Cisplatin, Dacarbazine With or Without Subcutaneous Interleukin-2, and Interferon Alfa-2b in Advanced Melanoma Outpatients: Results From an Italian Multicenter Phase III Randomized Clinical Trial

PURPOSE: Phase II and III studies have shown that the addition of interleukin-2 (IL-2) and interferon alfa-2b (IFNα-2b) in multiagent chemotherapy (CT) for advanced melanoma increases overall response (OR), albeit without clear evidence of an improvement in overall survival (OS). Treatment with high-dose IL-2 can cause severe toxicity and is normally administered in an inpatient setting. We conducted a multicenter prospective randomized clinical trial in outpatients with metastatic melanoma to compare CT with biochemotherapy (bioCT) using immunomodulant doses of IL-2 and IFNα-2b. PATIENTS AND METHODS: One hundred seventy-six eligible patients with advanced melanoma were randomized to receive CT (cisplatin and dacarbazine with or without carmustine every 21 days) or bioCT comprising the same CT regimen followed by low-dose subcutaneous IL-2 for 8 days and IFNα2b three times a week, both for six cycles. RESULTS: At a median follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus 11.0 months (P = .51), respectively. In the 89 CT-arm patients, 18 ORs (20.2%) (three complete responders [CRs] and 15 partial responders [PRs]) were observed according to World Health Organization criteria. In the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P = .70) were recorded. Treatment-related toxicity was fairly similar in both arms. CONCLUSION: The addition of low-dose immunotherapy did not produce a statistically significant advantage in OS, time to progression, or OR. However, the 11-month median OS in the bioCT arm does not differ greatly from the best results with high-dose IL-2–containing regimens reported in the literature. Furthermore, our treatment schedule was carried out on outpatients and had an acceptable level of toxicity.

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Cisplatin, Dacarbazine With or Without Subcutaneous Interleukin-2, and Interferon Alfa-2b in Advanced Melanoma Outpatients: Results From an Italian Multicenter Phase III Randomized Clinical Trial

Journal of Clinical Oncology ◽

10.1200/jco.20.6.1600 ◽

2002 ◽

Vol 20 (6) ◽

pp. 1600-1607 ◽

Cited By ~ 58

Author(s):

R. Ridolfi

Keyword(s):

Clinical Trial ◽

Randomized Clinical Trial ◽

Interleukin 2 ◽

Advanced Melanoma ◽

Interferon Alfa ◽

Phase Iii ◽

Multicenter Phase

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Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.10.1969 ◽

1993 ◽

Vol 11 (10) ◽

pp. 1969-1977 ◽

Cited By ~ 130

Author(s):

J A Sparano ◽

R I Fisher ◽

M Sunderland ◽

K Margolin ◽

M L Ernest ◽

...

Keyword(s):

Confidence Interval ◽

Interim Analysis ◽

Response Rate ◽

Interleukin 2 ◽

Advanced Melanoma ◽

Interferon Alfa ◽

Phase Iii ◽

High Dose ◽

Phase Iii Trial ◽

Ifn Alpha

PURPOSE To compare the response rate, survival, and toxicity of treatment with high-dose intravenous (IV) bolus interleukin-2 (IL-2) plus interferon alfa-2a (IFN-alpha) with high-dose IL-2 alone in patients with advanced melanoma in a randomized phase III trial design. PATIENTS AND METHODS Eighty-five patients with advanced melanoma were randomly assigned to receive IL-2 6 X 10(6) U/m2 per dose every 8 hours as tolerated for a maximum of 14 doses on days 1 through 5 and 15 through 19, or IL-2 4.5 X 10(6) U/m2 per dose, plus IFN-alpha 3 X 10(6) U/m2 using an identical schedule. A planned interim analysis was performed after 85 patients were entered, which forms the basis for this report. RESULTS Partial response (PR) occurred in two of 44 patients (5%; 95% confidence interval, 1% to 15%) receiving IL-2 alone, compared with four of 41 patients (10%; 95% confidence interval, 3% to 23%) receiving IL-2/IFN-alpha (P = .30). There were no complete responses (CRs). The median duration of response was 11.5 months (range, 2.0 to 15.7+). There was no significant difference in the median survival duration for patients receiving IL-2 alone (10.2 months) compared with patients receiving IL-2/IFN-alpha (9.7 months). The median and mean number of doses of IL-2 were equivalent in both groups, as was toxicity. There were three treatment-related deaths, two in the IL-2-alone arm and one in the IL-2/IFN-alpha arm. The trial was terminated after the first interim analysis based on predefined early-stopping rules, which included termination if the response rate in the IL-2/IFN-alpha arm was less than 25%. CONCLUSION Using the preparation, dose, and schedule of IL-2 in our trial, IFN-alpha failed to enhance significantly the response rate to high-dose IL-2 in the treatment of patients with advanced melanoma.

