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Melanoma: HELP
Articles by Thomas T. Amatruda
Based on 16 articles published since 2008
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Between 2008 and 2019, Thomas Amatruda wrote the following 16 articles about Melanoma.
 
+ Citations + Abstracts
1 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

Kaufman, Howard L / Kirkwood, John M / Hodi, F Stephen / Agarwala, Sanjiv / Amatruda, Thomas / Bines, Steven D / Clark, Joseph I / Curti, Brendan / Ernstoff, Marc S / Gajewski, Thomas / Gonzalez, Rene / Hyde, Laura Jane / Lawson, David / Lotze, Michael / Lutzky, Jose / Margolin, Kim / McDermott, David F / Morton, Donald / Pavlick, Anna / Richards, Jon M / Sharfman, William / Sondak, Vernon K / Sosman, Jeffrey / Steel, Susan / Tarhini, Ahmad / Thompson, John A / Titze, Jill / Urba, Walter / White, Richard / Atkins, Michael B. ·Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA. ·Nat Rev Clin Oncol · Pubmed #23982524.

ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts--including physicians, nurses, and patient advocates--to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

2 Clinical Trial Phase IIIb safety results from an expanded-access protocol of talimogene laherparepvec for patients with unresected, stage IIIB-IVM1c melanoma. 2018

Chesney, Jason / Awasthi, Sanjay / Curti, Brendan / Hutchins, Laura / Linette, Gerald / Triozzi, Pierre / Tan, Marcus C B / Brown, Russell E / Nemunaitis, John / Whitman, Eric / Windham, Christopher / Lutzky, Jose / Downey, Gerald F / Batty, Nicolas / Amatruda, Thomas. ·Department of Medicine, University of Louisville, Louisville, Kentucky. · Department of Medical Oncology, City of Hope, Duarte. · Earle A Chiles Research Institute, Providence Cancer Center, Portland, Oregon. · Department of Internal Medicine, Division of Hematology Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. · Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. · Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem. · Division of Surgical Oncology, University of South Alabama, Mobile, Alabama. · Department of Surgery, Ochsner Medical Center, New Orleans, Louisiana. · Department of Medical Hematology and Oncology, Mary Crowley Cancer Research Center, Dallas, Texas. · Department of Endocrine and Oncologic Surgery, Atlantic Melanoma Center, Atlantic Health System Cancer Care, Morristown, New Jersey. · Department of Oncology, Cone Health, Greensboro, North Carolina. · Division of Hematology and Oncology, Mount Sinai Medical Center, Miami Beach, Florida. · Center for Design and Analysis, Amgen Limited, Cambridge, UK. · Department of Clinical Research, Amgen Inc., Thousand Oaks, California. · Department of Hematology and Oncology, Minnesota Oncology, Fridley, Minnesota. ·Melanoma Res · Pubmed #29176501.

ABSTRACT: Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal tumors in patients with melanoma recurrence following surgery. We aim to describe the safety of talimogene laherparepvec. Intralesional talimogene laherparepvec was administered at less than or equal to 4 ml×10 PFU/ml at protocol day 1, then less than or equal to 4 ml×10 PFU/ml 21 days later, and then every 14 days. Treatment continued until complete response, absence of injectable tumors, progressive disease, intolerance, or US Food and Drug Administration approval. Adverse events were graded during and 30 days after the end of treatment. Lesions suspected to have herpetic origin were tested for talimogene laherparepvec DNA by quantitative PCR (qPCR). Between September 2014 and October 2015, 41 patients were enrolled with stage IIIB (22%), IIIC (37%), IVM1a (34%), IVM1b (5%), and IVM1c (2%) melanoma. The median age was 72 (range: 32-96) years and 54% of the patients were men. Patients had an ECOG performance status of 0 (68%) or 1 (32%). The median treatment duration was 13.1 (3.0-41.1) weeks. Treatment-related adverse events of greater than or equal to grade 3 were reported in three (7.3%) patients and included vomiting, upper abdominal pain, chills, hyperhidrosis, nausea, pyrexia, and wound infection. Suspected herpetic lesions were swabbed in five (12%) patients. One of the five tested positive for talimogene laherparepvec DNA by qPCR, but this lesion had been injected previously with talimogene laherparepvec. During the study, five patients completed treatment because of complete response per investigators. In the clinical practice setting, talimogene laherparepvec has a safety profile comparable to that observed in previous clinical trials. Talimogene laherparepvec (IMLYGIC) is now approved in the US, European Union, and Australia.

