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The development of a safe, effective preventive vaccine for human immunodeficiency virus (HIV) infection remains an area of vigorous research. Several highly innovative vaccine candidates are being developed, and more than 13 vaccine candidates have been tested in human phase I or II trials. All have produced antibody and several have produced modest neutralizing titers, but to date no reproducible evidence has suggested prolonged, high-titer neutralization across a diversity of HIV strains. Furthermore, only the live recombinant vector approaches have produced some evidence of cytotoxic T-cell responses. The principal obstacle to progress is the lack of definitive information on what constitutes a protective immune response. There is no animal model for HIV-induced disease. Hence, the identification of the correlates of immunity and more useful animal models is among the highest priorities for HIV vaccine research. Large-scale efficacy trials raise daunting scientific, ethical, and resource issues. Nonetheless, preparation in such trials is underway in order to be in a position to evaluate the most promising vaccine candidate. [ABSTRACT FROM AUTHOR]

Since the discovery of human immunodeficiency virus (HIV) in 1983, significant progress has been made toward the discovery, development, and licensing of anti-HIV drugs. In vitro screens against whole virus are now being complemented by screens against specific viral targets, resulting in the development of clinical candidates acting at several critical stages of the viral life cycle. Despite these advances, clinical therapy remains largely palliative. In addition, it has recently been recognized that HIV resistance to most drugs may pose even greater obstacles. Moreover, emerging data on immunopathogenesis raise the possibility that even if virus was eliminated from an infected individual, the patient's immune system might not be capable of restoration to normal function. In the face of such obstacles, deeper insights into the pathogenic mechanisms of disease, aggressive exploitation of those mechanisms for therapeutic gain, and continued commitment of both public and private sectors to support and collaborate in this research are needed.

Anticipating the availability of one or more candidate HIV vaccines for efficacy testing in the next few years, public health agencies are now planning for the conduct of large-scale efficacy trials. We expect these trials to be randomized, double-blind, placebo-controlled studies with prevention of infection as the primary goal. We discuss in detail factors that influence sample size. Factors most influential are the incidence rate of HIV infection in the study population and the minimum efficacy at which a vaccine is still considered acceptable. The smaller either of these factors is, the larger the sample size will be. The desire to complete trials quickly, the gradual accrual of benefit from vaccination, the inaccuracies of assays to detect infection, the need to counsel participants to avoid exposure to HIV, and loss to follow-up all tend to drive up sample size. To illustrate, 83 subjects per study arm suffice to detect 90% efficacy in a population with a 7% annual risk of infection. This assumes a 3-year study with accrual completed in 1 year, no loss to follow-up, and Types I and II error rates of 5 and 10%, respectively. In contrast, 4,254 subjects per arm are required to identify a 60% effective vaccine in a population with a 1% annual risk. The study is also shortened to 2 years, assumes a 5% annual loss to follow-up, and supposes that the full benefit of vaccination is achieved in 6 months. The most realistic assumptions indicate that trials are very likely to require several thousand participants. Limitations of the proposed designs are also discussed.

Randomized clinical trials are being conducted and/or sponsored by all scientific divisions of the National Institute of Allergy and Infectious Diseases (NIAID). External committees to review the progress of ongoing trials and to make recommendations to the Institute concerning continuation or termination are an integral part of many of these trials. These committees have evolved considerably from the ad hoc committees, called together when a need arose, which were used beginning in the mid 1970s. Currently, there are many monitoring committees operating for NIAID-sponsored trials. They function in a variety of ways, based partially on historical precedent and partially on the specialized requirements of the particular trial; there is no 'standard operating procedure' for the Institute, or even for divisions within the Institute. One of the major issues faced in establishing the data and safety monitoring board for AIDS treatment trials was access to the meetings of this board and to the reports of interim data that the board reviewed. After much discussion, procedures were established that restrict such access to a very limited group of programme and statistical centre staff. These procedures, while remaining controversial, appear necessary to ensure confidentiality and the integrity of the clinical trials process.

The clinician's armamentarium is no longer limited to zidovudine as the only antiretroviral agent that enhances both quality and length of life. ddI has shown clinical benefit in patients previously treated with zidovudine. Recently, the combination of zidovudine and ddC has been approved on the basis of surrogate marker activity; its clinical role awaits results of ongoing trials.

