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John M Kirkwood - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy of combination immunotherapy with Interferon Alfa 2b and tremelimumab in patients with stage iv melanoma
    Journal of Clinical Oncology, 2012
    Co-Authors: Ahmad A Tarhini, John Cherian, Stergios J Moschos, Hussein Tawbi, Yongli Shuai, William E Gooding, Cindy Sander, John M Kirkwood
    Abstract:

    Purpose We tested the hypothesis that the combination of tremelimumab and Interferon Alfa-2b acting via different and possibly synergistic mechanisms would overcome tumor immune tolerance and lead to significant and durable clinical responses. Patients and Methods We conducted a phase II study in which patients were administered tremelimumab 15 mg/kg/course (three cycles [one cycle = 4 weeks]) intravenously every 12 weeks. High-dose Interferon Alfa-2b (HDI) was administered concurrently, including intravenous induction at 20 MU/m2/d for 5 d/wk for 4 weeks followed by maintenance at 10 MU/m2/d subcutaneously three times a week for 8 weeks per course. From course 2 onward, HDI maintenance was administered subcutaneously. Results Thirty-seven patients with American Joint Committee on Cancer stage IV (9M1a, 6M1b, and 22M1c) were enrolled. Two patients had previously treated brain metastases. Grades 3 and 4 toxicities included neutropenia (six patients; 17%), diarrhea/colitis (four patients; 11%), liver enzyme...

  • neoadjuvant treatment of regional stage iiib melanoma with high dose Interferon Alfa 2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses
    Journal of Clinical Oncology, 2006
    Co-Authors: Stergios J Moschos, Janice Shipespotloe, Howard D Edington, Stephanie R Land, Uma N M Rao, Drazen M Jukic, John M Kirkwood
    Abstract:

    Purpose Adjuvant high-dose Interferon-Alfa-2b (HDI) improves disease-free and overall survival in patients with high-risk melanoma. However, its mechanism of action is largely unknown. Therefore, HDI was investigated in the neoadjuvant setting to assess clinical and pathologic responses after 4 weeks of HDI and to perform immunohistochemical evaluation of immune cell subsets and melanoma-associated antigens. Patients and Methods Patients with palpable regional lymph node metastases from melanoma (American Joint Committee on Cancer stage IIIB-C) underwent surgical biopsy at study entry and then received standard intravenous HDI (20 million units/m2, 5 days per week) for 4 weeks followed by complete lymphadenectomy and standard maintenance subcutaneous HDI (10 million units/m2 3 times per week) for 48 weeks. Biopsy samples were obtained before and after intravenous HDI and subjected to immunohistochemical analysis as well as routine pathologic study. Results Twenty patients were enrolled, and biopsy samples...

  • mechanisms and management of toxicities associated with high dose Interferon Alfa 2b therapy
    Journal of Clinical Oncology, 2002
    Co-Authors: John M Kirkwood, Sanjiv S. Agarwala, Ahmad A Tarhini, Catherine M Bender, Janice Shipespotloe, Barbara Smelko, Sandra S Donnelly, Lori Stover
    Abstract:

    PURPOSE: The toxicity associated with adjuvant high-dose Interferon-Alfa-2b therapy (HDI) for high-risk melanoma can lead to premature discontinuation. It is important to understand the expected adverse events and their underlying mechanisms and to anticipate and aggressively manage toxicity during treatment in order to ensure that patients receive the maximum therapeutic benefit. METHODS: The toxicity profile of HDI was reviewed by examining data from the United States cooperative group trials. Available published data related to the potential mechanisms responsible for the observed adverse events are discussed, and comprehensive recommendations for managing side effects are presented. RESULTS: The HDI regimen is associated with acute constitutional symptoms, chronic fatigue, myelosuppression, elevated liver enzyme levels, and neurologic symptoms. The majority of patients tolerate 1 year of therapy with an understanding of the anticipated toxicities in conjunction with appropriate dose modifications and ...

  • quality of life adjusted survival analysis of high dose adjuvant Interferon Alfa 2b for high risk melanoma patients using intergroup clinical trial data
    Journal of Clinical Oncology, 2002
    Co-Authors: Kerry L Kilbridge, John M Kirkwood, Frank G Haluska, Dana E Sock, Robert F Nease, Bernard F Cole, Michael A Atkins, John C Ruckdeschel, Jane C Weeks
    Abstract:

    PURPOSE: High-dose adjuvant Interferon Alfa-2b (IFNα2b) for high-risk melanoma is a 1-year regimen that improves relapse-free and overall survival but has significant toxicity. A quality-of-life–adjusted survival (QAS) analysis analysis of two cooperative group phase III trials, E1684 and E1690/S9111/C9190, was performed, incorporating patient values (utilities) for the toxicity of IFNα2b treatment and melanoma recurrence. PATIENTS AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity methodology was used with melanoma patient utilities and trial data to estimate the effect of IFNα2b on QAS. The increase or decrease in QAS that patients could expect from treatment was estimated based on their utilities. Eleven utility predictor questions were tested to identify patients with utilities that result in decreased QAS. RESULTS: Using E1684 data, IFNα2b would result in an increase in QAS for all sets of patient utilities. This benefit was significant (P < .05) for 16% of patients. Using E1690/S9111/C9...