3 Clinical Trial Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma. 2016

Andtbacka, Robert H I / Agarwala, Sanjiv S / Ollila, David W / Hallmeyer, Sigrun / Milhem, Mohammed / Amatruda, Thomas / Nemunaitis, John J / Harrington, Kevin J / Chen, Lisa / Shilkrut, Mark / Ross, Merrick / Kaufman, Howard L. ·University of Utah Huntsman Cancer Institute, Salt Lake City, Utah. · St. Luke's University Hospital and Temple University, Philadelphia, Pennsylvania. · University of North Carolina, Chapel Hill, North Carolina. · Advocate Lutheran General Hospital, Park Ridge, Illinois. · University of Iowa Hospitals and Clinics, Iowa City, Iowa. · Minnesota Oncology, Fridley, Minnesota. · Mary Crowley Cancer Research Center, Dallas, Texas. · The Institute of Cancer Research/The Royal Marsden Hospital, London, UK. · Amgen, Inc, Thousand Oaks, California. · The University of Texas MD Anderson Cancer Center, Houston, Texas. · Rutgers Cancer Institute of New Jersey, Rutgers, New Jersey. ·Head Neck · Pubmed #27407058.

ABSTRACT: BACKGROUND: Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma. RESULTS: DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec. CONCLUSION: Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016.

4 Clinical Trial Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial. 2016

Andtbacka, Robert H I / Ross, Merrick / Puzanov, Igor / Milhem, Mohammed / Collichio, Frances / Delman, Keith A / Amatruda, Thomas / Zager, Jonathan S / Cranmer, Lee / Hsueh, Eddy / Chen, Lisa / Shilkrut, Mark / Kaufman, Howard L. ·Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Robert.Andtbacka@hci.utah.edu. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Vanderbilt University Medical Center, Nashville, TN, USA. · University of Iowa Hospitals and Clinics, Iowa City, IA, USA. · University of North Carolina, Chapel Hill, NC, USA. · Emory University, Atlanta, GA, USA. · Minnesota Oncology, Fridley, MN, USA. · Moffitt Cancer Center, Tampa, FL, USA. · University of Washington School of Medicine, Seattle, WA, USA. · Saint Louis University Cancer Center, St Louis, MO, USA. · Amgen Inc., Thousand Oaks, CA, USA. · Rutgers Cancer Institute of New Jersey, Rutgers, NJ, USA. ·Ann Surg Oncol · Pubmed #27342831.

ABSTRACT: PURPOSE: Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In this study, we describe the patterns and time course of response to T-VEC from the phase III OPTiM trial of 436 patients with unresected stages IIIB-IV melanoma. METHODS: Lesion-level response analyses were performed based on the type of lesion (injected or uninjected cutaneous, subcutaneous, or nodal lesions; or visceral lesions [uninjected]), and the best percentage change from baseline of the sum of products of the longest diameters was calculated. Patients randomized to T-VEC (n = 295) who experienced a durable response (continuous partial or complete response for ≥6 months) were evaluated for progression prior to response (PPR), defined as the appearance of a new lesion or >25 % increase in total baseline tumor area. RESULTS: T-VEC resulted in a decrease in size by ≥50 % in 64 % of injected lesions (N = 2116), 34 % of uninjected non-visceral lesions (N = 981), and 15 % of visceral lesions (N = 177). Complete resolution of lesions occurred in 47 % of injected lesions, 22 % of uninjected non-visceral lesions, and 9 % of visceral lesions. Of 48 patients with durable responses, 23 (48 %) experienced PPR, including 14 who developed new lesions only. No difference in overall survival was observed, and median duration of response was not reached in patients with PPR versus those without PPR. CONCLUSIONS: Responses in uninjected lesions provide validation of T-VEC-induced systemic immunotherapeutic effects against melanoma. PPR did not negatively impact the clinical effectiveness of T-VEC.

5 Clinical Trial Dendritic Versus Tumor Cell Presentation of Autologous Tumor Antigens for Active Specific Immunotherapy in Metastatic Melanoma: Impact on Long-Term Survival by Extent of Disease at the Time of Treatment. 2015

Dillman, Robert O / McClay, Edward F / Barth, Neil M / Amatruda, Thomas T / Schwartzberg, Lee S / Mahdavi, Khosrow / de Leon, Cristina / Ellis, Robin E / DePriest, Carol. ·1 Caladrius Biosciences, Inc. , Irvine, California. · 2 California Cancer Associates for Research and Excellence (cCARE) , Institute for Melanoma Research & Education , Encinitas California. · 3 Genomics Institute Inc. , Laguna Beach, California. · 4 Minnesota Oncology , Fridley, Minnesota. · 5 The West Clinic , Memphis, Tennessee. · 6 Newport Doctors Medical Group , Newport Beach, California. · 7 Hoag Institute for Research and Education , Newport Beach, California. · 8 Cancer Biotherapy Research Group , Franklin, Tennessee. ·Cancer Biother Radiopharm · Pubmed #26083950.