Infections and malignancies account for most deaths in patients with AIDS and will continue to do so as long as HIV-induced immunosuppression is progressive and irreversible. Co-trimoxazole has emerged as the preferred agent for prevention of Pneumocystis carinii pneumonia. As appropriate broad-spectrum agents are developed, multiple opportunistic pathogen prophylaxis could become effective.

Infections and malignancies account for most deaths in patients with AIDS--and will continue to do so as long as HIV-induced immunosuppression is progressive and irreversible. Options available for prevention and improved management of such diseases are changing as new agents emerge, new combinations of agents are developed, and new indications for available agents are identified.

Zidovudine has proved to be an important palliative agent in all stages of HIV infection. It delays progression of disease in patients with asymptomatic or mildly symptomatic infection and decreases the frequency and severity of opportunistic disease in those with AIDS. The search for other, more effective antiretroviral agents goes on, with some promising possibilities.

In a single decade, the pandemic of human immunodeficiency virus (HIV) infection has become an international health, social, and economic emergency. Early and effective intervention is urgently needed for both prevention of HIV infection and for the amelioration of clinical disease. Results of therapeutic trials have suggested expanding the population for which chemotherapy is indicated. In this paper, we first review the findings from selected recent drug trials, using zidovudine and pentamidine as examples. We then discuss six issues that we believe to be crucial for future epidemiologic research in the service of vaccine and drug development: 1. To identify which complications of HIV infection most urgently require development of new therapies, we must characterize the frequency and severity of specific medical events (outcomes) in persons taking a variety of treatments. 2. Currently, acquired immunodeficiency syndrome (AIDS) therapeutic trials gauge the effectiveness of new therapies by their impact on such clinical parameters as the time to development of AIDS or death. These approaches take too long to provide information. We urgently need to identify surrogate markers of clinical outcome that will be useful in the early assessment of treatment efficacy. 3. Progress in vaccine development is being retarded because we do not have enough data from natural history studies on host immunologic responses to suggest that a given response is protective. We therefore need to identify natural correlates of immunity, which can help set priorities in vaccine development. 4. Discovery that a therapy works in the setting of a clinical trial is only a first step in intervention. We must also assess the impact of new therapies on the health of the public, evaluating access to health care, compliance, and other barriers to treatment. 5. Clinical trials are usually associated with the effort to prevent disease in infected persons. However, other trials are needed to assess efforts to interrupt viral transmission through use of condoms, use of virucides, and treatment of sexually transmitted diseases, and by effecting specific behavioral changes. 6. Traditional methods of conducting clinical therapeutic research may not be adequate to address urgent questions in the AIDS/HIV epidemic. We must develop innovative clinical research methods, including better use of data from observational studies, to infer what we can about the effect of treatment on the clinical course.

Flavone acetic acid (FAA) is a synthetic flavonoid compound which has recently begun clinical trials as an antitumor agent based on its striking activity in solid tumor model systems. The pharmacologic behavior of FAA in animals appears to be predictive of both its cytotoxic efficacy and its toxicity to normal tissues (principally the central nervous system and gastrointestinal tract). The design and conduct of phase I studies in man are based upon these principles, with the goal of maximizing their safety and efficacy.

N-methylformamide (NMF), a polar solvent, is currently being evaluated by the National Cancer Institute (NCI) as an antineoplastic agent because of its activity against colon, mammary, and lung tumor xenografts. Results from preclinical studies suggest that it has radiosensitizing, chemosensitizing, and differentiating activity. Its mechanism of action remains unknown, but may involve cellular depletion of glutathione, cell membrane changes, or modulation of proto-oncogene expression. Preclinical toxicology studies conducted in mice, rats, and beagle dogs showed reversible hepatotoxicity to be dose-limiting. Clinically, NMF is administered both orally and by intravenous (IV) injection. The bioavailability with oral administration is 90% to 95%. The highest reported plasma concentration of NMF is approximately 4 mmol/L in a patient who received a dose of 2,000 mg/m2 of IV NMF. Biphasic elimination with IV NMF is seen on both the daily for five days and weekly for 3 weeks schedule. Approximately 5% to 7% of the total administered IV dose is excreted in the urine. In phase I studies, dose-limiting toxicities included reversible hepatotoxicity, a generalized malaise syndrome, and nausea and vomiting. One partial response has been reported in the 111 patients treated on phase II trials in colorectal, head and neck, and renal carcinomas. Suggestions for the future development of this drug are presented.