  • developing indications for the use of sentinel lymph node biopsy and adjuvant high dose Interferon Alfa 2b in melanoma
    Archives of Dermatology, 2001
    Co-Authors: Robert W Dubois, Susan M Swetter, Michael B Atkins, Kelly M Mcmasters, Ron Halbert, Stanley J Miller, Ronald Shiell, John M Kirkwood
    Abstract:

    Objectives To convene a multidisciplinary panel of dermatologists, surgical oncologists, and medical oncologists to formally review available data on the sentinel lymph node (SLN) biopsy procedure and high-dose adjuvant Interferon Alfa-2b therapy for patients with melanoma and to rate the "appropriateness," "inappropriateness," or "uncertainty" of the procedure and therapy to guide clinical decision making in practice. Participants The panel comprised 13 specialists (4 dermatologists, 4 oncologists, and 5 surgeons) from geographically diverse areas who practiced in community-based settings (n = 8) and academic institutions (n = 5). Participants were chosen based on recommendations from the relevant specialty organizations. Evidence A formal literature review was conducted by investigators at Protocare Sciences Inc, Santa Monica, Calif, on the risks and benefits of performing an SLN biopsy in patients with stage I or II melanoma and adjuvant Interferon Alfa-2b therapy in patients with stage II or III disease. The MEDLINE database was searched from 1966 through July 2000, and supplemental information was obtained from various cancer societies and cancer research groups. Panel participants were queried on additional sources of relevant information. Unpublished, presented data were included in abstract form on 1 recently closed clinical trial. Consensus Process The RAND/UCLA Appropriateness Method was used to review and rate multiple clinical scenarios for the use of SLN biopsy and Interferon Alfa-2b therapy. The consensus method did not force agreement. Conclusions The panel rated 104 clinical scenarios and concluded that the SLN biopsy procedure was appropriate for primary melanomas deeper than 1.0 mm and for tumors 1 mm or less when histologic ulceration was present and/or classified as Clark level 4 or higher. The SLN biopsy was deemed inappropriate for nonulcerated Clark level 2 or 3 melanomas 0.75 mm or less in depth and uncertain in tumors 0.76 to 1.0 mm deep unless they were ulcerated or Clark level 4 or higher. Interferon Alfa-2b therapy was deemed appropriate for patients with regional nodal and/or in-transit metastasis and for node-negative patients with primary melanomas deeper than 4 mm. The panel considered the use of Interferon Alfa-2b therapy uncertain in patients with ulcerated intermediate primary tumors (2.01-4.0 mm in depth) and inappropriate for node-negative patients with nonulcerated tumors less than 4.0 mm deep. Specialty-specific ratings were conducted as well.

Janice K Albrecht - One of the best experts on this subject based on the ideXlab platform.

  • effect of treatment with pegInterferon or Interferon Alfa 2b and ribavirin on steatosis in patients infected with hepatitis c
    Hepatology, 2003
    Co-Authors: M Thierry D Poynard, Vlad Ratziu, Zobair M. Younossi, Stefan Zeuzem, Zachary Goodman, John G Mchutchison, Michael P Manns, Janice K Albrecht
    Abstract:

    It has been suggested that hepatitis C virus (HCV) and especially genotype 3 is associated with steatosis. We assess the effect of treatment with pegInterferon or Interferon Alfa-2b and ribavirin on steatosis. We analyzed 1,428 naive patients included in a randomized trial. A single pathologist scored steatosis at baseline and 24 weeks after the treatment. At baseline, steatosis was present in 935 of 1,428 patients (65%), including 175 (83%) of 210 patients with genotype 3 versus 760 (62%) of 1,218 with other genotypes (P <.001). The variables associated with steatosis in logistic regression were genotype 3 (P <.001), triglycerides greater than 1.7 mmol/L (P <.001), body mass index greater than 27 (P <.04), age greater than 40 years (P <.001), and septal fibrosis (P =.007). In genotype 3-infected patients, steatosis was associated with high viral load and with lower serum cholesterol. Steatosis was associated with lower sustained response rate, even after taking into account other factors (P <.001). Among virologic responders, steatosis was much improved in genotype 3, improvement of at least 1 grade in 77%, and disappearance in 46% compared with other genotypes, 46% and 29%, respectively (P <.001 both comparisons). In genotype 3 responders, the baseline low serum cholesterol was corrected by treatment (P <.001). Steatosis was associated with HCV genotype 3, triglycerides, high body mass index, age, fibrosis stage, and lower virologic response to treatment. In conclusion, sustained disappearance of the virus is associated with reduction of steatosis in genotype 3 as well as a correction of baseline low serum cholesterol.