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Three Phase II Cytokine Working Group Trials of gp100 (210M) Peptide Plus High-Dose Interleukin-2 in Patients With HLA-A2–Positive Advanced Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.13.3165 ◽

2008 ◽

Vol 26 (14) ◽

pp. 2292-2298 ◽

Cited By ~ 79

Author(s):

Jeffrey A. Sosman ◽

Carole Carrillo ◽

Walter J. Urba ◽

Lawrence Flaherty ◽

Michael B. Atkins ◽

...

Keyword(s):

Phase Ii ◽

Mononuclear Cells ◽

Interleukin 2 ◽

Advanced Melanoma ◽

Phase Iii ◽

Clinical Activity ◽

High Dose ◽

Phase Ii Trials ◽

Cell Immunity ◽

Three Phase

Purpose High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2–restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial. Patients and Methods In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment. Results From 1998 to 2003, 131 patients with HLA-A2–positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at ≥ 30 months. Immune studies including assays of CD3-ζ expression and numbers of CD4+/CD25+/FoxP3+ regulatory T cells, CD15+/CD11b+/CD14– immature myeloid-derived cells, and CD8+gp100 tetramer-positive cells in the blood did not correlate with clinical benefit. Conclusion The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.

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High-dose interleukin-2 (HD IL-2) in the treatment of advanced melanoma: The University of Pittsburgh experience.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.9075 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 9075-9075

Author(s):

Diwakar Davar ◽

Melissa Saul ◽

Ahmad A. Tarhini ◽

An Tran ◽

Kerry Trent ◽

...

Keyword(s):

Proportional Hazards ◽

Interleukin 2 ◽

Complete Response ◽

Median Number ◽

Cox Proportional Hazards ◽

Advanced Melanoma ◽

High Dose ◽

Severe Toxicity ◽

University Of Pittsburgh ◽

Radiological Data

9075 Background: IL-2 is a T-cell growth factor tested in a variety of regimens for advanced melanoma (MEL) and renal cell carcinoma (RCC). High-dose IL-2 (600,000-720,000 IU/kg administered intravenously every 8 hours for up to 14 consecutive doses) was approved by FDA for advanced MEL and RCC in 1998 based upon the durability of responses observed. Early studies of HD IL-2 reported overall (OR) and complete response (CR) rates of 16% and 8% respectively. Severe toxicity limited use to specialized centers with standardized protocols, either intensive care (ICU) or oncology specialty settings. The U Pittsburgh has treated 1022 patients with IL-2 at any dosage and we here present outcomes of 550 MEL pts treated with HD IL-2 in an oncology specialty non-ICU setting. Methods: Clinical and radiological data were collected on all pts treated with IL-2 using the UPCI Cancer Registry and Medical Archival System (MARS). Pharmacy records were reviewed for dosing details. The influence of baseline characteristics on treatment outcomes was assessed using Cox proportional hazards analysis. Results: A total of 848 pts received HD IL-2, of which 298 pts had RCC while 550 had MEL. Detailed pharmacy dosing records were reviewed from 176 pts treated over the past 12 years (2000-2012) who received a total of 3738 cycles. Of 165 pts evaluable for response, OR was documented in 24 pts (14.8%) and CR in 5 pts (3.0%). Median overall survival (OS) was 10.0 mos for all patients and 21.5 mos for responders (CR+PR). Median number of doses per cycle was 7. Toxicity was consistent with prior reports. HD IL-2 required ICU transfers in 5% and 1 death was attributed to HD IL-2. Pts with higher baseline lactate dehydrogenase (LDH) had poorer OS (p < 0.05). Conclusions: In this large and uniformly treated series of recent patients treated with IL-2 OR/CR rates with HD IL-2 are 14.8% and 3.0% respectively. Higher LDH is associated with poorer outcome. Biomarkers of response are currently being evaluated in banked clinical specimens collected from patients under the SPORE in Skin Cancer (P50 CA121973).