Pyrazole (NSC-45410) is a low molecular weight, heterocyclic compound which has been considered for reevaluation in the clinic as a potential cytotoxic agent (Fig. 1). Discovered in 1893, pyrazole is best known as an inhibitor of liver alcohol dehydrogenase (ki = 0.2 uM), and as a result, has been used extensively in studies of alcohol metabolism. In 1960, pyrazole was identified as being active in preclinical antitumor models, which led to preliminary clinical testing. The early Phase I studies were not followed by disease specific Phase II trials, and the clinical activity of the drug has never been evaluated. This omission was noted by the National Cancer Institute's Project for the Review of Old Drugs (PROD), at which time it was also noted that pyrazole is selectively toxic to thyroid tissue in an animal model. Hence, interest in pyrazole was revived for two reasons: (a) failure to screen it for clinical activity in the 1960's, and (b) current interest in discovering drugs with selective toxicity to specific tissues for evaluation of their activity in malignancies arising in the target tissue. In this review, we summarize the evidence which has accumulated concerning pyrazole's potential role as an anticancer agent.

Diaziquone, an aziridinylbenzoquinone currently in phase II-III trials, is an alkylating agent, the major toxic effect of which is myelosuppression. We report here on six cases of hypersensitivity attributable to diaziquone. In five patients an acute reaction characterized by hypotension, bronchospasm, and urticaria was observed. In one patient a delayed urticarial rash was noted. Resolution was rapid in all patients but one, who responded to standard treatment over a period of hours. No reaction was fatal. Approximately 2000 patients have been treated with diaziquone in clinical trials sponsored by the National Cancer Institute. It is suggested that the reaction may not be to the drug itself but to the vehicle (dimethylacetamide) in which diaziquone is formulated. Studies to elucidate the relative contribution of drug and vehicle are warranted.

5-methyltetrahydrohomofolate was developed in the 1970's as an antifolate with the potential to overcome methotrexate resistance. This review summarizes the preclinical and clinical data which have accumulated to date. It is concluded that more recent, better characterized antifolates offer greater potential in achieving the goals for which this drug was introduced.

Azacitidine has been undergoing clinical trials for almost 20 years and is internationally considered to have a useful place in the treatment of acute nonlymphocytic leukemia. However, its role in the various combinations for induction, intensification, maintenance, or relapse regimens has not yet been clearly defined. This review outlines the last 10 years' clinical experience with the drug in acute nonlymphocytic leukemia, analyzes what critical information has yet to be obtained, and suggests what phase III trials may still be feasible to gather that information.

Recent advances in delineating the molecular biology of human immunodeficiency virus type 1 (HIV-1) have led to innovative approaches to development of a vaccine for acquired immunodeficiency syndrome (AIDS). However, the lack of understanding of mechanisms of protective immunity against HIV-1, the magnitude of genetic variation of the virus, and the lack of effective animal models for HIV-1 infection and AIDS have impeded progress. The testing of AIDS vaccines also presents challenges. These include liability concerns over vaccine-related injuries; identification of suitable populations for phase 3 efficacy studies; balancing the ethical obligation to counsel research subjects to avoid high-risk behavior with the necessity to obtain vaccine efficacy data; and the effect of vaccine-induced seroconversion on the recruiting and welfare of trial volunteers. Several candidate AIDS vaccines are nevertheless currently under development, and some are undergoing phase 1 clinical trials. Rapid progress will depend on continued scientific advancement in conjunction with maximum use of resources, open information and reagent exchange, and a spirit of international collaboration.

Deoxycoformycin (dCF) is a promising new antineoplastic agent in the treatment of lymphoid malignancies, particularly hairy cell leukemia (HCL). Skin toxicity in the form of a maculopapular eruption has previously been reported but has not clearly been associated with idiosyncratic reactions. We present five cases of dCF-related hypersensitivity reactions in which additional systemic manifestations indicated an allergic etiology. The value of dCF in treating lymphoid neoplasms suggests that further study of the treatment of these reactions is indicated.

