Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nine patients with metastatic malignant melanoma were entered onto a phase II trial consisting of WR-2721, 740 mg/m2 i.v. over 15 min, followed 15 min after completion by cisplatin, 100 mg/m2 i.v. over 30 min in 250 cc of 3% saline, on days 1 and 8 every 4 weeks. Six patients received two full courses of chemotherapy and were considered evaluable for response. No patients obtained a response. Toxicity, assessed according to the National Cancer Institute Common Toxicity Criteria, was acceptable and usually transient. However, fatigue, which manifested as a decrease in performance status, was significant in six of eight patients in whom this side effect could be evaluated. This subjective toxicity was most likely due to the high-dose cisplatin therapy. The lack of response in six fully evaluable patients allowed us to conclude with greater than 95% confidence that the combination of high-dose cisplatin and WR-2721 in a split-course day 1 and 8 schedule has a true response rate of less than 40%. In view of the relatively high subjective toxicity observed in our study and the more encouraging results observed by other groups using a different dose schedule of WR-2721 plus cisplatin, we do not recommend the use of high-dose cisplatin plus WR-2721 as employed in this trial.
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PMID:High-dose cisplatin plus WR-2721 in a split course in metastatic malignant melanoma. A phase II study. 185 2

Recombinant interleukin 2 (IL-2) is a potent inducer of lymphokine-activated killer (LAK) activity directed against autologous and allogeneic tumors; these effects are mediated by CD3-negative, CD56-positive, and CD16-positive lymphocytes. Although IL-2 therapy has been associated with clinical responses, particularly in patients with renal cell carcinoma and melanoma, these responses have occurred with high, toxic doses of this cytokine. Since gamma-interferon (IFN-gamma) potentiates LAK activity in vitro and in animal models, we initiated a dose-escalating Phase I trial of IFN-gamma and IL-2 in patients with advanced cancer. Patients were treated three times weekly (Monday, Wednesday, and Friday) for 6 weeks with bolus injections of IL-2; each dose was preceded 2 h earlier by a s.c. injection of IFN-gamma. Patients were treated with IFN-gamma at 0.01, 0.05, 0.1, or 0.25 mg/m2/dose. At each IFN-gamma dose, cohorts of at least three patients were treated with IL-2 at 1, 2.5, 5.0, or 7.5 x 10(6) Cetus units/m2 dose. Patients with clinical responses continued therapy three times weekly, while those with stable disease at 6 weeks were then treated twice weekly. A total of 41 patients were treated, all with Eastern Cooperative Oncology Group performance status 0 or 1. All patients were evaluable for toxicity. Dose-limiting toxicities were cumulative fatigue and constitutional symptoms. One documented transmural myocardial infarct occurred. The maximally tolerated dose combination, based on analysis of IL-2 dose intensity, was 0.1 mg IFN-gamma/m2 and 7.5 x 10(6) Cetus units IL-2/m2 per dose. Two partial responses and two minor responses were observed. Treatment was not associated with dose-associated changes in peripheral blood lymphocyte phenotype, but there was a trend favoring IFN-gamma dose-associated rises in IL-2 induction of natural killer and LAK activity by treated patients' lymphocytes. Analysis of the cumulative effects of therapy on induction of natural killer and LAK activity by measurement of the median area under the curve of activation showed clear evidence of IFN-gamma and IL-2 dose-associated changes. The IL-2 dose effects on cell lysis were monotone, while the optimal IFN-gamma dose appeared to be 0.1 mg/m2/dose, with a bell-shaped dose-response curve described previously for other effects of this cytokine. Using this novel statistical method of evaluating the biological effects of treatment, the optimal biological dose was identical to the maximally tolerated dose.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phase I evaluation of combination therapy with interleukin 2 and gamma-interferon. 190 79

This study was undertaken to define the maximum tolerated dose (MTD) of recombinant interleukin-2 (IL-2) that could be combined with a fixed dose of alpha-2a-interferon (alpha-IFN) in an outpatient setting. The schedule called for IL-2 to be given by a 2-hour intravenous infusion 5 days a week for 4 weeks. The alpha-IFN was given at a dose of 6 x 10(6) U/m2/d intramuscularly 3 days per week (Monday, Wednesday, and Friday). The IL-2 dose was escalated in four dose levels from 1 to 4 x 10(6) U/m2/d. The MTD in this study of 17 patients was at the fourth dose level of IL-2 (4 x 10(6) U/m2/d). In addition to the usual IL-2 toxicities, debilitating fatigue limited outpatient administration of this dose. Although the response rate was low, with partial responses seen in only 1 of 15 patients, 2 of 5 patients with melanoma treated at the higher dose levels had objective tumor shrinkage with one partial and one minor response. Thus, an IL-2 dose of 3 x 10(6) U/m2/d combined with a recombinant alpha-2a-IFN dose of 6 x 10(6) U/m2/d is recommended for Phase II studies.
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PMID:A phase I study of an outpatient regimen of recombinant human interleukin-2 and alpha-2a-interferon in patients with solid tumors. 191 12