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Dosimetric Comparison between Treatment Plans of Patients Treated with Low-Dose-Rate Versus High-Dose-Rate Interstitial Prostate Brachytherapy as Monotherapy: Initial Findings of a Randomized Clinical Trial

Brachytherapy ◽

10.1016/j.brachy.2016.04.341 ◽

2016 ◽

Vol 15 ◽

pp. S185

Author(s):

Tibor Major ◽

Peter Agoston ◽

Kliton Jorgo ◽

Gabor Stelczer ◽

Csaba Polgar

Keyword(s):

Clinical Trial ◽

Dose Rate ◽

Randomized Clinical Trial ◽

Low Dose ◽

High Dose Rate ◽

High Dose ◽

Prostate Brachytherapy ◽

Low Dose Rate ◽

Rate Versus ◽

Treatment Plans

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Metastatic malignant melanoma treated with combined bolus and continuous infusion interleukin-2 and lymphokine-activated killer cells.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.7.1138 ◽

1990 ◽

Vol 8 (7) ◽

pp. 1138-1147 ◽

Cited By ~ 58

Author(s):

M H Bar ◽

M Sznol ◽

M B Atkins ◽

N Ciobanu ◽

K C Micetich ◽

...

Keyword(s):

Lymph Node ◽

Continuous Infusion ◽

Lung Metastases ◽

Interleukin 2 ◽

Advanced Melanoma ◽

Lak Cells ◽

High Dose ◽

Severe Toxicity ◽

Lymphokine Activated Killer Cells

Fifty patients with advanced melanoma received high-dose bolus and continuous infusion interleukin-2 (IL-2) with lymphokine-activated killer (LAK) cells in an attempt to improve the therapeutic index of this active but toxic therapy. Treatment began with up to nine bolus doses of IL-2 administered over 3 days. After 1 day of rest, patients underwent daily leukapheresis for 4 days, and the leukocytes were cultured with IL-2 in vitro to prepare LAK cells. Continuous infusion IL-2 was begun 1 day after the last leukapheresis and continued for up to 148 hours; LAK cells were administered on days 1, 2, and 4 of the infusion. Responding patients were eligible to receive up to two additional cycles of therapy at 3-month intervals. Most patients completed each cycle without dose reduction. One patient had a complete response and six patients had partial responses (14% response rate). The complete responder and three of the partial responders (8%) remain free from disease progression with follow-up of 21 to 24 months. Of these four patients with durable remissions, one had extensive liver and lymph node metastases, one had lymph node, pleural, and parenchymal lung metastases, and two had disease limited to lymph nodes or subcutaneous tissues. Seventeen patients (34%) required pressors for hypotension, three patients (6%) developed hemodynamically significant arrhythmias, and six patients (12%) developed dyspnea at rest, but none required intubation and there were no treatment-related deaths. Unacceptable toxicity developed in two patients during bolus IL-2 administration and therapy was aborted; both returned to baseline status within 4 days of discontinuing IL-2. Fever, oliguria, and elevated creatinine or transaminase levels occurred frequently but were also transient. Despite less frequent severe toxicity with this modified regimen, these results confirm the ability of IL-2 and LAK cell therapy to induce durable remissions in some patients with advanced melanoma.

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The Efficacy of Famotidine in improvement of outcomes in Hospitalized COVID-19 Patients: A phase III randomised clinical trial

10.21203/rs.3.rs-462937/v1 ◽

2021 ◽

Author(s):

Hamid Reza Samimagham ◽

Mehdi Hassani Azad ◽

Maryam Haddad ◽

Mohsen Arabi ◽

Dariush Hooshyar ◽

...

Keyword(s):

Clinical Trial ◽

Length Of Stay ◽

Oxygen Saturation ◽

Randomized Clinical Trial ◽

Complete Blood Count ◽

Clinical Signs ◽

Day Length ◽

Phase Iii ◽

Control Group ◽

High Dose

Abstract IntroductionAs the first randomized clinical trial, this study evaluated the effect of Famotidine on the improvement of outcomes of hospitalized patients with COVID-19.MethodThis phase III randomized clinical trial was designed with two parallel arms, placebo-controlled, single-blind, and concealed allocation, and recruited 20 patients. Oral Famotidine 160 mg four times a day was given to patients until the discharge day or for a maximum of 14 days. Patients’ temperature, respiration rate, oxygen saturation, lung infiltration, lactate dehydrogenase (LDH) level and complete blood count (CBC) were measured at the baseline (before the intervention) and on day 14 after the intervention or on discharge day. Length of stay in the hospital and length of stay in the ICU were also measured as secondary outcomes of the study.ResultsThe results showed a significant decrease in LDH (P = 0.01), mean WBC (P = 0.04) and length of stay (P = 0.04) of patients with COVID-19 in the group treated with Famotidine compared to the control group. There was also a significant increase in oxygen saturation (P = 0.01) in the group treated with Famotidine compared to the control group. Cough improvement was also higher in the oral Famotidine group compared to the control group (P = 0.02).ConclusionThis was the first clinical trial on the effect of Famotidine on the improvement of hospitalized COVID-19 patients, which indicated that high-dose Famotidine improves patients’ clinical signs and reduces the severity of the disease and duration of hospitalization.

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