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Biomedical subjects

B Leyland-Jones

Publications and source records attributed to B Leyland-Jones.

At least 19 recordsLinked to original sources
PubMed1992

Patient treatment on a compassionate basis: documentation of high adverse drug reaction rate.

The special exception mechanism was established by the Division of Cancer Treatment (DCT), National Cancer Institute (NCI), for the provision of anticancer drugs not yet approved by the Food and Drug Administration (FDA) to patients on a compassionate basis. Strict guidelines have been established for the distribution of drugs through this mechanism and for the reporting of adverse drug reactions (ADRs) with investigational drugs. These guidelines have been used to format the data base which is maintained on all ADRs submitted by investigators. In this paper, the incidence of ADRs with the eleven investigational drugs most frequently administered on special exception protocols was determined for a twelve month time period, January 1, 1985 through December 31, 1985. On special exception protocols, the overall incidence rate of ADRs was significantly greater than that seen on research protocols for the time period. For three drugs, Methyl-G, DBD, and AMSA, the ADR incidence rate was seven to fifteen-fold greater on special exception protocols than on research protocols. In an analysis of all ADRs submitted to the FDA for the twelve months time period, no difference was found in the frequency of distribution of either types of adverse effects or the causal assessments of ADRs on special exception and research protocols.

Antineoplastic Agents↗
PubMed1991

Phase I bioavailability and pharmacokinetic study of hexamethylene bisacetamide (NSC 95580) administered via nasogastric tube.

A Phase I clinical trial and pharmacological study of nasogastrically administered hexamethylene bisacetamide, a polar-planar compound with in vitro differentiating activity, was conducted in 14 adult patients with refractory cancer. Hexamethylene bisacetamide was administered as a 5% (w/v) solution via a nasogastric or gastrostomy tube every 4 h for 5 days, followed in 21 days by a 5-day continuous i.v. infusion at the same daily dose. Parenteral drug administration was then continued at the same interval in the absence of disease progression or unacceptable toxicity. Three patients each were treated at doses of 12 and 24 g/m2/day, while eight patients received a dose of 30 g/m2/day. Toxicity was comparable for both routes of drug administration at the above doses. Nasogastrically administered hexamethylene bisacetamide was well tolerated at the lower doses, whereas neurotoxicity and nausea and vomiting were the major, but manageable, toxicities at 30 g/m2/day. Metabolic acidosis, renal dysfunction, mucositis, and thrombocytopenia were the other commonly observed drug toxicities at this dose. No objective tumor responses were observed. Hexamethylene bisacetamide was rapidly absorbed from the gastrointestinal tract with a mean measured bioavailability of 99 +/- 15%. Pharmacokinetic parameters for hexamethylene bisacetamide and plasma concentrations of the two major metabolites, N-acetyl-1,6-diaminohexane and 6-acetamidohexanoic acid, were similar for either route of administration in individual patients. Hexamethylene bisacetamide exhibited apparent monoexponential plasma elimination after either nasogastric or parenteral administration with 27 to 60% of the administered dose being excreted in the urine as parent compound. Based on its demonstrated complete bioavailability and tolerability, nasogastric administration of hexamethylene bisacetamide can be directly and safely substituted for the comparable i.v. dose.

Acetamides↗
PubMed1991

Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies.

Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.

Antimetabolites, Antineoplastic↗
PubMed1990

A strategy for the development of two clinically active cisplatin analogs: CBDCA and CHIP.

The antitumor agent cisplatin has a broad antitumor spectrum and has been incorporated into regimens that are curative for some malignant diseases. However, one of the major limitations to its clinical usefulness is the incidence of severe toxicities involving several major organ systems. Therefore, much enthusiasm has been generated for the development of cisplatin analogs that demonstrate an improved therapeutic index in some preclinical models. The two most promising analogs are CBDCA (carboplatin) and CHIP (iproplatin). The preclinical and early clinical trial results have demonstrated that these two compounds show activity in cisplatin-responsive tumors. The preclinical background providing the rationale for the clinical development of these two analogs is described. We suggest a means of screening for each analog's clinical antitumor activity and determining the analogs' utility against specific malignant diseases compared with that of the parent compound or standard treatment.

Animals↗
PubMed1990

Hypersensitivity reactions from taxol.

