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Biomedical subjects

B G Redman

Publications and source records attributed to B G Redman.

At least 37 records · Page 2Linked to original sources
PubMed1994

Phase II trial of recombinant human macrophage colony-stimulating factor in metastatic soft tissue sarcoma.

This Phase II study was undertaken to access the activity of recombinant human macrophage colony stimulating factor (M-CSF) in metastatic soft tissue sarcoma based on the observation of a partial response in a patient with leiomyosarcoma during an earlier Phase I trial. Fifteen patients with metastatic soft tissue sarcoma (seven males and eight females) were entered on the trial between October 1990 and March 1991. Seven of these patients had leiomyosarcoma. One mg/M2 of M-CSF was administered by rapid intravenous infusion every 8 h on days 1-5 and 15-19. Treatment cycles were repeated at 35-day intervals. Patients were evaluated initially for response after the first cycle, and then following alternate cycles. One partial response was observed in a patient with metastatic small bowel leiomyosarcoma (response rate 7%, 95% confidence interval, 0-33%). Two additional patients had stable disease for 10-15 months on study. Four patients had clinically significant bleeding from tumor sites during M-CSF therapy. No evidence of toxicity directly attributable to M-CSF was observed in any patient. Mean monocyte counts increased in patients during the first 20 days of treatment (p = 0.013). At this dose and schedule, meaningful activity of M-CSF in previously treated patients with soft tissue sarcoma could not be demonstrated. However, the activity observed in patients with leiomyosarcoma in this trial and in the previous Phase I study are intriguing. Further studies of M-CSF in previously untreated patients with leiomyosarcoma may be warranted.

Adolescent↗
PubMed1993

A phase II study of dacarbazine and cisplatin in combination with outpatient administered interleukin-2 in metastatic malignant melanoma.

BACKGROUND: Based on prior experience with dacarbazine (DTIC) and an outpatient interleukin-2 (IL-2) regimen, the current study was conducted to improve the antitumor efficacy and assess the immunologic interactions between chemotherapy and IL-2. METHODS: Thirty-two patients were registered onto a treatment program, which included DTIC 750 mg/m2 with cisplatin 100 mg/m2, each by intravenous bolus on day 1. Recombinant IL-2 was administered on an outpatient basis intravenously by 15-30-minute infusion (24.0 x 10(6) IU/m2) daily on days 12-16 and 19-23 of a 28-day cycle for three cycles and then every 42 days for responding patients. RESULTS: There were responses in 13 of the 32 registered patients (41% response rate), including five complete and eight partial remissions. Responses in the liver, lung, spleen, lymph nodes, and soft tissue sites were noted. The median duration of response was 8.0 months (range, 3.0-20.0+ months), and the overall median survival duration was 10.2 months. Three patients (9%) are alive, free of disease, without any treatment at 32.0+, 36.0+, and 42.0+ months after initiation of treatment. Only minor nephrotoxicity was observed, and treatment delays were rare. CONCLUSIONS: Additional chemotherapeutic, hormonal, or biologic agents may be added to enhance efficacy further if they have toxicities that do not overlap.

Adolescent↗
PubMed1993

Immunotherapy for metastatic renal cell cancer: effect on the primary tumor.

The traditional approach to immunotherapy for metastatic renal cell cancer, to first reduce the tumor burden by nephrectomy and then offer systemic therapy, has been challenged recently. There is mounting evidence that objective responses in the metastatic disease can be achieved without prior nephrectomy, although responses in the primary tumor are much less frequent. We describe our experience that some patients may, in fact, have significant responses in extensive local disease and become surgical candidates after systemic immunotherapy. A 46-year-old patient who presented with a large renal primary tumor and pulmonary metastases was treated with high-dose interleukin 2 therapy. A complete response in the lung and partial response in the primary tumor was achieved. The patient then underwent resection of his primary tumor, and on histological evaluation only minimal residual cancer was present. He has no evidence of disease at 14 months. This case demonstrates that immunotherapy can achieve not only objective responses at metastatic sites but also in the primary tumor.