A phase I trial of piritrexim was conducted by use of a prolonged, low-dose oral schedule. A number of different regimens were tested, including daily dosing for 21 days followed by 7 days of no drug therapy; continuous dosing; and daily dosing for 5 of 7 days for 3 consecutive weeks followed by a week of rest. Dose escalation was accomplished by increasing the dosing frequency from once a day to twice a day and then to three times a day and by increasing the number of days of administration. Fifty-one patients with advanced cancer were entered in the study. One hundred twenty-four (96%) of 129 courses were considered assessable. Myelosuppression proved to be the dose-limiting toxic effect. Other toxic effects included stomatitis, nausea and vomiting, anorexia, diarrhea, skin rash, fatigue, and elevation of liver transaminase levels. Antitumor activity was observed in patients with melanoma and bladder cancer, and disease stabilization occurred in those with sarcoma and pheochromocytoma. The recommended dosing schedule for phase II clinical trials is 25 mg three times a day for 5 days for 3 consecutive weeks followed by 1 week of no drug therapy.
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PMID:Phase I trial of piritrexim capsules using prolonged, low-dose oral administration for the treatment of advanced malignancies. 198 18

Our group and others have conducted phase II trials of high-dose interleukin-2 (IL-2) or IL-2 with the adoptive transfer of in vitro activated lymphocytes in patients with advanced malignancies. Although durable complete and partial responses were seen in patients with renal cell carcinoma and metastatic melanoma, overall response rates were low and toxicity was substantial. In preclinical models, the combination of IL-2 and interferon-alpha has synergistic antitumor activity. Based on these data, and our prior experience with high-dose IL-2 (Cetus), we conducted a trial to determine the maximum tolerated dose of IL-2 (0.4, 0.8, and 1.2 mg/m2) administered together with a fixed dose of interferon-alpha 2b (3 x 10(6) u/m2) intravenously every 8 h on days 1-5 and 15-19. Patients were monitored in the intensive care unit and given pressor support for hypotension as needed. Twenty-four patients were entered (6, 10, and 8 at each IL-2 dose, respectively; 14 renal cell carcinoma, 7 melanoma, 2 colon, and 1 hepatoma). The median age was 56 years, the male to female ratio was 19:5, and performance status was 0 or 1 (Eastern Cooperative Oncology Group) in all patients. Toxicity was similar at all dose levels, but the onset was earlier in the treatment course as the dose of IL-2 was escalated in successive cohorts; therefore, more doses were withheld at the higher dose levels. The major toxicities resulting in the interruption or stopping of treatment were hypotension requiring pressors, dyspnea, and neurotoxicity. Grade 1 or 2 fever, nausea and vomiting, fatigue, and cutaneous reactions were common at all dose levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A phase I study of high-dose interleukin-2 in combination with interferon-alpha 2b. 207 39

This paper gives a short review on the function, pharmacokinetics, and therapeutic application of recombinant interferon-gamma (rIFN-gamma) in dermatology. Simultaneously, our own experiences are presented for 57 patients (phase II study) suffering from genital warts (21 patients), psoriatic arthritis (10 patients), psoriasis vulgaris (three patients), malignant melanoma (six patients), bowenoid papulosis (four patients), Behcet's disease (four patients), basal cell carcinoma (six patients), as well as herpes simplex recidivans, epidermodysplasia verruciformis, and mycosis fungoides (one patient each). We conclude that there might be an indication for treatment with rIFN-gamma in genital warts, bowenoid papulosis, Behcet's disease, and microbial infections, such as leprosy and cutaneous leishmaniasis. Even though there are reports of a limited beneficial effect of rIFN-gamma on arthritis and skin lesions in psoriasis, we failed to observe any in 10 patients. The main side effects in our low-dose study (50-100 micrograms/d) were mild fever (78%), fatigue (78%), and myalgia (65%). Laboratory tests revealed an increase in the serum triglyceride level, in particular, in psoriatic patients.
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PMID:Recombinant interferon-gamma (rIFN-gamma) in dermatology. 212 42