Taxol is an antitumor agent in clinical trial that has been shown to have activity against advanced ovarian carcinoma and melanoma. Hypersensitivity reactions (HSRs) have been one of the toxicities observed with administration of this drug. Of 301 patients treated, 32 patients have had definite (27 patients) or possible (five patients) hypersensitivity reactions to taxol. All but one patient had the reaction from the first or second exposure to this agent. Reactions occurred at a variety of doses and were characterized most frequently by dyspnea, hypotension, bronchospasm, urticaria, and erythematous rashes. Thirteen (41%) patients had received premedication designed to prevent such toxicity; nevertheless, they sustained HSRs. Prolonging the drug infusion appears to have somewhat reduced, but not obviated, the risk of HSRs. The cause (taxol itself or its excipient Cremophor EL; Badische Anilin und Soda-Fabrik AG [BASF], Ludwigshafen, Federal Republic of Germany) and the mechanism of these reactions to taxol are unknown. We provide guidelines to prevent or minimize such toxicity and treat reactions if they still occur.

Adult↗
PubMed1989

4-Ipomeanol: a novel investigational new drug for lung cancer.

4-Ipomeanol (IPO) is the first agent to undergo preclinical development at the National Cancer Institute (NCI) based principally on a specific biochemical-biological rationale for clinical investigation as an antineoplastic agent targeted against lung cancer. This disease-specific development of IPO was initially stimulated by observations that the compound was activated by metabolism, preferentially within the mammalian lung, specifically within bronchiolar Clara cells, and that its predominant toxicity was to the lung in most species. IPO is inactive or only minimally active against most conventional antitumor test systems. However, some human lung cancer cell lines, as well as a variety of fresh human lung tumor biopsy specimens, have been shown to be capable of mediating the in situ biotransformation of IPO to a potentially cytotoxic intermediate. In this report, the biochemistry, metabolism, preclinical pharmacology, and toxicology of IPO are reviewed and the clinical development plans for this unique and challenging new agent are presented.

Animals↗
PubMed1989

Pentostatin in hairy cell leukemia: treatment by the special exception mechanism.

An analysis of the clinical outcomes in 66 patients with hairy cell leukemia treated with pentostatin under the Special Exception mechanism of the Division of Cancer Treatment, National Cancer Institute, between 1983 and 1987 has revealed a favorable balance of risk and benefit. Hematologic parameters and performance status were improved in most patients treated outside the clinical trials mechanism. The treating physicians considered 37 patients (56%) to be complete responders and 15 patients (23%) to be partial responders. Four patients (6%) died while receiving pentostatin. Life-threatening leukopenia (wbc count, less than 1,000/mm3) was reported in 24% of patients, and severe or life-threatening infection occurred in 11%. The experience gained with these patients supplements the information presently being collected from the controlled clinical trials and supports the development of a group C treatment protocol.

Adult↗
PubMed1989

Autologous bone marrow transplantation. Current status and future directions.

PURPOSE: To assess the current status of high-dose chemotherapy with autologous marrow transplantation in hematologic malignancies and solid tumors. DATA IDENTIFICATION: Studies reported between 1978 and May 1988 were identified through computer searches using Medline and Cancerline and through extensive manual searching of bibliographies of identified books and articles. STUDY SELECTION: More than 160 studies that contained adequate response, toxicity, or survival data were selected for analysis, including peer-reviewed articles, book chapters, and proceedings of meetings. The most current or complete references were used for series reported more than once. DATA ANALYSIS: Information abstracted included regimen used, number of patients, response rates, disease-free and overall survival, and toxicities. A meta-analysis of the pooled data was done. RESULTS OF DATA ANALYSIS: For many tumor types, autologous marrow transplantation offers higher response rates than standard approaches. For leukemias and lymphomas, response rates of 60% to 80% may be achieved with the potential for cure. With solid tumors, response rates range from 30% in gliomas, 50% in melanomas and colon cancer, more than 60% in lung cancer, and 80% in breast cancer. Although responses tend to be short-lived, long-term survival can occasionally be seen. CONCLUSIONS: Results with autologous marrow transplantation can be improved through systematically developed, carefully designed clinical trials that may be facilitated by collaborative research. Studies should focus on disease-directed drug combinations, several courses of high-dose therapy, treatment at a time of lower tumor burden, and reducing toxicity with hematopoietic growth factors.