  • pegInterferon Alfa 2b plus ribavirin compared with Interferon Alfa 2b plus ribavirin for initial treatment of chronic hepatitis c a randomised trial
    The Lancet, 2001
    Co-Authors: Michael P Manns, Meihsiu Ling, Vinod K Rustgi, Stuart C. Gordon, Mitchell L. Shiffman, Zachary Goodman, John G Mchutchison, Robert Reindollar, Kenneth Koury, Janice K Albrecht
    Abstract:

    Summary Background A sustained virological response (SVR) rate of 41% has been achieved with Interferon Alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, pegInterferon Alfa-2b plus ribavirin was compared with Interferon Alfa-2b plus ribavirin. Methods 1530 patients with chronic hepatitis C were assigned Interferon Alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000–1200 mg/day orally, pegInterferon Alfa-2b 15 μg/kg each week plus 800 mg/day ribavirin, or pegInterferon Alfa-2b 1·5 μg/kg per week for 4 weeks then 0·5 μg/kg per week plus ribavirin 1000–1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. Findings The SVR rate was significantly higher (p=0·01 for both comparisons) in the higher-dose pegInterferon group (274/511 [54%]) than in the lower-dose pegInterferon (244/514 [47%]) or Interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the Interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups. Interpretation In patients with chronic hepatitis C, the most effective therapy is the combination of pegInterferon Alfa-2b 1·5 μg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.

  • a randomized double blind trial comparing pegylated Interferon Alfa 2b to Interferon Alfa 2b as initial treatment for chronic hepatitis c
    Hepatology, 2001
    Co-Authors: Karen L Lindsay, Christian Trepo, Stuart C. Gordon, Mitchell L. Shiffman, John C. Hoefs, Tobias Heintges, Eugene R Schiff, Zachary Goodman, Mark A Laughlin, Janice K Albrecht
    Abstract:

    Abstract This international, randomized, active-controlled, parallel-group, double-blind dose-finding study compared pegInterferon Alfa-2b (PegIntron™) to Interferon Alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three-times-weekly (TIW) Interferon Alfa-2b dose (3 MIU) or the once-weekly (QW) pegInterferon Alfa-2b (0.5, 1.0, or 1.5 μg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 pegInterferon Alfa-2b doses significantly ( P ≤ .042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow-up, as compared with Interferon Alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not dose-related above 1.0 μg/kg pegInterferon Alfa-2b because of a higher relapse rate among patients treated with 1.5 μg/kg pegInterferon Alfa-2b, particularly among patients infected with genotype 1. All 3 pegInterferon Alfa-2b doses decreased liver inflammation to a greater extent than did Interferon Alfa-2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, pegInterferon Alfa-2b maintained (0.5 μg/kg) or surpassed (1.0, 1.5 μg/kg) the clinical efficacy of Interferon Alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 μg/kg pegInterferon Alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation. (H EPATOLOGY 2001;34:395-403.)

  • is an a la carte combination Interferon Alfa 2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis c
    Hepatology, 2000
    Co-Authors: Thierry Poynard, Meihsiu Ling, Zachary Goodman, John G Mchutchison, Janice K Albrecht
    Abstract:

    Randomized trials have shown the enhancement of efficacy with Interferon Alfa-2b and ribavirin (IFN-R) in comparison with Interferon monotherapy (IFN) as first line treatment of chronic hepatitis C. Further definition of response based on disease, patient, and treatment characteristics is needed to determine the degree of benefit for the various patient subgroups. The aim of this study was to answer this question by analyzing the data from 1,744 naive patients included in trials that compared 24- or 48-week IFN-R treatment. Response factors were identified by logistic regression and receiver operating characteristics curves. Five independent characteristics were associated with a sustained loss of hepatitis C virus (HCV) RNA (<100 copies/mL) 24 weeks after the end of treatment: genotype 2 or 3, baseline viral load less than 3.5 million copies/mL, no or portal fibrosis, female gender, and age younger than 40 years. There was a significant advantage for IFN-R in comparison with IFN alone whatever the combination of factors. The most efficient strategy is to treat all patients for 24 weeks. If the 24-week polymerase chain reaction (PCR) is positive, treatment can be stopped. If the 24-week PCR is negative, patients with fewer than 4 favorable factors should be treated for an additional 24 weeks. Conclusion: The combination of IFN-R is better as first line treatment than IFN monotherapy. For patients who are PCR negative after 24 weeks of treatment, genotyping and baseline viral load, fibrosis stage, gender, and age are useful predictive factors in determining whether to continue an additional 24 weeks of treatment.

