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Biomedical subjects

D L Trump

Publications and source records attributed to D L Trump.

At least 19 recordsLinked to original sources
PubMed1992

High-dose oral tamoxifen, a potential multidrug-resistance-reversal agent: phase I trial in combination with vinblastine.

BACKGROUND: P-glycoprotein mediates resistance to natural-product anti-neoplastic agents like vinblastine through an active transport process resulting in reduced intracellular concentration of these agents. The triphenylethylene antiestrogen tamoxifen and its major metabolite N-desmethyltamoxifen at concentrations of 4-6 microM enhance the intracellular concentration of natural-product antineoplastics and augment the cytotoxicity of such drugs three-fold to 10-fold in a variety of human and murine cell lines. PURPOSE: On the basis of these preclinical findings, we conducted a phase I clinical trial of high-dose, oral tamoxifen administered in conjunction with a 5-day continuous infusion of vinblastine. METHODS: We studied 53 patients with advanced epithelial tumors. Tamoxifen was given orally as a loading dose on day 1, followed by two doses a day on days 2-13. Vinblastine was given as a 120-hour continuous infusion (1.5 mg/m2 per day) on days 9-13 of each tamoxifen course. The starting dose of tamoxifen was 40 mg/m2 administered twice a day following a loading dose of 150 mg/m2. The maximum dose was 260 mg/m2 twice a day following a loading dose of 680 mg/m2. Treatment cycles were repeated every 28 days. RESULTS: The dose-limiting toxic effects of tamoxifen were neurologic and began within 3-5 days after the start of treatment. They consisted of tremor, hyperreflexia, dysmetria, unsteady gait, and dizziness. One patient experienced a grand mal seizure 24 hours after the last tamoxifen dose. Toxic effects were rapidly reversible. Asymptomatic prolongation of the QT interval on electrocardiogram occurred at doses of tamoxifen of 80 mg/m2 or higher given twice a day. No coagulation or ophthalmologic abnormalities occurred. Tamoxifen did not enhance the toxicity of vinblastine. Mean plasma concentrations of tamoxifen or N-desmethyltamoxifen at 260 mg/m2 tamoxifen given twice a day for 13 days were 6.04 and 6.56 microM, respectively. There was no relationship between plasma antiestrogen content and the development of neurotoxic effects. CONCLUSIONS: Tamoxifen at 150 mg/m2 given twice a day following a loading dose of 400 mg/m2 results in plasma levels of tamoxifen and N-desmethyltamoxifen of 4 and 6 microM, respectively, without dose-limiting toxicity. We recommend this dose for phase II trials of tamoxifen to modulate P-glycoprotein-mediated drug resistance. IMPLICATIONS: Our study demonstrates that high-dose tamoxifen can be safely administered and that plasma concentrations that may inhibit P-glycoprotein function can be achieved.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Modulation of O6-alkylguanine-DNA alkyltransferase-mediated carmustine resistance using streptozotocin: a phase I trial.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance may be mediated by repair of chloroethylated guanine before stable cross-linking occurs. Guanine adducts may be repaired by the enzyme O6-alkylguanine-DNA alkyltransferase (O6-AGAT). Such repair irreversibly inactivates O6-AGAT. Streptozotocin (STZ) forms adducts at the O6 position of guanine; repair of these adducts consumes O6-AGAT. In vivo STZ potentiates BCNU cytotoxicity. The purpose of this trial was to determine the maximum tolerated dose of BCNU that can be administered together with STZ. The STZ dose was 500 mg/m2/day for 4 days and was not escalated. BCNU was given 4 h after the third dose of STZ at a starting dose of 75 mg/m2. A total of 43 patients were entered in the study. There were 4 dose escalations, reaching a maximum tolerated BCNU dose of 175 mg/m2. At this dose, thrombocytopenia was the dose-limiting toxicity (one patient, 25-49 x 10(9)/liter; 2 patients, less than 25 x 10(9)/liter); neutropenia was less severe (2 patients, 2.0-3.9 x 10(9)/liter, 1 patient, 1.0-1.9 x 10(9)/liter). Two other commonly seen toxicities were elevations in the serum alkaline phosphatase and mild elevations in the serum creatinine. Peripheral blood lymphocyte O6-AGAT levels decreased from a mean of 212 fmol/mg protein pretherapy to 8.2 fmol/mg protein on day 3 prior to BCNU (P = 0.03). Three partial responses were seen. There were no therapy-related fatalities, and toxicity was easily managed. This study established that 150 mg of BCNU can be administered safely together with STZ, 500 mg/m2/day for 4 days. Additional studies are required to determine whether O6-AGAT-mediated BCNU resistance is suppressed.