Antineoplastic Agents↗
PubMed1988

Cephalotaxine esters: antileukemic advance or therapeutic failure?

Clinical trials conducted in the People's Republic of China and the United States of the antileukemic efficacy of the cephalotaxine esters are reviewed. Harrington has been incorporated into combination regimens for the treatment of newly diagnosed acute nonlymphocytic leukemia (ANLL) in China, and activity with cephalotaxine esters has also been noted in chronic myelogenous leukemia. While the investigational agent homoharringtonine has shown some activity in the United States in ANLL, investigator interest in the United States has waned because of toxicity and inconvenient schedules. The Chinese trials have used different schedules than have U.S. studies and have been associated with less toxicity. These trials provide new information that may lead to further investigations of the cephalotaxine esters in the United States.

Alkaloids↗
PubMed1988

The role of methotrexate in osteosarcoma.

High-dose methotrexate (MTX) is one of the agents currently used in intensive adjuvant chemotherapy regimens for nonmetastatic osteosarcoma. To elucidate the role of high-dose MTX in this disease, we present the history of trials conducted with MTX from the first single-agent studies through progressively complex combination regimens. With this background, some of the basic issues concerning MTX therapy in osteosarcoma are discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

The application of a two-stage design for clinical trials in patients with recurrent head and neck cancer.

Cytotoxic chemotherapy produces modest benefits for patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN). Prospective randomized clinical trials have failed to demonstrate unequivocal superiority of aggressive multidrug regimens over single agents. Despite this, phase II trials frequently result in encouraging preliminary observations that compare favorably to historical single-agent data. While providing for a useful method of screening for anti-tumor activity, phase II studies have limited use in determining the relative value of a new treatment program. Results of phase II studies are considerably influenced by patient selection factors and criteria used to establish therapeutic benefits (responses). Furthermore, estimations of true levels of efficacy (response rates) are dependent on sample sizes, which are usually limited in such trials. We propose that newly developed combinations containing at least one known active agent in this disease should be tested in a controlled setting after their toxicity pattern has been well established. The conduct of the usual phase II study in these situations will probably not provide useful new information, since responses are likely to be observed. We describe a two-stage design applied to terminate a trial if at the first stage there is no evidence of improvement over the control arm. This method allows for early termination of studies involving relatively inefficient treatment regimens and, at the same time, continuation of those with a high likelihood to result in significant therapeutic improvements over a control arm. Loss of power is negligible and sample sizes can be reduced significantly. The rationale behind this method and its simplicity are attractive features for a widespread application for new drug development strategies in this and other diseases.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Pyrazole: preclinical reassessment.

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.

Animals↗
PubMed1988

The systemic administration of intravenous melphalan.

Melphalan (L-phenylalanine mustard) is a bifunctional alkylating agent that is commonly administered orally to treat a wide variety of malignancies, including cancers of the breast and ovary, as well as multiple myeloma. Although commercially available in Europe and Canada, intravenous (IV) melphalan remains investigational in the United States. The role of IV melphalan in cancer chemotherapy is not well defined, despite its manageable toxicity and higher and more predictable blood levels following IV administration compared with oral administration. In addition, unlike oral melphalan, an extensive phase I evaluation of IV melphalan has not been undertaken. At lower doses (eg, 30 to 70 mg/m2), both as a single agent and in combination, the activity of IV melphalan has been evaluated in only a limited number of diseases. However, striking activity has been observed in previously untreated patients with rhabdomyosarcoma, a disease not generally considered responsive to alkylating agents. When administered at high doses (greater than 140 mg/m2) requiring bone marrow reinfusion, melphalan effects a high response rate (but no improvement in survival) in a variety of nonhematologic tumor types, including resistant tumors such as melanoma and colon carcinoma. In contrast, in poor-prognosis patients with non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or neuroblastoma, high-dose melphalan-containing regimens have yielded both high response rates and improved survival, despite considerable toxicity. Additional clinical trials will be necessary to define the spectrum of activity of lower doses of IV melphalan and to define subgroups of patients most likely to benefit from high-dose melphalan.

Administration, Oral↗
PubMed1988

Teniposide in the treatment of leukemia: a case study of conflicting priorities in the development of drugs for fatal diseases.

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.

Antineoplastic Combined Chemotherapy Protocols↗