ABSTRACT: In patients with metastatic melanoma, sequential single-arm and randomized phase II trials with a therapeutic vaccine consisting of autologous dendritic cells (DCs) loaded with antigens from self-renewing, proliferating, irradiated autologous tumor cells (DC-TC) showed superior survival compared with similar patients immunized with irradiated tumor cells (TC). We wished to determine whether this difference was evident in cohorts who at the time of treatment had (1) no evidence of disease (NED) or (2) had detectable disease. Eligibility criteria and treatment schedules were the same for all three trials. Pooled data confirmed that overall survival (OS) was longer in 72 patients treated with DC-TC compared with 71 patients treated with TC (median OS 60 versus 22 months; 5-year OS 51% versus 32%, p=0.004). Treatment with DC-TC was associated with longer OS in both cohorts. Among 70 patients who were NED at the time that treatment was started, OS was better for DC-TC: 5-year OS 73% versus 43% (p=0.015). Among 73 patients who had detectable metastases, OS was better for DC-TC: median 38.8 months versus 14.7 months, 5-year OS 33% versus 20% (p=0.025). This approach is promising as an adjunct to other therapies in patients who have had metastatic melanoma.

6 Clinical Trial Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. 2015

Andtbacka, Robert H I / Kaufman, Howard L / Collichio, Frances / Amatruda, Thomas / Senzer, Neil / Chesney, Jason / Delman, Keith A / Spitler, Lynn E / Puzanov, Igor / Agarwala, Sanjiv S / Milhem, Mohammed / Cranmer, Lee / Curti, Brendan / Lewis, Karl / Ross, Merrick / Guthrie, Troy / Linette, Gerald P / Daniels, Gregory A / Harrington, Kevin / Middleton, Mark R / Miller, Wilson H / Zager, Jonathan S / Ye, Yining / Yao, Bin / Li, Ai / Doleman, Susan / VanderWalde, Ari / Gansert, Jennifer / Coffin, Robert S. ·Robert H.I. Andtbacka, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT · Howard L. Kaufman, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ · Frances Collichio, University of North Carolina Medical Center, Chapel Hill, NC · Thomas Amatruda, Minnesota Oncology, Fridley, MN · Neil Senzer, Mary Crowley Cancer Research Center, Dallas · Merrick Ross, University of Texas MD Anderson Cancer Center, Houston, TX · Jason Chesney, University of Louisville, Louisville, KY · Keith A. Delman, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA · Lynn E. Spitler, Northern California Melanoma Center, San Francisco · Gregory A. Daniels, University of California San Diego Medical Center, Moores Cancer Center, La Jolla · Yining Ye, Bin Yao, Ai Li, Ari Vander Walde, and Jennifer Gansert, Amgen, Thousand Oaks, CA · Igor Puzanov, Vanderbilt University, Nashville, TN · Sanjiv S. Agarwala, St Luke's University Hospital and Health Network, Bethlehem, and Temple University School of Medicine, Philadelphia, PA · Mohammed Milhem, University of Iowa Hospitals and Clinics, Iowa City, IA · Lee Cranmer, University of Arizona, Tucson, AZ · Brendan Curti, Earle A. Chiles Research Institute, Portland, OR · Karl Lewis, University of Colorado Cancer Center, Aurora, CO · Troy Guthrie, Baptist Cancer Institute, Jacksonville · Jonathan S. Zager, Moffitt Cancer Center, Tampa, FL · Gerald P. Linette, Washington University School of Medicine, St Louis, MO · Kevin Harrington, Institute of Cancer Research, Royal Marsden Hospital, London · Mark R. Middleton, National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom · Wilson H. Miller Jr, McGill University, Montreal, Quebec, Canada · and Susan Doleman and Robert S. Coffin, Amgen, Woburn, MA. ·J Clin Oncol · Pubmed #26014293.

ABSTRACT: PURPOSE: Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial. PATIENTS AND METHODS: Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously ≥ 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate. RESULTS: Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P < .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P = .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in ≥ 2% of T-VEC-treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred. CONCLUSION: T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial. T-VEC was well tolerated and resulted in a higher DRR (P < .001) and longer median OS (P = .051), particularly in untreated patients or those with stage IIIB, IIIC, or IVM1a disease. T-VEC represents a novel potential therapy for patients with metastatic melanoma.