Adult↗
PubMed1992

Choice of starting dose and escalation for phase I studies of antitumor agents.

The standard approaches to initial dose selection and dose escalation in phase I trials may be inappropriately conservative. These approaches mandate accrual of large numbers of patients, most of whom are treated at low and potentially ineffective doses. We compared the clinically determined maximum tolerable dose (MTD) with the starting dose of 45 drugs that had undergone phase I studies during the period 1977-1989. We also examined the number of dose-escalation steps required to achieve the MTD in relation to nonhematologic and hematologic dose-limiting toxicity. The median ratio of MTD to starting dose for all drugs was 20 (range, < 1-433) and the median number of dose levels studied to reach the MTD was 8 (range, 0-23). For drugs with nonhematologic dose-limiting toxicity, the median ratio of MTD to starting dose was 30 (range, 3-385) as compared with 12.8 (range, < 1-433) for those with hematologic dose-limiting toxicity (P = 0.023). The median number of dose-escalation steps required to reach the MTD was 9 (range, 2-18) for drugs with nonhematologic dose-limiting toxicity as compared with 5.5 (range, 0-23) for those with hematologic dose-limiting toxicity (P = 0.038). We also examined the response rate for 1,110 patients treated with 21 phase-I-study drugs for which response information was available. Responses were reported for 29 patients (2.6%). Among the 476 patients treated at the 3 highest dose steps, 17 responded (3.6%), which is double the response rate obtained at the lower doses (P = 0.08). It is suggested that although the usual methods for choosing starting doses and dose-escalation schemes for phase I studies are safe, they are overly conservative and delay opportunities for therapeutic benefit in phase I and subsequent phase II trials.

Antineoplastic Agents↗
PubMed1992

Phase I study of BCNU and intravenous 6-mercaptopurine in patients with anaplastic gliomas.

On the basis of response rates of up to 50%, BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] is the primary drug used in the chemotherapy of anaplastic gliomas. Preclinical data obtained in several experimental systems show that the cytotoxicity of chloroethylnitrosoureas can be increased by the concomitant use of thiopurines. In this phase I trial, patients with anaplastic gliomas received standard-dose BCNU (200 mg/m2 x 1) in combination with escalating doses of intravenous 6-mercaptopurine (200, 350, 500, and 750 mg/m2 daily x 3), with BCNU being given on day 3 to maximize the effect of the drugs on cellular DNA. No increase in hematologic toxicity was demonstrated as the dose of 6-mercaptopurine was increased. Responses and stabilization of disease were observed in several patients. Due to the safety of and the evidence of activity found for this regimen in the present trial, 750 mg/m2 6-mercaptopurine has been incorporated into subsequent studies.

Adolescent↗
PubMed1992

Trimetrexate in advanced renal cell carcinoma. An ECOG phase II trial.

Thirty-four chemotherapy-naive, ambulatory patients with advanced renal cell cancer were treated with the non-classical antifol trimetrexate at the intravenous dose of 12 mg/m2 daily x 5 every three weeks (8 mg/m2 qd x 5 for greater than 30% bone marrow previously irradiated). One patient experienced a partial response lasting 24 weeks for a response rate of 3% (exact 95% CI, 0.1 to 15.3%). Toxicity was manageable and primarily myelosuppression, gastrointestinal, and mucosal. Trimetrexate has little activity in advanced renal cell carcinoma at this dose and schedule.