The pharmacokinetics of cis-dichlorodiam-minoplatinum (II) (cisplatin) have been studied in seven patients, of whom four received the drug as a one hour infusion and three received it as a 20 h infusion. The patients receiving the drug over one hour exhibited biphasic clearance of total platinum with a rapid initial phase (8.7-22.5 min) and a prolonged second phase (30.5-106 h). Free (ultrafilterable) cisplatin was readily detectable in this group and was rapidly cleared (half-life about 22 min). The volume of distribution of the drug was 50.3-65.6 liters and it was 26.6-50% excreted in the urine in 48 h. In the patients receiving the 20 h infusion, a more complex plasma elimination curve was seen, with the appearance of a secondary peak. Free drug was not detectable in these patients and they showed less urinary excretion (21.4-25.9% at 48 h) than the one hour group. Cisplatin was bound to several plasma proteins, including albumin, transferrin, and gamma-globulin. The data indicate that cisplatin is retained in the body more extensively after a 20 h infusion than after a one hour infusion.

Five cases of hypersensitivity reactions to amsacrine are reported. These five cases are compared to the three cases previously published. Sixty-two reports on the clinical use of amsacrine in a variety of solid tumors and hematological malignancy were reviewed. Nine cases of hypersensitivity were described in the 2095 patients reported in these clinical trials. The approximate incidence of hypersensitivity to amsacrine is 0.4%.

We have tested methyl glyoxal bis-guanyl hydrazone (NSC 32946) for antitumor activity in patients with colorectal carcinoma and non-small cell bronchogenic carcinoma. The drug dose was 500 mg/m2 administered by single weekly injection, and with a provision dose escalation. No responses were seen in 38 evaluable patients with colorectal cancer, including 17 who had received no prior chemotherapy. Three responses were seen among 42 patients with bronchogenic carcinoma. These included one each with epidermoid carcinoma, adenocarcinoma and large cell anaplastic carcinoma. None of these responders had received prior chemotherapy. Toxicity of the drug was predominantly gastrointestinal, namely nausea, vomiting and diarrhea, and tended to increase with repeated drug doses. Neurologic symptoms of various sorts were also prominent. We conclude that methyl-G is of marginal benefit in this dose and schedule to patients with bronchogenic carcinoma.

Promising results in the treatment of indolent lymphomas have been reported with the use of 2'deoxycoformycin. This antimetabolite, an adenosine deaminase inhibitor, also shows particular efficacy in hairy cell leukemia. Of 65 patients treated to date, 44 have achieved complete and lasting remission after a limited course of deoxycoformycin. While results are not as striking as those in hairy cell leukemia, deoxycoformycin may also be a valuable adjunct to alkylating agents in the treatment of CLL. The drug also is being studied in the treatment of mycosis fungoides and other lymphoid neoplasms. Side effects in all neoplasms are dose- and schedule-dependent.

Arabinosyl-5-azacytosine is a new compound which has been selected by the Division of Cancer Treatment, National Cancer Institute for clinical development as an antineoplastic agent based on its high degree of activity against a broad range of tumor types in preclinical studies. Therapeutic activity has been observed against murine and human leukemias, transplantable murine solid tumors, and human tumor xenografts. Arabinosyl-5-azacytosine exhibited a broader spectrum of activity against human solid tumors than cytosine arabinoside. Arabinosyl-5-azacytosine is phosphorylated to the nucleotide level by deoxycytidine kinase. Upon further anabolism to the triphosphate level, it can be incorporated into DNA. The mechanism of cytotoxicity is thought to be related to inhibition of DNA synthesis. Leukemic and solid tumor cell lines that are resistant to cytosine arabinoside due to deletion of deoxycytidine kinase activity are cross-resistant to arabinosyl-5-azacytosine. Unlike cytosine arabinoside, arabinosyl-5-azacytosine does not readily undergo deamination. Schedule dependence has been demonstrated in mice bearing L1210 leukemia, with superior activity seen with multiple doses administered on each treatment day compared to administration of larger but less frequently administered doses. From preliminary data in solid tumor models, however, antitumor activity did not appear to be superior with continuous infusion compared to that observed on a bolus schedule. Preclinical toxicology studies indicated that the bone marrow and gastrointestinal tract were the main target organs. A single large dose of arabinosyl-5-azacytosine could be tolerated by both mice and dogs. When administered as a continuous infusion, the toxicity was related to both the dose and duration of exposure, suggesting that toxicity resulted from a critical time above a threshold concentration as opposed to the total area under the concentration-time curve. Phase I clinical trials have been initiated to determine the maximum tolerated dose on a low dose continuous infusion schedule for 72 hours and also on a high dose short infusion daily times five schedule.