7 Clinical Trial A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma : a North Central Cancer Treatment Group study, N0775. 2013

Kottschade, Lisa A / Suman, Vera J / Perez, Domingo G / McWilliams, Robert R / Kaur, Judith S / Amatruda, Thomas T / Geoffroy, Francois J / Gross, Howard M / Cohen, Peter A / Jaslowski, Anthony J / Kosel, Matthew L / Markovic, Svetomir N. ·Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. kottschade.lisa@mayo.edu ·Cancer · Pubmed #22915053.

ABSTRACT: BACKGROUND: Increasing evidence shows chemotherapy in combination with vascular endothelial growth factor (VEGF) inhibition is a clinically active therapy for patients with metastatic melanoma (MM). METHODS: A phase 2 trial was conducted in chemotherapy-naive patients with unresectable stage IV MM who were randomized to temozolomide (200 mg/m(2) on days 1 through 5) and bevacizumab (10 mg/kg intravenously on days 1 and 15) every 28 days (Regimen TB) or nab-paclitaxel (100 mg/m(2) , or 80 mg/m(2) post-addendum 5 secondary to toxicity, on days 1, 8, and 15), bevacizumab (10 mg/kg on days 1 and 15), and carboplatin (area under the curve [AUC] 6 on day 1, or AUC 5 post-addendum 5) every 28 days (Regimen ABC). Accrual goal was 41 patients per regimen. The primary aim of this study was to estimate progression-free survival rate at 6 months (PFS6) in each regimen. A regimen would be considered promising if its PFS6 rate was > 60%. RESULTS: Ninety-three eligible patients (42 TB and 51 ABC) were enrolled. The majority of patients had M1c disease (20 TB and 26 ABC). The median PFS and overall survival times with ABC were 6.7 months and 13.9 months, respectively. Median PFS time and median overall survival with TB were 3.8 months and 12.3 months, respectively. The most common severe toxicities (≥ grade 3) in both regimens were cytopenias, fatigue, and thrombosis. Among the first 41 patients enrolled onto each regimen, PFS6 rate was 32.8% (95% confidence interval: 21.1%-51.2%) for TB and 56.1% (90% confidence interval: 44.7%-70.4%) for ABC. CONCLUSIONS: The addition of bevacizumab to nab-paclitaxel and carboplatin shows promising activity despite tolerability issues.

8 Clinical Trial Tumor stem cell antigens as consolidative active specific immunotherapy: a randomized phase II trial of dendritic cells versus tumor cells in patients with metastatic melanoma. 2012

Dillman, Robert O / Cornforth, Andrew N / Depriest, Carol / McClay, Edward F / Amatruda, Thomas T / de Leon, Cristina / Ellis, Robin E / Mayorga, Cheryl / Carbonell, Denysha / Cubellis, James M. ·Hoag Institute for Research and Education, Newport Beach, CA 92658, USA. robert.dillman@hoag.org ·J Immunother · Pubmed #22996370.

ABSTRACT: Only 10% of metastatic melanoma patients survive 5 years, even though many can achieve substantial tumor reduction by surgical resection and/or radiation therapy and/or systemic therapy. An effective, nontoxic, consolidation immunotherapy could benefit such patients. We initiated a randomized trial to compare 2 promising patient-specific immunotherapy cell products. Patients had to have a diagnosis of metastatic melanoma and availability of an autologous melanoma cell line. Patients were stratified by whether their most advanced stage had been regional or distant metastases, and by whether they had measurable disease at the time of treatment, then they were randomized to receive irradiated autologous proliferating tumor cells or autologous dendritic cells (DC) loaded with antigens from such cells. Both products were injected subcutaneously in 500 µg of granulocyte-macrophage colony stimulating factor, weekly for 3 weeks and then monthly for 5 months. Patients in the 2 arms did not differ in baseline characteristics. All patients received prescribed therapy. Treatment was well tolerated. At the time of initial analysis, with no patients lost to follow-up, 50% of patients deceased, and all surviving patients followed for at least 6 months after randomization, survival is superior in the DC arm (hazard ratio, 0.27; 95% confidence interval, 0.098-0.729) with median survival not reached versus 15.9 months, and 2-year survival rates of 72% versus 31% (P=0.007). This trial provides evidence that a DC vaccine is associated with longer survival compared with a tumor cell vaccine, and is consistent with previous data suggesting a survival benefit from this patient-specific immunotherapy.