Adult↗
PubMed1992

Hypercalcemia and neuroendocrine carcinoma of the prostate: a report of three cases and a review of the literature.

PURPOSE: Hypercalcemia is a rare complication of prostate cancer, and no definite association with any histologic subtype of prostatic malignancy has been documented. We have recently seen three patients who developed hypercalcemia in the setting of prostate cancer. All had neuroendocrine carcinoma of the prostate (NCPs), which prompted an exploration of the potential association of hypercalcemia with NCP. DESIGN: An extensive review of literature published in the English-language was conducted to identify cases of hypercalcemia associated with prostate cancer and well-documented cases of NCP. RESULTS: We found 17 reported cases of hypercalcemia clearly associated with prostate cancer and a total of 61 cases of well-documented NCP. Including our cases, 11 of the 20 reported cases of hypercalcemia associated with prostate carcinoma were in patients with neuroendocrine carcinomas. CONCLUSION: Hypercalcemia in the setting of prostate cancer should prompt a search for unusual histologies.

Adenocarcinoma↗
PubMed1992

High-dose carboplatin and etoposide with autologous bone marrow transplantation in refractory germ cell cancer: an Eastern Cooperative Oncology Group protocol.

PURPOSE: A phase II trial was undertaken to assess the feasibility, toxicity, and efficacy of high-dose carboplatin and etoposide with autologous bone marrow transplantation in patients with relapsed or refractory germ cell tumors. PATIENTS AND METHODS: Forty patients with recurrent germ cell cancer received carboplatin 500 mg/m2 and etoposide 400 mg/m2 given at 7, 5, and 3 days before marrow infusion. Autologous marrow infusion (day 0) was accomplished using one half of the bone marrow harvested before chemotherapy. Patients who achieved a complete or partial response with the first cycle of treatment received a second identical cycle of chemotherapy followed by infusion of the remaining cryopreserved bone marrow. RESULTS: Objective responses were obtained in 17 of the 38 patients (45%) assessable for response, including eight partial and nine complete remissions. Five of these patients remain in continuous complete remission with minimal follow-up of 1 year. Toxicity encountered was primarily hematologic, and five patients (13%) died of treatment-related complications. Significant toxicities often seen with high-dose cisplatin (ototoxicity, neurotoxicity, and renal toxicity) were manageable in this regimen of high-dose carboplatin. CONCLUSIONS: This trial confirms the curative potential of high-dose carboplatin and etoposide in highly refractory germ cell cancer.

Adolescent↗
PubMed1992

Metastatic bladder cancer. Natural history, clinical course, and consideration for treatment.

Patients with metastatic transitional-cell carcinoma of the bladder have a poor prognosis with brief survival. Controversy exists as to the clonality of bladder cancer, as well as the natural history of muscle-invasive disease that subsequently becomes metastatic. Newer molecular biologic techniques may help us identify and understand the molecular changes involved in transforming normal urothelium into the malignant phenotype. In addition, newer chromosomal markers may enable us to determine the prognosis and the potential for progression to invasion and metastases. Additional work to find the optimum doses and dosing schedules and combinations of chemotherapeutic agents for metastatic transitional-cell carcinoma will be necessary before we can improve survival for all patients with this disease.

Antineoplastic Agents↗
PubMed1991

A phase I study of SR-2508 and cyclophosphamide administered by intravenous injection.