  • Interferon Alfa 2b alone or in combination with ribavirin as initial treatment for chronic hepatitis c
    The New England Journal of Medicine, 1998
    Co-Authors: John G Mchutchison, Meihsiu Ling, Vinod K Rustgi, Stuart C. Gordon, Mitchell L. Shiffman, Eugene R Schiff, Zachary Goodman, Susannah Cort, Janice K Albrecht
    Abstract:

    Background Only 15 to 20 percent of patients with chronic hepatitis C have a sustained virologic response to Interferon therapy. We compared the efficacy and safety of recombinant Interferon Alfa-2b alone with those of a combination of Interferon Alfa-2b and ribavirin for the initial treatment of patients with chronic hepatitis C. Methods We randomly assigned 912 patients with chronic hepatitis C to receive standard-dose Interferon Alfa-2b alone or in combination with ribavirin (1000 or 1200 mg orally per day, depending on body weight) for 24 or 48 weeks. Efficacy was assessed by measurements of serum hepatitis C virus (HCV) RNA and serum aminotransferases and by liver biopsy. Results The rate of sustained virologic response (defined as an undetectable serum HCV RNA level 24 weeks after treatment was completed) was higher among patients who received combination therapy for either 24 weeks (70 of 228 patients, 31 percent) or 48 weeks (87 of 228 patients, 38 percent) than among patients who received interfe...

Michael B Atkins - One of the best experts on this subject based on the ideXlab platform.

  • pembrolizumab plus pegylated Interferon Alfa 2b or ipilimumab for advanced melanoma or renal cell carcinoma dose finding results from the phase ib keynote 029 study
    Clinical Cancer Research, 2018
    Co-Authors: Michael B Atkins, John A Thompson, Wenjen Hwu, Stephen F Hodi, David F Mcdermott, Donald P Lawrence, Nancy Ann Dawson, D J Wong, Shailender Bhatia, Marihella James
    Abstract:

    Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated Interferon Alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805-15. ©2018 AACR.

  • phase iii trial comparing concurrent biochemotherapy with cisplatin vinblastine dacarbazine interleukin 2 and Interferon Alfa 2b with cisplatin vinblastine and dacarbazine alone in patients with metastatic malignant melanoma e3695 a trial coordinated
    Journal of Clinical Oncology, 2008
    Co-Authors: Michael B Atkins, Jeffrey A Sosman, Vernon K Sondak, Lawrence E Flaherty, Jessie J Hsu, Sandra M Lee, Gary I Cohen, J M Kirkwood
    Abstract:

    Purpose Phase II trials with biochemotherapy (BCT) have shown encouraging response rates in metastatic melanoma, and meta-analyses and one phase III trial have suggested a survival benefit. In an effort to determine the relative efficacy of BCT compared with chemotherapy alone, a phase III trial was performed within the United States Intergroup. Patients and Methods Patients were randomly assigned to receive cisplatin, vinblastine, and dacarbazine (CVD) either alone or concurrent with interleukin-2 and Interferon Alfa-2b (BCT). Treatment cycles were repeated at 21-day intervals for a maximum of four cycles. Tumor response was assessed after cycles 2 and 4, then every 3 months. Results Four hundred fifteen patients were enrolled, and 395 patients (CVD, n = 195; BCT, n = 200) were deemed eligible and assessable. The two study arms were well balanced for stratification factors and other prognostic factors. Response rate was 19.5% for BCT and 13.8% for CVD (P = .140). Median progression-free survival was sign...

  • randomized trial of an allogeneic melanoma lysate vaccine with low dose Interferon Alfa 2b compared with high dose Interferon Alfa 2b for resected stage iii cutaneous melanoma
    Journal of Clinical Oncology, 2007
    Co-Authors: Malcolm S. Mitchell, Marc S Ernstoff, Michael B Atkins, Judith Abrams, John A Thompson, Mohammed Kashanisabet, Ronald C Deconti, Wenjen Hwu, Eric D Whitman, Frank G Haluska
    Abstract:

    Purpose To compare the overall survival (OS) of patients with resected stage III melanoma administered active specific immunotherapy and low-dose Interferon Alfa-2b (IFN-α-2b) with the OS achieved using high-dose IFN-α-2b. Patients and Methods An Ad Hoc Melanoma Working Group of 25 investigators treated 604 patients from April 1997 to January 2003. Patients were stratified by sex and number of nodes and were randomly assigned to receive either 2 years of treatment with active specific immunotherapy with allogeneic melanoma lysates and low-dose IFN-α-2b (arm 1) or high-dose IFN-α-2b alone for 1 year (arm 2). Active specific immunotherapy was injected subcutaneously (SC) weekly for 4 weeks, at week 8, and bimonthly thereafter. IFN-α-2b SC was begun on week 4 and continued thrice weekly at 5 MU/m2 for 2 years. IFN-α-2b in arm 2 was administered according to the Eastern Cooperative Oncology Group 1684 study regimen. Results Median follow-up time was 32 months for all patients and 42 months for surviving patie...

  • developing indications for the use of sentinel lymph node biopsy and adjuvant high dose Interferon Alfa 2b in melanoma
    Archives of Dermatology, 2001
    Co-Authors: Robert W Dubois, Susan M Swetter, Michael B Atkins, Kelly M Mcmasters, Ron Halbert, Stanley J Miller, Ronald Shiell, John M Kirkwood
    Abstract:

    Objectives To convene a multidisciplinary panel of dermatologists, surgical oncologists, and medical oncologists to formally review available data on the sentinel lymph node (SLN) biopsy procedure and high-dose adjuvant Interferon Alfa-2b therapy for patients with melanoma and to rate the "appropriateness," "inappropriateness," or "uncertainty" of the procedure and therapy to guide clinical decision making in practice. Participants The panel comprised 13 specialists (4 dermatologists, 4 oncologists, and 5 surgeons) from geographically diverse areas who practiced in community-based settings (n = 8) and academic institutions (n = 5). Participants were chosen based on recommendations from the relevant specialty organizations. Evidence A formal literature review was conducted by investigators at Protocare Sciences Inc, Santa Monica, Calif, on the risks and benefits of performing an SLN biopsy in patients with stage I or II melanoma and adjuvant Interferon Alfa-2b therapy in patients with stage II or III disease. The MEDLINE database was searched from 1966 through July 2000, and supplemental information was obtained from various cancer societies and cancer research groups. Panel participants were queried on additional sources of relevant information. Unpublished, presented data were included in abstract form on 1 recently closed clinical trial. Consensus Process The RAND/UCLA Appropriateness Method was used to review and rate multiple clinical scenarios for the use of SLN biopsy and Interferon Alfa-2b therapy. The consensus method did not force agreement. Conclusions The panel rated 104 clinical scenarios and concluded that the SLN biopsy procedure was appropriate for primary melanomas deeper than 1.0 mm and for tumors 1 mm or less when histologic ulceration was present and/or classified as Clark level 4 or higher. The SLN biopsy was deemed inappropriate for nonulcerated Clark level 2 or 3 melanomas 0.75 mm or less in depth and uncertain in tumors 0.76 to 1.0 mm deep unless they were ulcerated or Clark level 4 or higher. Interferon Alfa-2b therapy was deemed appropriate for patients with regional nodal and/or in-transit metastasis and for node-negative patients with primary melanomas deeper than 4 mm. The panel considered the use of Interferon Alfa-2b therapy uncertain in patients with ulcerated intermediate primary tumors (2.01-4.0 mm in depth) and inappropriate for node-negative patients with nonulcerated tumors less than 4.0 mm deep. Specialty-specific ratings were conducted as well.

  • high dose Interferon Alfa 2b does not diminish antibody response to gm2 vaccination in patients with resected melanoma results of the multicenter eastern cooperative oncology group phase ii trial e2696
    Journal of Clinical Oncology, 2001
    Co-Authors: John M Kirkwood, Sanjiv S. Agarwala, David H Lawson, Michael B Atkins, Joseph G Ibrahim, Keirsten Collins, Ruth Mascari, Donna M Morrissey, Paul B Chapman
    Abstract:

    PURPOSE: High-dose Interferon Alfa-2b (IFNα2b) is the only established adjuvant therapy of resectable high-risk melanoma. GM2-KLH/QS-21 (GMK) is a chemically defined vaccine that is one of the best developed of a range of vaccine candidates for melanoma. A single-institution phase III trial conducted at Memorial Hospital served as the impetus for an intergroup adjuvant E1694/S9512/C509801 trial, which recently completed enrollment of 880 patients. To build on the apparent benefit of IFNα2b in resectable high-risk American Joint Committee on Cancer (AJCC) stage IIB or III melanoma, this phase II study was designed to evaluate the combination of GMK and IFNα2b. The E2696 trial was undertaken to evaluate the toxicity and other effects of the established adjuvant high-dose IFNα2b regimen in relation to immune responses to GMK and to evaluate the potential clinical and immunologic effects of the combined therapies. PATIENTS AND METHODS: This trial enrolled 107 patients with resectable high- or very high–risk m...