9 Clinical Trial A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma : a North Central Cancer Treatment Group Study, N057E(1). 2011

Kottschade, Lisa A / Suman, Vera J / Amatruda, Thomas / McWilliams, Robert R / Mattar, Bassam I / Nikcevich, Daniel A / Behrens, Robert / Fitch, Tom R / Jaslowski, Anthony J / Markovic, Svetomir N. ·Mayo Clinic Rochester, Rochester, Minnesota 55905, USA. kottschade.lisa@mayo.edu ·Cancer · Pubmed #21472717.

ABSTRACT: BACKGROUND: There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). ABI-007 is an albumin-bound formulation of paclitaxel that has demonstrated single-agent activity against metastatic melanoma. METHODS: A parallel phase II trial was conducted in patients with unresectable stage IV melanoma who were either chemotherapy naive (CN) or previously treated (PT). The treatment regimen consisted of ABI-007 (100 mg/m(2) ) and carboplatin area under the curve (AUC2) administered on days 1, 8, and 15 every 28 days. The primary aim of this study was objective response rate (RECIST). RESULTS: Seventy-six patients (41 CN and 35 PT) were enrolled between November 2006 and July 2007. Three patients withdrew consent prior to starting treatment. The median number of treatment cycles was 4. There were 10 (25.6%) responses (1 complete response [CR] and 9 partial responses [PRs]) in the CN cohort (90% CI, 16.7%-42.3%) and 3 (8.8%) responses (3 PRs) in the PT cohort (90% CI, 2.5%-21.3%). Median progression-free survival was 4.5 months in the CN cohort and 4.1 months in the PT cohort. Median overall survival (OS) was 11.1 months in the CN group and 10.9 months in the PT group. Severe toxicities in both groups (Common Terminology Criteria for Adverse Effects v.3.0 ≥grade 3) included neutropenia, thrombocytopenia, neurosensory problems, fatigue, nausea, and vomiting. CONCLUSIONS: The weekly combination of ABI-007 and carboplatin appears to be moderately well tolerated, with promising clinical activity as therapy in patients who are chemotherapy naive and with modest antitumor activity in those previously treated.

10 Clinical Trial Phase II multicenter trial of maintenance biotherapy after induction concurrent Biochemotherapy for patients with metastatic melanoma. 2009

O'Day, Steven J / Atkins, Michael B / Boasberg, Peter / Wang, He-Jing / Thompson, John A / Anderson, Clay M / Gonzalez, Rene / Lutzky, Jose / Amatruda, Thomas / Hersh, Evan M / Weber, Jeffrey S. ·Melanoma Program, The Angeles Clinic and Research Institute, 2001 Santa Monica Blvd, Suite 560 W, Santa Monica, CA 90404, USA. soday@theangelesclinic.org ·J Clin Oncol · Pubmed #19917850.

ABSTRACT: PURPOSE: Biochemotherapy improves responses in metastatic melanoma, but not overall survival, in randomized trials. We developed a maintenance biotherapy regimen after induction biochemotherapy in an attempt to improve durability of responses and overall survival. PATIENTS AND METHODS: One hundred thirty-three chemotherapy-naïve patients with metastatic melanoma without CNS metastases were treated at 10 melanoma centers. The biochemotherapy induction regimen included cisplatin, vinblastine, dacarbazine, decrescendo interleukin-2 (IL-2), and interferon alfa-2b with granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine support. Patients not experiencing disease progression were eligible for maintenance biotherapy with low-dose IL-2 and GM-CSF followed by intermittent pulses of decrescendo IL-2 over 12 months. Patients were observed for response, progression-free survival, toxicity, and overall survival. RESULTS: The response rate to induction biochemotherapy was 44% (95% CI, 35% to 52%; complete response, 8%; partial response, 36%; stable disease, 29%). The median number of biochemotherapy cycles was four, and the median number of maintenance biotherapy cycles was five. The median progression-free survival was 9 months, and the median survival was 13.5 months. The 12-month and 24-month survival rates were 57% and 23%, respectively. Twenty percent of patients remain alive (12 without disease), with median follow-up of 30 months (95% CI, 25+ to 45+ months). Thirty-nine percent of patients developed CNS metastases. The median times to CNS progression and death were 8 months and 5 months, respectively. CONCLUSION: Maintenance biotherapy after induction biochemotherapy seems to prolong progression-free survival and improve overall survival compared with recent multicenter trials of biochemotherapy or chemotherapy. The regimen should be studied in a randomized clinical trial in patients with advanced metastatic melanoma. CNS progression remains a formidable challenge.

11 Clinical Trial Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. 2009

Senzer, Neil N / Kaufman, Howard L / Amatruda, Thomas / Nemunaitis, Mike / Reid, Tony / Daniels, Gregory / Gonzalez, Rene / Glaspy, John / Whitman, Eric / Harrington, Kevin / Goldsweig, Howard / Marshall, Tracey / Love, Colin / Coffin, Robert / Nemunaitis, John J. ·Mary Crowley Cancer Research Centers, Dallas, TX 75201, USA. nsenzer@marycrowley.org ·J Clin Oncol · Pubmed #19884534.