SR-2508, a less lipophilic ane neurotoxic analogue of the nitroimidazole, misonidazole, has exhibited significant chemosensitization properties in preclinical studies with alkylating agents. A phase I trial was carried out to assess toxicity and possible pharmacological interactions of the combination of short infusions of SR-2508 and cyclophosphamide (CP). Patients were randomly assigned to receive either CP alone followed in 3 wk by CP + SR-2508, or CP + SR-2508 followed by CP alone. All additional courses were CP + SR-2508. The maximum tolerated dose of the combination was determined by dose escalation of SR-2508 while the dose of CP remained fixed, initially 1.0 g/m2, and then a second maximum tolerated dose was determined with CP at 1.6 g/m2. One hundred seventeen evaluated courses were administered to 39 patients, the majority of whom had received prior treatment. Somewhat unexpectedly, reversible grade 4 granulocytopenia was the dose-limiting toxicity occurring in four of five evaluable first combination courses at level 6 (SR-2508, 11.3 g/m2; CP, 1.0 g/m2), the initial maximum tolerated dose. SR-2508 enhanced CP-induced myelosuppression as exhibited by the significant difference (p less than 0.001) between the 27 paired courses (CP versus CP + SR-2508) for WBC nadirs over levels 1 to 6. The neurotoxicity encountered was similar to that seen in past clinical trials, being reversible, mild, and usually peripheral in nature. There was one treatment-related death (neutropenic sepsis) on study. No other significant toxicity was seen. SR-2508 exhibited linear pharmacokinetics over the dose range studied. The SR-2508 area under the concentration-time curve increased linearly with dose (r = 0.858; p less than 0.001). No other parameters were dose related. Neither drug appeared to affect the pharmacokinetics of the other, and CP pharmacokinetic values were consistent with those from prior studies. Due to the interaction noted between the two agents and the preclinical data suggesting preferential enhancement of antitumor efficacy under this combination, phase II study appears warranted.

Adult↗
PubMed1991

A phase II study of taxol in patients with malignant melanoma.

Based on results of a phase I study demonstrating antitumor activity of taxol in patients with melanoma, 34 patients with documented metastatic melanoma received taxol, 250 mg/m2, as a 24-hours infusion, repeated every 21 days, in this phase II study. All patients received premedication with dexamethasone, diphenhydramine and cimetidine. Four patients experienced anaphylactic reactions and stopped treatment. Other significant toxicity of this drug included short-lived but severe neutropenia (less than 1,000/mm2) and peripheral neurotoxicity. Four of 28 evaluable patients demonstrated objective response (14%) (confidence interval, 4%-33%) including 3 complete responses and 1 partial response. Two complete responders are continuing at 25+ and 38+ months after achieving CR. Minor evidence of anti-tumor activity was noted in five additional patients. Taxol has significant activity in melanoma and should be further studied in combination with other agents in this disease.

Adult↗
PubMed1991

Complications of hepatic arterial infusion chemotherapy.

Chemotherapy by direct hepatic arterial infusion (HAI) results in reduction in tumor mass in a large percentage of patients. The authors reviewed records for 45 patients with metastatic cancer of the gastrointestinal tract who underwent HAI chemotherapy with floxuridine, administrated via an implanted pump. Twenty-seven of the 45 patients suffered complications, including gastrointestinal ulceration (18%), hepatitis (24%), sclerosing cholangitis (7%), and abscess (2%). The complication rates in this series were similar to those previously reported. The toxicity of HAI chemotherapy continues to limit its efficacy.

Aged↗
PubMed1991

Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole.

