the NCI's program allows it to respond to incorporate promising new agents or targets as they arise and to prioritize them for use of preclinical and clinical resources. Agents in development through the NCI are derived from a number of diverse sources including its own screening efforts, academia, and numerous collaborations with the pharmaceutical and biotechnology industries. NCI works closely with collaborators to ensure complementary, non-duplicative clinical development and attempts to ensure that the full potential of promising agents is explored. A number of compounds in early clinical development or about to enter the clinic are discussed briefly in this manuscript.