Biomedical subjects

E Poplin

Publications and source records attributed to E Poplin.

14 recordsLinked to original sources

PubMed1999

Leucovorin, 5-fluorouracil, and gemcitabine: a phase I study.

Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU). The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0-2, and signed informed consent. Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m2, 5FU 255 mg/m2 and gemcitabine 600 mg/m2. 5FU and gemcitabine were escalated in tandem to 340 mg/m2 and 800 mg/m2 and thereafter to 425 mg/m2 and 1000 mg/m2, respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1-32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses. The maximum tolerated dose is leucovorin 20 mg/m2, 5FU 340 mg/m2, and gemcitabine 800 mg/m2. The impact of drug sequence remains undetermined.

Adult↗

PubMed1998

Phase Ib trial of bryostatin 1 in patients with refractory malignancies.

A Phase Ib trial of bryostatin 1, a macrocyclic lactone and protein kinase C (PKC) activator, was conducted in patients with refractory nonhematological malignancies with the primary goal of determining whether down-regulation of peripheral blood mononuclear cell (PBMNC) PKC activity could be achieved in vivo in humans. Patients (four patients/cohort) received bryostatin 1 (25 microg/m2) as a 1-h infusion weekly three times every 4 weeks, but to study the schedule dependence of pharmacokinetics and pharmacodynamics, the first dose was administered according to one of three schedules: (a) a 1-h infusion; (b) a 24-h infusion; or (c) a split course (12.5 microg/m2 as a 30-min infusion) on days 1 and 4. Conventional toxicities (grades I-III) included myalgias, fever, anemia, fatigue, phlebitis, and headache; in addition, two patients in cohort 3 experienced transient elevations in liver function tests, although these patients had preexisting liver metastases. No objective clinical responses were encountered. Effects on PBMNC PKC activity were heterogeneous. Several patients in cohorts 1 and 2 experienced significant declines in activity (approximately 50%) that were sustained in some cases for periods of > or = 72 h. Comparison of 72-h with baseline values for all three patient cohorts combined revealed a trend toward PKC down-regulation (P = 0.06; signed rank test). For each schedule, plasma bryostatin 1 levels were below the level of detection of a platelet aggregation-based bioassay (3-4 nm). Bryostatin 1 administration failed to produce consistent alterations in lymphocyte immunophenotypic profiles, interleukin 2-induced proliferation, or cytotoxicity, although two of three samples from patients in cohort 3 did show significant posttreatment increases in proliferation. Moreover, in some patients, bryostatin 1 treatment increased lymphokine-activated killer cell activity. These findings indicate that bryostatin 1 doses of 25 microg/m2 can induce in vivo PBMNC PKC down-regulation in at least a subset of patients and raise the possibility that higher bryostatin 1 doses may be more effective in achieving this effect.

Adult↗

PubMed1996

Phase I trial of Adozelesin using the treatment schedule of daily x5 every 3 weeks.

CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6-30 mcg/m2/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m2/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m2/day to be repeated every 4-6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.

Adult↗

PubMed1996

A pilot trial of continuous infusion 5-fluorouracil with levamisole for adjuvant therapy of colon cancer.

The relatively high response rate demonstrated with the use of continuous infusion 5-Fluorouracil (CIFU) 200 to 300 mg/m2 per day in disseminated colon cancer is the rationale behind a NCI-sponsored intergroup trial (INT 0153) for postoperative adjuvant therapy of stage III colon cancer. Because CIFU necessitates a significant reduction in the dose of the modulator leucovorin compared with bolus 5-FU, a pilot study of continuous infusion 5-FU in several doses with levamisole was conducted to determine any unexpected toxicity of this combination, and to assess completion rates of levamisole was conducted to determine any unexpected toxicity of this combination, and to assess completion rates of this dose intensive schedule. CIFU, scheduled as two 12-week cycles, was administered at 250 mg/m2 per day. Pending toxicity at the initial dose, CIFU was to be escalated (300 mg/m2) or de-escalated (200 mg/m2). All but one patient entered on this trial completed 24 weeks of adjuvant CIFU+levamisole. Eight patients (57%) completed 24 weeks of therapy with the 2-week scheduled break. One of these 8 patients required a dose reduction without interrupting the schedule. Six patients had toxicity from the CIFU, which obliged us to interrupt the schedule. Limiting toxicities were stomatitis and hand-foot syndrome. No dose-limiting hematologic toxicity was encountered. Three patients (21%) had catheter problems that required replacement. These data suggest that up to 30% of patients started on this regimen may require dose reduction, shorter infusion courses with rest breaks, or both to complete 24 weeks of adjuvant treatment in order to achieve desired dose intensity.