CD4-CD8 Ratio↗
PubMed1992

Difluorodeoxycytidine (dFdC)--gemcitabine: a phase I study.

Difluorodeoxycytidine (dFdC) demonstrated broad spectrum activity in preclinical models. A phase 1 study utilizing twice weekly injections was conducted in 50 eligible and evaluable patients. Twenty-nine patients received drug by 30 minute infusion at doses of 5-90 mg/m2 and 22, by 5 minute bolus at 30-150 mg/m2. The primary dose limiting toxicities were marrow suppression and flu-like symptomatology. Thrombocytopenia was dose limiting at 75 mg/m2 on the infusion schedule and 150 mg/m2 on the 5 minute schedule. Flu-like symptoms with fever, rigors and malaise occurred the day of injection in many patients. One patient with renal cell carcinoma attained a partial response. Evaluation of the drug's efficacy and schedule dependency continue.

Adult↗
PubMed1992

Effect of calcium replacement on the hemodynamic changes associated with high dose interleukin-2 therapy.

Administration of high-dose IL-2 results in hemodynamic changes that are similar to those seen in septic shock. These include a decrease in systemic vascular resistance (SVR) with a resultant drop in mean arterial pressure (MAP). Hypocalcemia is seen in septic shock and with IL-2 administration. Calcium replacement in septic shock has been reported to result in hemodynamic improvement; we therefore administered calcium to patients receiving high dose IL-2 to correct ionized hypocalcemia. Five consecutive patients underwent invasive hemodynamic monitoring before and during IL-2 administration. Calcium chloride was administered to correct ionized hypocalcemia, and hemodynamic parameters were monitored before and after calcium administration. Ionized hypocalcemia was associated with an elevation in parathyroid hormone levels. There was no toxicity related to the administration of calcium. An improvement in the MAP and SVR was seen early and late (after a dose of IL-2 was held) in the IL-2 treatment cycle; there were minimal effects at other points. Because of the potential hemodynamic benefit of calcium replacement, we recommend that ionized hypocalcemia be corrected in patients receiving high-dose IL-2.

Adult↗
PubMed1992

Reversible cardiomyopathy after high-dose interleukin-2 therapy.

We observed two patients who developed moderate global myocardial dysfunction during therapy with high-dose interleukin-2 (IL-2). Although cardiac enzymes became markedly elevated at the completion of a full course of IL-2, patients exhibited no ischemic symptoms. Serial echocardiography documented global myocardial dysfunction, which resolved in 5 days in one patient but persisted beyond 4 weeks in another. Asymptomatic reversible myocardial injury can occur with high-dose IL-2 and can persist beyond 4 weeks after stopping therapy. Review of the literature suggests an IL-2-associated myocarditis as an etiology.

Adult↗
PubMed1992

Phase I trial of recombinant macrophage colony-stimulating factor by rapid intravenous infusion in patients with cancer.

Fourteen patients were entered into a phase I dose-escalation trial of macrophage colony-stimulating factor (M-CSF). M-CSF was administered to inpatients by rapid 15 min i.v. infusion every 8 h x 5 days, repeated after a 9-day rest. Dose levels evaluated were 20, 40, 80, 330, and 1,100 micrograms/m2. Monitoring of patients every 4 h included vital signs, daily complete blood count (CBC), and serum chemistries (SGOT, creatinine, and bilirubin) while receiving M-CSF. No clinical or laboratory evidence of toxicity was seen. The average serum t1/2 varied with dose level. At 330 and 1,100 micrograms/m2, the serum t1/2 was 25 and 84 min, respectively, implying a saturable mechanism of clearance. After 5 days of treatment, the t1/2 decreased by twofold, consistent with enhancement of the saturable mechanism. Monocyte cytotoxicity against the A375 melanoma cell line was evaluated pretreatment and day 5 of each cycle. No consistent enhancement of monocyte cytotoxicity was seen. No effect on peripheral blood monocyte number was seen until the 1,100 micrograms/m2 dose level. At this dose level, the mean monocyte number on day 5 was increased compared to baseline (1,300 mm3 vs. 300/mm3). Clinical activity was seen in two patients with previously progressive leiomyosarcoma metastatic to the liver. A partial response (PR) lasting 7 months occurred at the 330 micrograms/m2 dose level while a patient treated at 1,100 micrograms/m2 has had stable disease for 20+ months. The maximum tolerated dose (MTD) of M-CSF was not determined. Based on clinical responses, a phase II trial is warranted in patients with metastatic soft tissue sarcoma.