A new antimetabolite, 2'-deoxycoformycin (pentostatin), has striking antitumor activity in several lymphoid neoplasms. Isolated from cultured soil organisms, this purine analogue is a potent inhibitor of adenosine deaminase (ADA), and is thus selectively toxic to lymphocytes. Early clinical trials showed that high doses of pentostatin caused severe and unpredictable toxicity, but responses in refractory lymphoid malignancies were encouraging. Careful pharmacologic studies led to the definition of a safe and effective low weekly dose, at which protracted ADA inhibition occurs in neoplastic cells. The most sensitive tumor identified is hairy cell leukemia, in which durable remissions are achieved in more than 90% of patients with a relatively brief course of treatment. Other responsive diseases include chronic lymphocytic leukemia, prolymphocytic leukemia, mycosis fungoides, and acute T-cell lymphoma or leukemia. Response has been seen in acute lymphocytic leukemia, but the higher doses required are substantially more toxic. Pentostatin is valuable for treatment of indolent lymphoid malignancies and may be useful in non-cancer-related lymphocyte research.

The role of thymidine in the treatment of cancer has been under clinical investigation for nearly a decade. Clinical trials have demonstrated that it lacks antitumor activity in its own right. In this review, the mechanism of action and rationale for the use of thymidine as a biochemical modulator of standard agents such as 5-fluorouracil, 1-beta-D-arabinofuranosylcytosine, and methotrexate are summarized. With this background, the clinical trials which have been conducted with thymidine, either alone or in combination, are described. We suggest a number of further studies of the role of thymidine in the biochemical modulation of antimetabolites.

Trimetrexate is a 2,4-diaminoquinazoline inhibitor of dihydrofolate reductase (DHFR) which is cytotoxic in vitro and in vivo to several tumors resistant to methotrexate. It is more lipophilic than the parent antifolate, and is not transported by the reduced folate carrier. These features promise activity greater than that of methotrexate in the clinic; its inability to undergo polyglutamylation may also enhance the therapeutic index. In preclinical models, the activity of trimetrexate was highly schedule dependent, being superior on repeated dose schedules. Phase I studies have demonstrated that myelosuppression is the major toxic effect of trimetrexate on all schedules tested in man. Phase II studies will evaluate a 5-day schedule initially; trials in multiple tumor types and examination of the role of schedule are already under way.

Suramin was given to ten outpatients with acquired immunodeficiency syndrome (AIDS) presenting as Kaposi's sarcoma (KS) or as an AIDS-related complex (ARC). Side-effects associated with the administration of 6.2 g of suramin over 5 weeks included fevers, rashes, urinary abnormalities, and transient rises in hepatic aminotransferases. Peak serum levels of over 100 micrograms/ml were attained. There was evidence of HTLV-III infectivity and replication in lymphocytes from four patients before therapy. The detectable virus level fell in each case by the time of the last dose, and in three cases it became undetectable at the end of therapy. In each case, viral replication was again detected in the weeks or months following the administration of suramin. Despite this in-vivo virustatic effect, no significant clinical or immunological improvement was observed using this short-term regimen. However, the results provide a rationale for investigating longer-term regimens.

Thirty-nine patients with advanced metastatic adenocarcinoma of the pancreas were treated with a combination of 5-fluorouracil, Adriamycin, and mitomycin-C (FAM). Twenty-seven of these patients had measurable disease, and ten (37%) achieved a partial response. An additional three patients had evidence of disease stabilization. The median survival period of responding patients was 12 months, compared with 3.5 months for nonresponders (P < 0.01). The median survival period for all patients was 6 months. Moderate myelosuppression constituted the treatment-limiting toxicity. The FAM combination is an active and well-tolerated regimen for pancreatic cancer and may have an application in the management of patients with less advanced disease.