Adult↗

PubMed1995

Adjuvant continuous infusion 5-FU, whole-abdominal radiation, and tumor bed boost in high-risk stage III colon carcinoma: a Southwest Oncology Group Pilot study.

PURPOSE: Results of a combined modality adjuvant pilot program of low-dose continuous-infusion 5-fluorouracil, whole-abdominal radiation, and tumor bed boost in patients with colon cancer with involved nodes and serosal involvement are presented. METHODS AND MATERIALS: Forty-one eligible patients with completely resected T3N1-2M0 colon cancer (modified Astler-Coller C2) were treated with 5-fluorouracil (5-FU) at a dose of 200 mg/m2/day by continuous infusion and 30 Gy of concomitant whole-abdominal radiation in 1 Gy fractions. An additional 16 Gy boost to the tumor bed was administered in 1.6 Gy fractions. After completion of combined modality treatment and a 21-day rest period, patients received 4 days of 5-FU at a dose of 1000 mg/m2 by continuous infusion every 28 days for nine cycles. RESULTS: Five-year disease-free and overall survival estimates were 58 and 67%, respectively, for all T3N1-2 patients. Five-year disease-free and overall survival estimates for the 19 patients with four or fewer nodes were both 61%. Five-year disease-free survival and overall survival estimates for the 20 patients with more than four involved nodes were 55% and 74%, respectively (the exact number of involved nodes were unknown for two patients). Disease-free and overall survival estimates for patients treated with 5-FU and radiation compare favorably to the 5-FU plus levamisole arm of the intergroup adjuvant colon study (Int 0035/SWOG 8591) in patients with more than four positive nodes where the 5-year disease-free and overall survival estimates were 35% and 39%, respectively. Disease-free and overall survival estimates for patients with four or fewer nodes in the 5-FU plus levamisole arm of the intergroup study were 64 and 68%, which is not markedly different from results obtained with radiation and 5-FU in the current study. There were no treatment-related fatalities. Seventeen percent of patients had severe and 7% had life-threatening toxicity of any kind. One patient had an acute partial bowel obstruction and two patients had chronic low grade enteritis. CONCLUSION: Continuous infusion 5-FU and whole-abdominal radiation with tumor bed boost should be further investigated in a larger trial of T3N1-2 colon cancer.

Adult↗

PubMed1995

Phase I study of monoclonal antibody-ricin A chain immunoconjugate Xomazyme-791 in patients with metastatic colon cancer.

The immunoconjugate XMMCO-791/RTA consists of ricin A chain bound to a murine monoclonal antibody MoAb 791T. This monoclonal antibody (MoAb) binds to a glycoprotein of 72 kD, which is expressed on human colorectal carcinoma, ovarian carcinoma, and osteogenic sarcoma. XMMCO-791/RTA was tested in a Phase I trial with proposed dose escalation steps of 0.02, 0.04, 0.15, and 0.2 mg/kg per day. Twelve patients with metastatic colorectal carcinoma were treated at 0.02, 0.03, and 0.04 mg/kg per day dose levels administered over 1 hour on days 1-5. Study-related toxicities were hypotension (6 patients); greater than 10% weight gain (6 patients); peripheral edema (9 patients); fever (4 patients); confusion (3 patients); diarrhea (3 patients); proteinuria, as identified by dipstick (3 patients), greater than 0.6 mg/dl decrease in serum albumin (11 patients); greater than 25% decrease in oncotic pressure (10 patients), and a decrease in ionized calcium (8 patients). Six patients received a second course of treatment. HAMA levels developed in 9 patients and titers increased with number of courses administered. Decreased overall toxicity, in comparison to the first course, was noted, but one patient had an allergic-type response (hypotension, crushing chest pain, diaphoresis) after the test dose of the second course (HAMA level > 10,000 IgG). Life-threatening toxicity in the form of fluid shift, resulting in noncardiac pulmonary edema and third-spacing occurred after course 1 in 1 of 3 patients at the 0.04 mg/kg per day level. No further dose escalation was attempted and no antitumor activity was seen.