Based on the report of some activity of combination therapy with dacarbazine (DTIC) and interferon alpha-2a (rIFN alpha-2a) in disseminated melanoma, we conducted a phase II study to determine the feasibility and efficacy in a large series of patients. DTIC was administered in 79 patients at the dose of 800 mg/m2 every 3 weeks and rIFN alpha-2a was given daily at the dose of 9 X 10(6) IU for the first 10 weeks and three times a week thereafter. Among the 75 evaluable patients, 25% achieved an objective response, with 8% complete and 17% partial remissions. The regression occurred within a mean time of 1.9 +/- 1.03 months from starting therapy and the mean duration of response was 8.2 +/- 4.2 months. The major side effects were vomiting, anorexia, fever, fatigue, and myalgia. There was one death related to sepsis after myelosuppression. In the other patients bone marrow and liver toxicities were not remarkable. Our data reveal that a combination regimen of rIFN alpha-2a with a cytotoxic agent has some therapeutic activity in the management of advanced malignant melanoma.
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PMID:Phase II study of interferon alpha-2a and dacarbazine in advanced melanoma. 222 Jun 60

Ninety-seven evaluable patients with measurable, advanced, malignant melanoma were treated with recombinant alpha interferon in a cooperative phase II efficacy trial, whose primary objective was to estimate the response rate. Interferon (rIFN alpha-2a, Roferon-A) was injected subcutaneously daily for 70 days. Dose was escalated in four steps from three million units to 36 million units over ten days. Eight patients responded objectively and six patients (6%) had a complete response. The median duration of complete response was 11 months. Patients achieving complete response had only cutaneous, nodal, or pulmonary disease; some had extensive prior therapy; some could tolerate no more than three million units per day. Few patients could tolerate the target dose of 36 million units daily for 70 days. Limiting toxicity was primarily fatigue. Interferon in tolerable doses is effective in a small subset of patients with melanoma. Comparison of published trials of dacarbazine and recombinant alpha interferon indicates the two drugs have similar activity.
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PMID:Phase II study of recombinant alpha-interferon in malignant melanoma. 223 1

Merbarone, a nonsedating derivative of thiobarbituric acid, has demonstrated excellent activity against certain murine tumors, including L1210 and P388 leukemias, B16 melanoma, and M5076 sarcoma. Preclinical studies suggested that the antitumor effects of this drug were schedule dependent, since repeated dosing increased killing of tumor cells when compared to intermittent injections. We have completed a Phase I clinical and pharmacological study of merbarone in which the drug was administered both as a 2-h infusion and as a continuous i.v. infusion over 24 h. In view of the increased toxicity observed in animals following bolus injections and the possibility of schedule-dependent anticancer activity, a schedule of drug administration daily for 5 days was selected. Fifty patients with advanced cancer were treated at dose levels that ranged from 100 to 1500 mg/m2/day. When the drug was administered by peripheral vein, phlebitis was observed at the infusion site at daily doses greater than or equal to 150 mg/m2. Therefore, all patients who received drug doses greater than or equal to 200 mg/m2 were treated by continuous i.v. infusion using central venous catheters. Renal insufficiency, initially observed at a dose of 1000 mg/m2/day, was the dose-limiting toxic reaction at 1500 mg/m2/day. Three of five patients treated at the highest dose level were unable to complete the infusion due to this effect. Marked hypouricemia was observed in all patients. Other toxic effects were mild and included nausea, fatigue, leukopenia, thrombocytopenia, and anorexia. Alopecia was noted in several patients who received doses greater than or equal to 1000 mg/m2/day. No major antitumor effects were observed. Dose-dependent, steady-state plasma concentrations of merbarone were reached within 24-48 h after beginning the continuous i.v. infusion. Elimination of drug from plasma followed a two-compartment model, with a t1/2 alpha of 4.2 h and a t1/2 beta of 15.3 h. Renal excretion of merbarone and its major metabolites accounted for less than 30% of the administered dose. We conclude that merbarone is relatively well tolerated with few constitutional symptoms. The current formulation of the drug causes phlebitis when administered by peripheral vein, and renal insufficiency is commonly observed at daily doses which exceed 1250 mg/m2. The recommended dose for extended Phase II evaluation is 1000 mg/m2/day daily for 5 days administered by central venous catheter.
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PMID:Phase I clinical and pharmacological study of merbarone. 229 63

A 32-year-old man was seen with shortness of breath and increasing fatigue. Echocardiography revealed an intracavitary mass occupying the entire left atrium. The lesion was resected using cardiopulmonary bypass and found to be a large malignant melanoma. This case represents the rare occasion in which antemortem diagnosis of malignant melanoma within left atrium permitted successful palliative surgical resection. The patient is alive and active 6 months after operation.
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PMID:Intracavitary melanoma of the left atrium. 230 53


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