During a phase I trial of 3-day simultaneous continuous intravenous infusions of varying doses of fluorouracil (5FUra) and 7.7 mg/kg/d of dipyridamole, we examined the relationships between 5FUra dose and steady-state plasma concentration (Css) and the percentage reduction in WBCs, as well as the percentage frequency of stomatitis. The 5FUra was administered at doses ranging from 185 mg/m2/d times three to 3,600 mg/m2/d times three. In 42 patients, 86 cycles of 5FUra plus dipyridamole and 28 cycles of 5FUra alone were analyzed. The Css of 5FUra varied even within the same dose level. When patients receiving the same 5FUra dose were considered, the interpatient coefficient of variation of 5FUra Css in cycles of 5FUra plus dipyridamole was 23% +/- 4.2%. For courses of 5FUra alone, the coefficient of variation of 5FUra was 15.6% +/- 6.5%. When the occurrence of any degree of stomatitis was related to the Css 5FUra, with patients grouped in cohorts of 2-mumol/L increments, the following equations accurately described the frequency of stomatitis: for 5FUra plus dipyridamole, percentage frequency of stomatitis = 100(1-e-0.114Css), r2 = 0.88; for 5FUra alone, percentage frequency stomatitis = 100(1-e0.122Css), r2 = 0.80. When 5FUra dose was substituted for Css, these relationships were as follows: percentage frequency of stomatitis = 100(1-e-0.00031 [dose]), r2 = 0.85; and percentage frequency of stomatitis = 100(1-e-0.00051 [dose]), r2 = 0.80. When the relationship between the percentage reduction in WBC and Css 5FUra was examined, statistically significant relationships were also apparent: for 5FUra plus dipyridamole, percentage reduction in WBC = 100(1-e-0.085Css), r2 = 0.46; for 5FUra alone, percentage reduction in WBC = 100(1-e-0.060Css), r2 = 0.61. When 5FUra dose was substituted for Css, these relatinships were as follows: percentage reduction in WBC = 100(1-e-0.00023 [dose]), r2 = 0.40; percentage reduction in WBC = 100(1-e-0.00024 [dose]), r2 = 0.65. The relationship between either Css 5FUra or dose 5FUra and either stomatitis or myelosuppression were also well described by the modified Hill equation (J Theor Biol 20:171-201, 1968). These analyses indicate that it should be possible to develop therapeutic regimens wherein 5FUra is administered to achieve a targeted Css determined by the risk and severity of toxicity deemed acceptable.

Bone Marrow Diseases↗
PubMed1991

Vinblastine fails to improve response of renal cancer to interferon alfa-n1: high response rate in patients with pulmonary metastases.

One hundred sixty-five patients were randomized to receive either interferon alfa-n1 (Wellferon; Burroughs Wellcome Co, Research Triangle Park, NC) alone or with vinblastine. An initial six-cycle induction treatment consisted of interferon given at daily doses of 3, 5, 20, 20, and 20 x 10(6) U/m2 every 2 weeks. Vinblastine at a dose of 10 mg/m2 (later decreased to 5 mg/m2) was given on day 1 of alternate cycles. Toxicities were generally well tolerated. The overall response rate was 10% with no significant difference between treatment arms. Survival was also not significantly different for the arms. A small subset of patients (16) with metastases only to the lungs had a high complete response (CR) and partial response (PR) rate of 44%. Responses were durable, and overall survival of this group was much better than that of the other patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Phase I trial of 5-fluorouracil and dipyridamole administered by seventy-two-hour concurrent continuous infusion.

Forty-seven patients with advanced malignancies were treated with a concurrent 72-h continuous infusion of 5-fluorouracil (FUra) and dipyridamole. The FUra dose was escalated over the dose range of 185 to 3600 mg/m2/day for 3 days. Dipyridamole was administered in a fixed dose of 7.7 mg/kg/day for 3 days. A total of 155 courses of therapy were completed of which there were 31 paired courses of the combination and FUra alone, at the same dose of FUra and in the same patient. This was for purposes of analysis of pharmacokinetics and modulation of FUra toxicity by dipyridamole. Stomatitis was the dose-limiting toxicity experienced by patients entered into this trial. Myelosuppression was not a serious problem. Increasing FUra plasma concentration was associated with greater leukopenia and stomatitis. Dipyridamole did not appear to modulate the systemic toxicity of FUra. The pharmacokinetics of FUra were altered by the concurrent administration of dipyridamole. Dipyridamole promoted the total body clearance of FUra which resulted in lower mean steady-state FUra plasma concentrations when compared with courses of FUra alone administered at the same dose level. These differences were statistically significant over the course of the trial. For courses of the combination, FUra exhibited linear pharmacokinetics over the dose range studied. Total body clearance of FUra declined slightly at the higher dose levels, but the differences were not significant. For courses of FUra alone, total body clearance was significantly decreased above the dose level of 2300 mg/m2/day. At the maximal tolerated dose of FUra, 2300 mg/m2/day x3, mean steady-state FUra plasma concentration and total body clearance were 6.6 microM and 122 liters/h/m2, respectively, for courses of the combination. The corresponding pharmacokinetic parameters were 7.4 microM and 103 liters/h/m2 for courses when FUra was given alone. Further evaluation of the utility of this regimen and basis of these pharmacokinetic observations appear warranted.