Zachary Goodman - One of the best experts on this subject based on the ideXlab platform.

  • effect of treatment with pegInterferon or Interferon Alfa 2b and ribavirin on steatosis in patients infected with hepatitis c
    Hepatology, 2003
    Co-Authors: M Thierry D Poynard, Vlad Ratziu, Zobair M. Younossi, Stefan Zeuzem, Zachary Goodman, John G Mchutchison, Michael P Manns, Janice K Albrecht
    Abstract:

    It has been suggested that hepatitis C virus (HCV) and especially genotype 3 is associated with steatosis. We assess the effect of treatment with pegInterferon or Interferon Alfa-2b and ribavirin on steatosis. We analyzed 1,428 naive patients included in a randomized trial. A single pathologist scored steatosis at baseline and 24 weeks after the treatment. At baseline, steatosis was present in 935 of 1,428 patients (65%), including 175 (83%) of 210 patients with genotype 3 versus 760 (62%) of 1,218 with other genotypes (P <.001). The variables associated with steatosis in logistic regression were genotype 3 (P <.001), triglycerides greater than 1.7 mmol/L (P <.001), body mass index greater than 27 (P <.04), age greater than 40 years (P <.001), and septal fibrosis (P =.007). In genotype 3-infected patients, steatosis was associated with high viral load and with lower serum cholesterol. Steatosis was associated with lower sustained response rate, even after taking into account other factors (P <.001). Among virologic responders, steatosis was much improved in genotype 3, improvement of at least 1 grade in 77%, and disappearance in 46% compared with other genotypes, 46% and 29%, respectively (P <.001 both comparisons). In genotype 3 responders, the baseline low serum cholesterol was corrected by treatment (P <.001). Steatosis was associated with HCV genotype 3, triglycerides, high body mass index, age, fibrosis stage, and lower virologic response to treatment. In conclusion, sustained disappearance of the virus is associated with reduction of steatosis in genotype 3 as well as a correction of baseline low serum cholesterol.

  • pegInterferon Alfa 2b plus ribavirin compared with Interferon Alfa 2b plus ribavirin for initial treatment of chronic hepatitis c a randomised trial
    The Lancet, 2001
    Co-Authors: Michael P Manns, Meihsiu Ling, Vinod K Rustgi, Stuart C. Gordon, Mitchell L. Shiffman, Zachary Goodman, John G Mchutchison, Robert Reindollar, Kenneth Koury, Janice K Albrecht
    Abstract:

    Summary Background A sustained virological response (SVR) rate of 41% has been achieved with Interferon Alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, pegInterferon Alfa-2b plus ribavirin was compared with Interferon Alfa-2b plus ribavirin. Methods 1530 patients with chronic hepatitis C were assigned Interferon Alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000–1200 mg/day orally, pegInterferon Alfa-2b 15 μg/kg each week plus 800 mg/day ribavirin, or pegInterferon Alfa-2b 1·5 μg/kg per week for 4 weeks then 0·5 μg/kg per week plus ribavirin 1000–1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. Findings The SVR rate was significantly higher (p=0·01 for both comparisons) in the higher-dose pegInterferon group (274/511 [54%]) than in the lower-dose pegInterferon (244/514 [47%]) or Interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the Interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups. Interpretation In patients with chronic hepatitis C, the most effective therapy is the combination of pegInterferon Alfa-2b 1·5 μg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.

  • a randomized double blind trial comparing pegylated Interferon Alfa 2b to Interferon Alfa 2b as initial treatment for chronic hepatitis c
    Hepatology, 2001
    Co-Authors: Karen L Lindsay, Christian Trepo, Stuart C. Gordon, Mitchell L. Shiffman, John C. Hoefs, Tobias Heintges, Eugene R Schiff, Zachary Goodman, Mark A Laughlin, Janice K Albrecht
    Abstract:

    Abstract This international, randomized, active-controlled, parallel-group, double-blind dose-finding study compared pegInterferon Alfa-2b (PegIntron™) to Interferon Alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three-times-weekly (TIW) Interferon Alfa-2b dose (3 MIU) or the once-weekly (QW) pegInterferon Alfa-2b (0.5, 1.0, or 1.5 μg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 pegInterferon Alfa-2b doses significantly ( P ≤ .042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow-up, as compared with Interferon Alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not dose-related above 1.0 μg/kg pegInterferon Alfa-2b because of a higher relapse rate among patients treated with 1.5 μg/kg pegInterferon Alfa-2b, particularly among patients infected with genotype 1. All 3 pegInterferon Alfa-2b doses decreased liver inflammation to a greater extent than did Interferon Alfa-2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, pegInterferon Alfa-2b maintained (0.5 μg/kg) or surpassed (1.0, 1.5 μg/kg) the clinical efficacy of Interferon Alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 μg/kg pegInterferon Alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation. (H EPATOLOGY 2001;34:395-403.)