Antineoplastic Agents↗
PubMed1991

Sequential dacarbazine/cisplatin and interleukin-2 in metastatic melanoma: immunological effects of therapy.

Thirteen previously untreated patients with metastatic melanoma entered into a phase II chemo-immunotherapy trial were monitored immunologically during treatment. Treatment consisted of dacarbazine (DTIC) 750 mg/m2 and cisplatin 100 mg/m2 on day 1 followed by interleukin-2 (IL-2) 4 x 10(6) U/m2 by daily intravenous bolus on days 12-16 and 19-23. Cycles were repeated every 28 days. On days 1 (pretreatment), 12, 16, and 23 of each cycle, lymphokine-activated killer (LAK) cell and natural killer cell activity as well as total lymphocyte count and CD3, CD4, CD8, and CD56 lymphocyte subsets were analyzed. Despite pretreatment with full-dose cytotoxic chemotherapy, all patients were able to respond immunologically to IL-2. Spontaneous LAK cell activity was generated by the end of each course of IL-2 administration and persisted for at least 5 days thereafter. Lymphocytosis was maximum at 5 days after IL-2 administration and included increased numbers of all measured lymphocyte subsets. IL-2 administration caused a relative increase in CD56+ cells and a relative decrease in CD3+ cells. There was a direct correlation between the increase in LAK cell activity and the increase in CD56+ lymphocytes. Antitumor responses occurred in five patients but these responses did not correlate with any of the measured changes in LAK activity or lymphocyte subsets. DTIC and cisplatin administered in this schedule does not abrogate the immunological effects of IL-2.

Adolescent↗
PubMed1990

Antitumor efficacy of interleukin-2 alone and in combination with adriamycin and dacarbazine in murine solid tumor systems.

Recombinant interleukin-2 (IL-2)/chemotherapy combinations have recently entered clinical trial. The rationale for sequencing has primarily been empiric or based on in vitro data. To establish in vivo models for chemoimmunotherapy trials, we investigated IL-2 alone and in combination with dacarbazine (DTIC) and adriamycin. IL-2 (as a single agent given i.v. at 1-3 x 10(5) Cetus units once daily for 5 days, repeated 7-10 days later), was highly active against an immunogenic line of colon adenocarcinoma no. 11/A [tumor growth inhibition (T/C) = 0% with cures]. It was modestly active against colon adenocarcinoma no. 38 (T/C = 39%), mammary adenocarcinoma no. 16/C (T/C = 18%), and B16 melanoma (T/C = 21%). IL-2 was inactive against colon adenocarcinoma no. 7/A (T/C = 83%). Combination trials were done using DTIC and IL-2 against colon no. 7/A and upstaged colon no. 11/A. The combination of adriamycin and IL-2 was tested against mammary adenocarcinoma no. 16/C. In the DTIC/IL-2 combination trials, the combination was superior over either agent used alone. In the IL-2/adriamycin trials, the combination was no better than adriamycin alone at optimum dosages.

Adenocarcinoma↗
PubMed1990

A phase I-II study of dacarbazine in combination with outpatient interleukin-2 in metastatic malignant melanoma.