ABSTRACT: PURPOSE: Treatment options for metastatic melanoma are limited. We conducted this phase II trial to assess the efficacy of JS1/34.5-/47-/granulocyte-macrophage colony-stimulating factor (GM-CSF) in stages IIIc and IV disease. PATIENTS AND METHODS: Treatment involved intratumoral injection of up to 4 mL of 10(6) pfu/mL of JS1/34.5-/47-/GM-CSF followed 3 weeks later by up to 4 mL of 10(8) pfu/mL every 2 weeks for up to 24 treatments. Clinical activity (by RECIST [Response Evaluation Criteria in Solid Tumors]), survival, and safety parameters were monitored. RESULTS: Fifty patients (stages IIIc, n = 10; IVM1a, n = 16; IVM1b, n = 4; IVM1c, n = 20) received a median of six injection sets; 74% of patients had received one or more nonsurgical prior therapies for active disease, including dacarbazine/temozolomide or interleukin-2 (IL-2). Adverse effects were limited primarily to transient flu-like symptoms. The overall response rate by RECIST was 26% (complete response [CR], n = 8; partial response [PR], n = 5), and regression of both injected and distant (including visceral) lesions occurred. Ninety-two percent of the responses had been maintained for 7 to 31 months. Ten additional patients had stable disease (SD) for greater than 3 months, and two additional patients had surgical CR. On an extension protocol, two patients subsequently achieved CR by 24 months (one previously PR, one previously SD), and one achieved surgical CR (previously PR). Overall survival was 58% at 1 year and 52% at 24 months. CONCLUSION: The 26% response rate, with durability in both injected and uninjected lesions including visceral sites, together with the survival rates, are evidence of systemic effectiveness. This effectiveness, combined with a limited toxicity profile, warrants additional evaluation of JS1/34.5-/47-/GM-CSF in metastatic melanoma. A US Food and Drug Administration-approved phase III investigation is underway.

12 Clinical Trial Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. 2009

Perez, Domingo G / Suman, Vera J / Fitch, Tom R / Amatruda, Thomas / Morton, Roscoe F / Jilani, Shamim Z / Constantinou, Costas L / Egner, James R / Kottschade, Lisa A / Markovic, Svetomir N. ·Metro-Minnesota Community Clinical Oncology Program, St Louis Park, Minnesota, USA. ·Cancer · Pubmed #19090009.

ABSTRACT: BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in the growth and metastatic progression of melanoma. Exposure of melanoma cells to chemotherapy induces VEGF overproduction, which in turn may allow melanoma cells to evade cell death and become chemotherapy resistant. Therefore, in patients with metastatic melanoma, the combination of chemotherapy with an agent that specifically targets VEGF might be able to control tumor growth and progression more effectively than chemotherapy alone. METHODS: A 2-stage phase 2 clinical trial was conducted in patients with unresectable stage IV (metastatic) melanoma to assess antitumor activity and the toxicity profile of the combination of carboplatin (area under the curve 6 iv on Day 1 of a 28-day cycle), paclitaxel (80 mg/m2 iv on Days 1, 8, and 15), and bevacizumab (10 mg/kg iv on Days 1 and 15). Treatment was continued until progression or intolerable toxicity. RESULTS: Fifty-three patients (62.3% male) were enrolled. Nine (17%) patients achieved partial remission, and another 30 (57%) achieved stable disease for at least 8 weeks. Median progression-free survival and median overall survival were 6 months and 12 months, respectively. One patient died after 8 treatment cycles from intracranial hemorrhage into undiagnosed brain metastases. The most common severe (grade>or=3) toxicities were neutropenia (53%), thrombocytopenia (11%), hypertension (9%), and anemia (8%). CONCLUSIONS: This combination of carboplatin, paclitaxel, and bevacizumab appears to be moderately well tolerated and clinically beneficial in patients with metastatic melanoma. Further study of this combination is warranted.