  • a randomized double blind trial comparing pegylated Interferon Alfa 2b to Interferon Alfa 2b as initial treatment for chronic hepatitis c
    Hepatology, 2001
    Co-Authors: Karen L Lindsay, Christian Trepo, Stuart C. Gordon, Mitchell L. Shiffman, John C. Hoefs, Tobias Heintges, Eugene R Schiff, Zachary Goodman, Mark Laughlin, Ruji Yao
    Abstract:

    This international, randomized, active-controlled, parallel-group, double-blind dose-finding study compared pegInterferon Alfa-2b (PegIntron) to Interferon Alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three-times-weekly (TIW) Interferon Alfa-2b dose (3 MIU) or the once-weekly (QW) pegInterferon Alfa-2b (0.5, 1.0, or 1.5 microg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 pegInterferon Alfa-2b doses significantly (P < or =.042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow-up, as compared with Interferon Alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not dose-related above 1.0 microg/kg pegInterferon Alfa-2b because of a higher relapse rate among patients treated with 1.5 microg/kg pegInterferon Alfa-2b, particularly among patients infected with genotype 1. All 3 pegInterferon Alfa-2b doses decreased liver inflammation to a greater extent than did Interferon Alfa-2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, pegInterferon Alfa-2b maintained (0.5 microg/kg) or surpassed (1.0, 1.5 microg/kg) the clinical efficacy of Interferon Alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 microg/kg pegInterferon Alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation.

  • is an a la carte combination Interferon Alfa 2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis c
    Hepatology, 2000
    Co-Authors: Thierry Poynard, Meihsiu Ling, Zachary Goodman, John G Mchutchison, Janice K Albrecht
    Abstract:

    Randomized trials have shown the enhancement of efficacy with Interferon Alfa-2b and ribavirin (IFN-R) in comparison with Interferon monotherapy (IFN) as first line treatment of chronic hepatitis C. Further definition of response based on disease, patient, and treatment characteristics is needed to determine the degree of benefit for the various patient subgroups. The aim of this study was to answer this question by analyzing the data from 1,744 naive patients included in trials that compared 24- or 48-week IFN-R treatment. Response factors were identified by logistic regression and receiver operating characteristics curves. Five independent characteristics were associated with a sustained loss of hepatitis C virus (HCV) RNA (<100 copies/mL) 24 weeks after the end of treatment: genotype 2 or 3, baseline viral load less than 3.5 million copies/mL, no or portal fibrosis, female gender, and age younger than 40 years. There was a significant advantage for IFN-R in comparison with IFN alone whatever the combination of factors. The most efficient strategy is to treat all patients for 24 weeks. If the 24-week polymerase chain reaction (PCR) is positive, treatment can be stopped. If the 24-week PCR is negative, patients with fewer than 4 favorable factors should be treated for an additional 24 weeks. Conclusion: The combination of IFN-R is better as first line treatment than IFN monotherapy. For patients who are PCR negative after 24 weeks of treatment, genotyping and baseline viral load, fibrosis stage, gender, and age are useful predictive factors in determining whether to continue an additional 24 weeks of treatment.

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  • randomized trial of an allogeneic melanoma lysate vaccine with low dose Interferon Alfa 2b compared with high dose Interferon Alfa 2b for resected stage iii cutaneous melanoma
    Journal of Clinical Oncology, 2007
    Co-Authors: Malcolm S. Mitchell, Marc S Ernstoff, Michael B Atkins, Judith Abrams, John A Thompson, Mohammed Kashanisabet, Ronald C Deconti, Wenjen Hwu, Eric D Whitman, Frank G Haluska
    Abstract:

    Purpose To compare the overall survival (OS) of patients with resected stage III melanoma administered active specific immunotherapy and low-dose Interferon Alfa-2b (IFN-α-2b) with the OS achieved using high-dose IFN-α-2b. Patients and Methods An Ad Hoc Melanoma Working Group of 25 investigators treated 604 patients from April 1997 to January 2003. Patients were stratified by sex and number of nodes and were randomly assigned to receive either 2 years of treatment with active specific immunotherapy with allogeneic melanoma lysates and low-dose IFN-α-2b (arm 1) or high-dose IFN-α-2b alone for 1 year (arm 2). Active specific immunotherapy was injected subcutaneously (SC) weekly for 4 weeks, at week 8, and bimonthly thereafter. IFN-α-2b SC was begun on week 4 and continued thrice weekly at 5 MU/m2 for 2 years. IFN-α-2b in arm 2 was administered according to the Eastern Cooperative Oncology Group 1684 study regimen. Results Median follow-up time was 32 months for all patients and 42 months for surviving patie...