Because of encouraging response rates published with recombinant interleukin-2 (rIL-2) alone in metastatic malignant melanoma (MMM), dacarbazine (DTIC) and rIL-2 were sequentially combined to evaluate efficacy, toxicity, pharmacokinetics, and immunologic interaction. Thirty-two patients aged 18 to 67 years have received 127 courses of treatment. The dose of DTIC was 1.0 g/m2 as a 24-hour infusion every 28 days on day 1. Recombinant interleukin-2 (2.0, 3.0, 4.0, or 5.0 x 10(6) Cetus units/m2) was administered as a 30-minute infusion on days 15 through 19 and 22 through 26 of each 28-day cycle. Seven of 32 patients (22%) who received therapy had a remission, one complete and six partial. The complete response was in a lung mass. Partial responses were seen in lymph nodes, liver, and lung. The median duration of response was 4.7 months. One patient is in persistent partial remission of the liver for greater than 2 years. One patient had residual mediastinal disease resected after partial response and remains without evidence of disease for 18+ months. This regimen was generally well tolerated, did not create overlapping toxicity, and produced encouraging responses in visceral sites. This provides a framework for future combinations of chemotherapy with rIL-2 alone or in combination with other biologic response modifiers in an outpatient setting.

Adolescent↗
PubMed1990

Phase II trial of high-dose intermittent interleukin-2 in metastatic renal cell carcinoma: a Southwest Oncology Group study.

A phase II trial of intermittent high-dose recombinant interleukin-2 (rIL-2) was initiated to evaluate the response rate, remission duration, and toxic effects in patients with measurable metastatic renal cell carcinoma. The rIL-2 was administered as a bolus intravenous infusion at a dose level of 10.0 x 10(6) U/m2 three times weekly, preceded by indomethacin (50 mg orally). Dose reductions of rIL-2 for hypotension and other grade 3 or 4 toxic effects were permitted. Forty-four patients were entered and 41 were eligible. Previous treatment included nephrectomy (23 patients), radiation therapy (seven), and hormone therapy (three). Most toxic effects observed were moderate and included nausea, vomiting, anorexia (85%); hypotension (85%); fever, chills (78%); central nervous system changes (24%); myelosuppression (27%); and creatinine elevation (15%). Four instances of grade 4 toxicity were observed and included nausea, vomiting with dehydration; hypotension; and myocardial infarction. Thirty patients (73%) required dose adjustments because of toxicity. Five responses (12%) were seen, which included one complete and four partial. Sites of response included lung, liver, and soft tissue; the duration of response ranged from 2 to 20+ months. These results demonstrate that this schedule of rIL-2 can be administered in an outpatient setting, and can produce tumor regression in patients with metastatic renal cell carcinoma, including durable complete responses.

Adult↗
PubMed1990

A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer.

Twenty-six patients with metastatic cancer were entered into a phase I trial of concurrent recombinant interleukin-2 (IL-2) and recombinant interferon-gamma (IFN-gamma). IL-2 was administered as a continuous intravenous infusion for 5 days. IFN-gamma was administered by a daily intramuscular (IM) injection during the 5 days of IL-2 administration. Treatment was repeated twice after 9-day rest periods. After a 2-week rest, patients without evidence of tumor progression were retreated. Natural killer (NK)- and lymphokine-activated killer (LAK)-cell activity were assayed in each patient before treatment, on day 1, and on day 5 of each cycle. Constitutional symptoms occurred in most patients but were not dose-limiting. Other toxicities included hypotension responsive to fluids, transient elevations in liver function tests, erythema/pruritus, eosinophilia, and transient leukopenia/thrombocytopenia. The maximum-tolerated dose (MTD) of the combination was 1 x 10(6) U/m2/d of IL-2 combined with 0.50 mg/m2/d of IFN-gamma. The dose-limiting toxicity was pulmonary manifesting as rales and shortness of breath. The dose of the combination that resulted in the optimal generation of in vivo LAK-cell activity was a dose of at least 0.25 mg/m2/d of IFN-gamma combined with 1 x 10(6) U/m2/d of IL-2. Objective clinical responses were seen in five of 26 patients. These included a partial response of 2 months duration in a patient with non-Hodgkin's lymphoma (NHL), mixed responses in a patient with NHL and two patients with renal cell carcinoma (RCC), and an ongoing assessable response in a patient with bone metastases from RCC. The recommended dose for phase II trials of this combination is 0.50 mg/m2 of IFN-gamma and 1 x 10(6) U of IL-2.