Adult↗
PubMed1990

Psychological and mood disturbance associated with the diagnosis and treatment of testis cancer and other malignancies.

Eighty-seven men with testis cancer (TC) and 35 men with other cancers (OC) completed measures of mood (Profile of Mood States) and of personality and psychopathology (Millon Clinical Multiaxial Inventory). Effects of primary disease, phase of diagnosis and treatment, locoregional vs. cytotoxic treatment, age, and marital status on these measures were examined. TC patients appeared more distressed during treatment, particularly during cytotoxic as compared to locoregional treatment, than before or after treatment, and more distressed than OC patients. Being married appeared to buffer the stress of cancer and its treatment. Although treatment, particularly cytotoxic therapy, appeared to result in transient distress, results did not offer strong evidence that cancer and its treatment typically precipitate severe psychopathology.

Adaptation, Psychological↗
PubMed1990

A phase II trial of carboplatin (NSC 241240) in advanced prostate cancer, refractory to hormonal therapy. An Eastern Cooperative Oncology Group pilot study.

Twenty-nine patients with metastatic prostate cancer progressing after hormonal therapy (orchiectomy 19, diethylstilbestrol 10) and who had never received cytotoxic therapy were treated with carboplatin. Patients had good clinical performance status (66% PS 0,1) and adequate renal (creatinine less than 2.0 mg/dL) and bone marrow function. The standard dose of carboplatin administered was 400 mg/sq m. Seventeen patients received this dose and 12 either 320 mg/sq m or 250 mg/sq m based on reduced renal function or prior radiation. Five patients had bidimensionally measurable disease: one experienced a partial regression of cervical lymph node metastases of 97 days duration. Twenty-four patients had metastatic disease evaluable by clinical status, bone scan and acid phosphatase. In one patient greater than 50% reduction in number of abnormal areas of bone scan uptake occurred; 3 patients experienced improvement in clinical status; in no patient did an elevated prostate acid phosphatase return to normal. All patients entered on study have progressed and died: median time to progression was 94 days (6 to 625 days); median survival was 297 days (6-1152 days). The primary toxicity of carboplatin was myelosuppression. The median WBC and platelet nadirs after cycle one were 3150/cu mm and 93,000/cu mm, respectively. Dose escalations to grade 2 or greater myelosuppression were mandated. Twenty-six achieved at least grade 2 myelosuppression during carboplatin treatment. We conclude that carboplatin administered at this dose and schedule has no important activity in hormone refractory prostate cancer.

Bone Neoplasms↗
PubMed1990

Evaluation of carboplatin (NSC 241240) in patients with recurrent or metastatic renal cell carcinoma.

Eighteen evaluable patients with metastatic or recurrent renal cell carcinoma were treated with carboplatin. Fourteen patients received 400 mg/m2 as the initial dose, and four patients received reduced doses based on prior radiation therapy and/or elevated serum creatinine. No responses were seen. Median survival of these 18 patients was 8.3 months. Risk group status which previously has been identified as an important indicator of survival was predictive for survival in this study. Patients in the most favorable risk groups had a median survival of 21.2 months vs. 6.6 months for the most unfavorable risk groups. No lethal toxicities occurred with the administration of carboplatin; however, 66% of patients received doses of sufficient magnitude to cause severe or life threatening thrombocytopenia or anemia.

Anemia↗