13 Article Estimating Survival in Melanoma Patients With Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA). 2017

Sperduto, Paul W / Jiang, Wen / Brown, Paul D / Braunstein, Steve / Sneed, Penny / Wattson, Daniel A / Shih, Helen A / Bangdiwala, Ananta / Shanley, Ryan / Lockney, Natalie A / Beal, Kathryn / Lou, Emil / Amatruda, Thomas / Sperduto, William A / Kirkpatrick, John P / Yeh, Norman / Gaspar, Laurie E / Molitoris, Jason K / Masucci, Laura / Roberge, David / Yu, James / Chiang, Veronica / Mehta, Minesh. ·Minneapolis Radiation Oncology, Minneapolis, Minnesota. Electronic address: psperduto@mropa.com. · MD Anderson Cancer Center, Houston, Texas. · University of California San Francisco, San Francisco, California. · Minneapolis Radiation Oncology, Minneapolis, Minnesota; Massachusetts General Hospital, Boston, Massachusetts. · Massachusetts General Hospital, Boston, Massachusetts. · University of Minnesota Biostatistics, Minneapolis, Minnesota. · Memorial Sloan Kettering Cancer Center, New York, New York. · University of Minnesota, Minneapolis, Minnesota. · US Oncology, Minneapolis, Minnesota. · Duke University, Durham, North Carolina. · University of Colorado Denver, Denver, Colorado. · University of Maryland, Baltimore, Maryland. · Centre Hospitalier de l' Universite de Montreal, Montreal, Canada. · Yale University, New Haven, Connecticut. · Miami Cancer Institute, Miami, Florida. ·Int J Radiat Oncol Biol Phys · Pubmed #29063850.

ABSTRACT: PURPOSE: To update the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for a markedly heterogeneous patient population, patients with melanoma and brain metastases, using a larger, more current cohort, including molecular markers. METHODS: The original Melanoma-GPA is based on data from 483 patients whose conditions were diagnosed between 1985 and 2005. This is a multi-institutional retrospective database analysis of 823 melanoma patients with newly diagnosed brain metastases from January 1, 2006, to December 31, 2015. Multivariable analyses identified significant prognostic factors, which were weighted and included in the updated index (Melanoma-molGPA). Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios to design the updated Melanoma-molGPA in which scores of 4.0 and 0.0 are associated with the best and worst prognoses, as with all of the diagnosis-specific GPA indices. Log-rank tests were used to compare adjacent classes. RESULTS: There were 5 significant prognostic factors for survival (age, Karnofsky performance status [KPS], extracranial metastases [ECM], number of brain metastases, and BRAF status), whereas only KPS and the number of brain metastases were significant in the original Melanoma-GPA. Median survival improved from 6.7 to 9.8 months between the 2 treatment eras, and the median survival times for patients with Melanoma-molGPA of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 4.9, 8.3, 15.8, and 34.1 months (P<.0001 between each adjacent group). CONCLUSIONS: Survival and our ability to estimate survival in melanoma patients with brain metastases has improved significantly. The updated Melanoma-molGPA, a user-friendly tool to estimate survival, will facilitate clinical decision making regarding whether and which treatment is appropriate and will also be useful for stratification of future clinical trials. To further simplify use, a free online/smart phone app is available at brainmetgpa.com.

14 Article The Prognostic Value of BRAF, C-KIT, and NRAS Mutations in Melanoma Patients With Brain Metastases. 2017

Sperduto, Paul W / Jiang, Wen / Brown, Paul D / Braunstein, Steve / Sneed, Penny / Wattson, Daniel A / Shih, Helen A / Bangdiwala, Ananta / Shanley, Ryan / Lockney, Natalie A / Beal, Kathryn / Lou, Emil / Amatruda, Thomas / Sperduto, William A / Kirkpatrick, John P / Yeh, Norman / Gaspar, Laurie E / Molitoris, Jason K / Masucci, Laura / Roberge, David / Yu, James / Chiang, Veronica / Mehta, Minesh. ·Minneapolis Radiation Oncology, Minneapolis, Minnesota. Electronic address: psperduto@mropa.com. · MD Anderson Cancer Center, Houston, Texas. · University of California San Francisco, San Francisco, California. · Minneapolis Radiation Oncology, Minneapolis, Minnesota; Massachusetts General Hospital, Boston, Massachusetts. · Massachusetts General Hospital, Boston, Massachusetts. · Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota. · Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medical Oncology, University of Minnesota, Minneapolis, Minnesota. · US Oncology, Minneapolis, Minnesota. · Duke University, Durham, North Carolina. · University of Colorado Denver, Denver, Colorado. · University of Maryland, Baltimore, Maryland. · Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada. · Yale University, New Haven, Connecticut. · Miami Cancer Institute, Miami, Florida. ·Int J Radiat Oncol Biol Phys · Pubmed #28721890.