Adenocarcinoma↗

PubMed1995

Phase I clinical trial of pyrazoloacridine NSC366140 (PD115934).

The pyrazoloacridine (PZA) analogue NSC366140 (PD115934) entered clinical trial based on unique preclinical characteristics including solid tumor selectivity in vitro, marked antitumor activity in vivo against murine solid tumors, selectivity against noncycling cells, and activity against multidrug-resistant tumor cells. After identification of the pre-clinical efficacy and an acceptable toxicity profile, a Phase I study of PZA was carried out. A total of 28 patients was entered and received a total of 67 treatment courses. The drug was administered via a 1-h infusion every 21 days. The starting dose was 30 mg/m2 with 2-fold dose escalations through 480 mg/m2. The next dose escalation was 50%, to 720 mg/m2. Grade I through grade IV toxicities were observed. Since no dose-limiting toxicities were observed at 480 mg/m2, and up to grade IV toxicities were observed at 720 mg/m2, an intermediate dose, 600 mg/m2, was evaluated. Dose-limiting toxicities at 720 mg/m2 were hematological (grade III and IV neutropenia) in four of six patients and neurological (up to grade III cerebral toxicities, including restlessness, dizziness, agitation/anxiety, personality changes, and nightmares, as well as myoclonus) in three of six patients treated. The pharmacokinetic parameters which helped predict these toxicities included area under the curve and peak plasma level. Pharmacokinetic studies showed interpatient variations in all parameters studied. The mean area under the curve levels of PZA at the highest two dose levels in patients were near the level detected in mice at their maximum tolerated total dose. The recommended starting dose for Phase II trials using this schedule is 600 mg/m2.

Acridines↗

PubMed1994

Response rates--an evolution.

The documented frequency of response of cancers to common chemotherapy agents and combinations appears to have decreased over the decades. Multiple reasons exist for this decline including: changes in eligibility and evaluability criteria; changes in the type of patients entered onto trial; and, altered criteria for response and methods for response assessment. The disinclination to publish negative results also permits a bias in a favor of overestimating a drug's efficacy. Circumspection now is advised in assessing data from older trials.

Antineoplastic Agents↗

PubMed1993

Amonafide treatment of refractory esophageal cancer. A Southwest Oncology Group study.

Amonafide, a synthetic benzisoquinolinedione, was evaluated for treatment of squamous esophageal cancer. Eleven men and 5 women were eligible with a median performance status of 1 and median age of 63 years. Six had no prior treatment. All patients had measurable disease. Therapy consisted of amonafide 300 mg/m2d days 1-5 every 21 days. Thirty-five courses of therapy were delivered. The median number of courses received was two. Sixteen patients are evaluable for toxicity. Thirteen are evaluable for response. Toxicity was severe. Seven patients were hospitalized for toxicity. Six patients had grade IV granulocytopenia; two, grade IV thrombocytopenia. Angioedema developed in one patient; severe exfoliative dermatitis in another. A single partial response, with the decrease in size a supraclavicular node, was noted in a previously untreated patient. Amonafide, in this dose and schedule, is associated with occasionally severe toxicity precluding its likely use in squamous cell esophageal carcinoma.

Adenine↗

PubMed1992

SWOG 8825: melphalan GM-CSF: a phase I study.

The use of intravenous melphalan at higher doses is limited by severe myelosuppression. It was postulated that GM-CSF would permit the use of higher dose melphalan with only moderate myelosuppression easily manageable in an outpatient setting. Therefore, a phase I study of intravenous melphalan utilizing GM-CSF (recombinant granulocyte-macrophage colony-stimulating factor) support was initiated. Intravenous melphalan at doses of 15-45 mg/m2 was administered every 28 days. GM-CSF was utilized at doses of 10-20 micrograms/kg/day subcutaneously Days 2-21 on a 28-day cycle. Twenty-five patients received 53 courses of therapy. The dose-limiting toxicities were severe or life-threatening granulocytopenia and thrombocytopenia. Utilizing 20 micrograms/kg/day GM-CSF, the maximum tolerated dose (MTD) of melphalan is 30 mg/m2 and, with 10 mg/kg/day GM-CSF, the maximum tolerated melphalan dose is only 20 mg/m2. One patient with ovarian cancer achieved a partial response. Because the reported MTD of intravenous melphalan without GM-CSF is 30 mg/m2, GM-CSF has not allowed sufficient escalation of the intravenous melphalan dose for routine outpatient use.