  • pegylated Interferon Alfa 2b treatment for patients with solid tumors a phase i ii study
    Journal of Clinical Oncology, 2002
    Co-Authors: Ronald M Bukowski, Marc S Ernstoff, Martin Gore, John Nemunaitis, Robert Amato, Samir Gupta, Craig Tendler
    Abstract:

    PURPOSE: The efficacy of Interferon Alfa has been established in treating advanced melanoma and renal cell carcinoma (RCC) patients. We conducted a phase I/II study to determine the maximum-tolerated dose (MTD), the safety and tolerability, and the preliminary efficacy of once-weekly pegylated Interferon Alfa-2b (IFNα-2b) in patients with advanced solid tumors (primarily RCC). PATIENTS AND METHODS: To determine the MTD, 35 patients with a variety of advanced solid tumors received 0.75 to 7.5 μg/kg/wk of pegylated IFNα-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 μg/kg/wk for up to 12 weeks. Patients with a response or stable disease after 12 weeks were eligible for the extension protocol and were treated for up to 1 year or until disease progression. RESULTS: The MTD for pegylated IFNα-2b at 12 weeks was 6.0 μg/kg/wk. One year of 6.0 μg/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and sa...

  • high dose Interferon Alfa 2b significantly prolongs relapse free and overall survival compared with the gm2 klh qs 21 vaccine in patients with resected stage iib iii melanoma results of intergroup trial e1694 s9512 c509801
    Journal of Clinical Oncology, 2001
    Co-Authors: John M Kirkwood, Joseph Ibrahim, Sanjiv S. Agarwala, Jeffrey A Sosman, Vernon K Sondak, Marc S Ernstoff
    Abstract:

    PURPOSE: Vaccine alternatives to high-dose Interferon Alfa-2b therapy (HDI), the current standard adjuvant therapy for high-risk melanoma, are of interest because of toxicity associated with HDI. The GM2 ganglioside is a well-defined melanoma antigen, and anti-GM2 antibodies have been associated with improved prognosis. We conducted a prospective, randomized, intergroup trial to evaluate the efficacy of HDI for 1 year versus vaccination with GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 (GMK) for 96 weeks (weekly × 4 then every 12 weeks × 8). PATIENTS AND METHODS: Eligible patients had resected stage IIB/III melanoma. Patients were stratified by sex and number of positive nodes. Primary end points were relapse-free survival (RFS) and overall survival (OS). RESULTS: Eight hundred eighty patients were randomized (440 per treatment group); 774 patients were eligible for efficacy analysis. The trial was closed after interim analysis indicated inferiority of GMK compared with HDI. For...

  • high and low dose Interferon Alfa 2b in high risk melanoma first analysis of intergroup trial e1690 s9111 c9190
    Journal of Clinical Oncology, 2000
    Co-Authors: John M Kirkwood, Marc S Ernstoff, Vernon K Sondak, Joseph G Ibrahim, Jon M Richards, Lawrence E Flaherty, Thomas J Smith, Uma Rao, Mary Steele, Ronald H Blum
    Abstract:

    PURPOSE: Pivotal trial E1684 of adjuvant high-dose Interferon Alfa-2b (IFNα2b) therapy in high-risk melanoma patients demonstrated a significant relapse-free and overall survival (RFS and OS) benefit compared with observation (Obs). PATIENTS AND METHODS: A prospective, randomized, three-arm, intergroup trial evaluated the efficacy of high-dose IFNα2b (HDI) for 1 year and low-dose IFNα2b (LDI) for 2 years versus Obs in high-risk (stage IIB and III) melanoma with RFS and OS end points. RESULTS: A total of 642 patients were enrolled (608 patients eligible), of whom a majority (75%) had nodal metastasis (50% had nodal recurrence). Unlike E1684, E1690 allowed entry of patients with T4 (> 4 mm) deep primary tumors, regardless of nodal dissection, and 25% of the patients entered onto this trial had deep primary tumors (compared with 11% in E1684). At 52 months’ median follow-up, HDI demonstrated an RFS benefit exceeding that of LDI compared with Obs. The 5-year estimated RFS rates for the HDI, LDI, and Obs arms ...