Fourteen patients developed severe central nervous system (CNS) toxicity after receiving an investigational antitumor agent, fludarabine phosphate (FAMP). The CNS toxicity has the distinctive features of delayed onset and progressive clinical course. Visual deficits were the most common presenting symptom and developed eventually in most cases. Deterioration of mental status and progressive encephalopathy were also observed. The development of clinical CNS toxicity appears dose-related; thirteen of 36 patients (36.1%) who received FAMP at high doses (greater than or equal to 96 mg/m2/day for 5-7 days per course) developed neurotoxicity, while only one of 443 patients (0.2%) who received the drug at low doses (less than or equal to 125 mg/m2 per course) developed similar toxicity. Although the precise mechanism responsible for this toxicity is yet unknown, progressive demyelination appears to be the responsible process. Extensive review of the clinical data failed to identify factors which might contribute to the development of CNS toxicity. Patients on trials of FAMP should be meticulously monitored for the possible development of neurotoxicity.

Fifteen patients with advanced gastric cancer were treated with the combination of Ftorafur, Adriamycin and mitomycin-C (FAM II). Three patients showed partial responses, in five the disease remained stable for at least 3 months and seven showed progression while on treatment. All responding patients showed survival in excess of 12 months. Hematologic toxicity was of only moderate severity. Median white count nadir was 3500 cells/mm3 and median platelet nadir was 187,000 cells/mm3. Four patients had white count nadirs from 2000--2500 cells/mm3 and three had nadirs from 500--1500 cells/mm3; also there were four with platelet nadirs less than 100,000/mm3. However, no drug-related infections occurred and no platelet transfusions were required. The major non-hematologic toxicities of the regimen were nausea, vomiting, dizziness, vertigo, and rhinorrhea. These toxicities were limiting and resulted in termination of the trial because of poor patient acceptance and the failure of the combination to exhibit a therapeutic advantage over the similar combination (FAM) that employed weekly 5-fluorouracil in place of Ftorafur.

Thirty-five patients with metastatic malignant melanoma underwent treatment with chlorozotocin administered as a single dose of 120 mg/m2 by means of rapid intravenous infusion every six weeks. There were 1 complete and 4 partial remissions with an overall response rate of 14%. The median duration of response was 18 weeks; the patient in complete remission continues disease-free in excess of 42 weeks. The sites of response included: lung, 2; subcutaneous, 2; and lymph node, 1. There was minimal myelotoxicity: for the first cycle, the median white blood cell count nadir was 5400/mm3, and the platelet nadir was 210,000/mm3. No evidence of cumulative platelet toxicity was observed. Chlorozotocin is active against metastatic melanoma to the same degree as other chloroethylnitrosoureas in clinical use, but without causing bone marrow toxicity. These data suggest that chlorozotocin should be evaluated in combination with other agents active against melanoma.

This paper suggests a development plan for antifolate analogs, based upon disease classifications that the National Cancer Institute has successfully utilized for the development of anthracycline and platinum analogs. Diseases are classified according to the role of the parent compound in standard therapy: 1) those in which methotrexate is an important component of standard treatment strategies that have state-of-the-art effectiveness; 2) those in which methotrexate has antitumor activity but no clear role in standard state-of-the-art treatment strategies; and 3) those in which methotrexate has insufficient activity to warrant its use alone or in combination. Developmental plans are specified for each of these disease classes. Trimetrexate is used as a specific example for these plans, although this method of drug development is equally applicable to other methotrexate analogs.

Teniposide, a semisynthetic epipodophyllotoxin, was found to be highly active against murine leukemias, and the combination of teniposide with cytosine arabinoside (ara-C) was curative in murine leukemia models. The antitumor activity in preclinical models prompted introduction of teniposide into the clinic in 1971. Although teniposide as a single agent rarely produced a complete remission in heavily pretreated leukemia patients, teniposide plus ara-C produced complete remissions in some patients with refractory and relapsed acute lymphoblastic leukemia (ALL). Innovative front-line and salvage regimens using teniposide have been developed that incorporate a multi-drug strategy with early intensification, rotation of drug combinations in maintenance, and regional therapy in an effort to improve the cure rate in leukemia. However, as the complexity of these regimens increases, the contribution of an individual component such as teniposide becomes less clear. Although some of these regimens for newly diagnosed and relapsed ALL are now thought to represent the best available therapy, teniposide remains an investigational agent. In this review, we outline and discuss the conflicts arising from the need to answer drug-specific issues, and, at the same time, facilitate the implementation of innovative, curative regimens.