Adolescent↗
PubMed1989

Low-dose continuous infusion 5-fluorouracil and cisplatin: phase II evaluation in advanced colorectal carcinoma.

A study was performed to evaluate the combination of low-dose continuous infusion 5-fluorouracil (LDCI-FU) (300 mg/m2 daily for 28 days) and cisplatin (20 mg/m2 days 1-5 and 24-28). Patients were treated for 28 days with a subsequent 14-day rest period. A total of 24 patients were entered on the study and were evaluable for response and toxicity. All patients were previously untreated, with a median age of 61.5 years and median performance status of 70% (Karnofsky). Bidimensional measurable disease was required. Complete responses were noted in 2 of 24 (8%) patients lasting 8+ and 9 months. Partial responses were observed in 8 of 24 (33%), with a median duration of response of 6 months. Median survival for the 24 patients was 9+ months. Toxicities included nausea and vomiting (25%), hand-foot syndrome (21%), diarrhea (4%), myelosuppression (21%), neurotoxicity (13%), gastric ulceration (13%), mucositis (17%), nephrotoxicity (4%), and subclavian vein thrombosis (21%). This combination demonstrated antineoplastic activity; however, its efficacy parallels other trials utilizing both single agent 5-fluorouracil (5-FU) and different variations of the 5-FU/cisplatin in combination. The impact of this combination on survival and comparison to other regimens requires a randomized trial.

Adenocarcinoma↗
PubMed1987

Phase I trial of spiromustine (NSC 172112) and evaluation of toxicity and schedule in a murine model.

Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly X 3. Concurrent murine studies confirmed spiromustine as a schedule independent drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.

Animals↗
PubMed1987

Prospective evaluation of adrenal insufficiency in patients with adrenal metastasis.

Fifteen consecutive patients with metastatic carcinoma who demonstrated bilateral adrenal metastasis on abdominal computed tomography (CT) were evaluated by the cosyntropin challenge test. Primary sites of tumors included lung, ten; colon, two; gastric, one; ovarian, one; and unknown primary, one. Bilateral adrenal enlargement was defined as greater than 1 cm on CT scan. Adrenal insufficiency was defined as a failure to increase serum cortisol by at least 5 micrograms/100 ml to a minimum of 15 micrograms/100 ml at either 30 or 60 minutes postcosyntropin. No patient had previously been on corticosteroids. All patients were questioned and examined for symptoms/signs of adrenal insufficiency. Five patients (33%) were found to have adrenal insufficiency based on the cosyntropin test. Of the clinical parameters evaluated, all five patients had nausea, anorexia, and orthostatic hypotension. The clinical onset of adrenal insufficiency was insidious; no patient experienced acute adrenal crisis. We conclude that adrenal insufficiency is not a rare occurrence in patients with metastatic cancer and bilateral adrenal involvement on CT scan.

Adrenal Gland Neoplasms↗
PubMed1987

Colonic small cell undifferentiated carcinoma: a distinct pathological diagnosis with therapeutic implications.

A case of metastatic primary small cell undifferentiated carcinoma of the colon responding to combination chemotherapy is reported. A review of small cell undifferentiated carcinoma of the gastrointestinal tract with attention to the colon is discussed. Recommendations for the management of this rare neoplasm are presented based on its similarity to the more common bronchogenic small cell undifferentiated carcinoma.

Adenocarcinoma↗