Adenocarcinoma↗

PubMed1988

Colon cancer: medical therapy.

Fluorouracil is the major chemotherapy agent currently available for colon cancer. It is utilized alone or in combination in a variety of schedules, though the optimal schedule has not yet been identified. In addition to the use for metastatic disease, fluorouracil also is useful for adjuvant treatment or in combination with radiation therapy for treatment of locoregional disease.

Colonic Neoplasms↗

PubMed1987

Combined therapies for squamous-cell carcinoma of the esophagus, a Southwest Oncology Group Study (SWOG-8037).

Conservative treatment of esophageal cancer with radiation therapy has afforded few long-term survivors. In order to improve outcome, patients with locoregional disease were treated using a combined modality approach. Patients were treated with chemotherapy consisting of a 96-hour continuous infusion of 5-fluorouracil (5-FU), 1,000 mg/m2/d, days 1 to 4 and days 29 to 32; cisplatin 75 mg/m2, day 1 and 29; and radiation 3,000 rad, days 1 to 19. In the absence of progressive disease, patients underwent esophagectomy. One hundred twenty-eight patients were registered of whom 113 were eligible and 106 were evaluable. Toxicity included gastrointestinal (GI) symptoms, mucositis, and myelosuppression. One hundred two patients completed chemoradiotherapy. Following its completion, 11 patients refused surgery, six were considered poor surgical risks, and 14 had progressive disease. Of the remaining 71 patients, 16 had unresectable disease, 13 had residual disease which was incompletely resected, 24 had disease which could be completely resected, and 18 were without disease on pathologic examination. The overall operability rate was 63% and the overall resectability rate, 49%. Surgical mortality was 11%. Eighty-nine of 113 eligible patients have died, with a median survival of 12 months and a 2-year survival of 28%. The median postsurgical survival for all 71 patients was 14 months and was 32 months for those patients attaining complete remission (CR). Combined modality therapy remains an investigational approach. Attempts should be directed at increasing response rate to initial therapy. A randomized comparison between combined modality treatment and radiation therapy is necessary to definitively determine the usefulness of this more aggressive approach.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1987

Small cell carcinoma of the lung: influence of age on treatment outcome.

Two hundred twenty-three patients between 29 and 78 years of age with small cell cancer of the lung were studied in serial protocols at the University of Maryland Cancer Center from 1975 to 1982. Each of these patients received chemotherapy consisting of doxorubicin, cyclophosphamide, and etoposide. In this paper we explore age and its interaction with the patient's extent of disease as it relates to clinical outcome variables such as the achievement of a complete response (CR), survival times, and various measures of toxicity. Preliminary evidence is found to suggest that an age-extent of disease interaction affects both the probability of obtaining a CR and the length of survival. Patients of all ages can benefit from treatment of small cell carcinoma of the lung, with CR as the treatment goal. However, increased toxicity and early death remain as barriers to successful treatment of the elderly.

Actuarial Analysis↗

PubMed1986

Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous infusion.

A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m2 per day for 5 days and repeated every 21-28 days. The patient population had a median age of 55 years (range 38-76) and a median Karnofsky performance status of 80 (range 60-100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/microliter (range 100-4800) in 8 heavily pretreated patients treated at 350 mg/m2 per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m2 and had WBC nadirs of 800/microliter and 600/microliter. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m2 per day, nadir 85,000/microliter). Neither hyponatremia nor symptomatic hypo-osmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m2 per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09-6.79 micrograms/ml. Steady state was achieved in 14.5 +/- 5.9 h (mean +/- SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t 1/2 of 5.3 +/- 3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543 +/- 150 micrograms/ml h and reflected a cyclophosphamide total-body clearance (CLTB) of 103 +/- 31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6-4.3 micrograms/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3% +/- 7.6% and 15.1% +/- 2.0% of the administered daily dose, respectively. The t1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m2 as an i.v. bolus.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