ABSTRACT: PURPOSE: Brain metastases are a common problem in patients with melanoma, but little is known about the effect of gene mutations on survival in these patients. METHODS AND MATERIALS: We created a retrospective multi-institutional database of 823 patients with melanoma and brain metastases diagnosed between 2006 and 2015. Clinical parameters, gene mutation status (BRAF, C-KIT, NRAS), and treatment were correlated with survival. Treatment patterns and outcomes were compared with a prior era (1985-2005). RESULTS: BRAF status was known in 584 of 823 patients (71%). BRAF, NRAS, and C-KIT mutations were present in 51%, 22%, and 11% of tested patients, respectively. The median time from primary diagnosis to brain metastasis was 32 months, and overall median survival (MS) from the time of initial treatment of brain metastases was 10 months. MS for BRAF-positive and BRAF-negative patients was 13 months and 9 months, respectively (P=.02). There was no significant difference in MS in patients with or without NRAS or C-KIT mutations. The time from primary diagnosis to brain metastasis did not vary by mutation and was not associated with survival after the diagnosis of brain metastases. MS for the 1985 to 2005 and 2006 to 2015 cohorts was 6.7 months and 10.0 months, respectively (P<.01). Reflecting treatment-trend changes, use of whole-brain radiation therapy decreased from 48% to 26% during this period. Among BRAF-positive patients, 71% received targeted BRAF and/or MEK inhibitors and 57% received some combination of targeted therapy, chemotherapy, and/or immunotherapy. CONCLUSIONS: For melanoma patients with brain metastases, BRAF-positive patients survive longer than BRAF-negative patients and overall survival has improved from 1985-2005 to 2006-2015.

15 Article Prognostic significance of microscopic tumor burden in sentinel lymph node in patients with cutaneous melanoma. 2015

Kim, Chul / Economou, Sam / Amatruda, Thomas T / Martin, Jena C / Dudek, Arkadiusz Z. ·Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, U.S.A. · Plastic Surgery Consultants, Edina, MN, U.S.A. · Minnesota Oncology, Fridley, MN, U.S.A. · Hospital Pathology Associates, Minneapolis, MN, U.S.A. · University of Illinois at Chicago, Chicago, IL, U.S.A. adudek@uic.edu. ·Anticancer Res · Pubmed #25550564.

ABSTRACT: BACKGROUND/AIM: Sentinel lymph node (SLN) biopsy provides useful prognostic information for patients with melanoma. The present study sought to determine the prognostic value of SLN tumor burden on overall survival (OS) and disease-free survival (DFS). We also assessed its association with non-sentinel lympth node (NSLN) involvement. PATIENTS AND METHODS: We conducted a retrospective review of 138 patients with cutaneous melanoma, who were found to have positive SLNs from 2000 to 2011. SLN tumor burden was measured in the maximum diameter of the largest tumor focus. OS and DFS were assessed by the Kaplan-Meier method and Cox proportional hazard regression model. A logistic regression model was used to evaluate the association between SLN tumor burden and NSLN positivity. RESULTS: On multivariable analysis, SLN tumor burden was significantly associated with OS (hazard ratio (HR)>1 vs. ≤ 1 mm=5.15; 95% confidence interval (CI)=2.32-11.44; p<0.0001) and DFS rate (HR>1 vs. ≤ 1 mm=3.02; 95% CI=1.37-6.67; p=0.0064). On univariate analysis, SLN tumor burden was significantly associated with NSLN positivity (OR>1 vs. ≤ 1 mm=3.41; 95% CI=1.03-11.27; p=0.04). CONCLUSION: SLN tumor burden, by measuring the maximum diameter of the largest tumor focus, is significantly associated with OS, DFS and NSLN involvement.

16 Article Serial monitoring of circulating tumor cells predicts outcome of induction biochemotherapy plus maintenance biotherapy for metastatic melanoma. 2010

Koyanagi, Kazuo / O'Day, Steven J / Boasberg, Peter / Atkins, Michael B / Wang, He-Jing / Gonzalez, Rene / Lewis, Karl / Thompson, John A / Anderson, Clay M / Lutzky, Jose / Amatruda, Thomas T / Hersh, Evan / Richards, Jon / Weber, Jeffrey S / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA. ·Clin Cancer Res · Pubmed #20371696.

ABSTRACT: PURPOSE: Molecular biomarkers in blood are promising for assessment of tumor progression and treatment response. We hypothesized that serial monitoring of circulating tumor cells (CTC) with the use of multimarker quantitative real-time reverse transcriptase-PCR assays could be a surrogate predictor of outcome for melanoma patients enrolled in a multicenter phase II clinical trial of biochemotherapy (BCT) combined with maintenance biotherapy (mBT). EXPERIMENTAL DESIGN: Blood specimens were collected from 87 patients before and during induction BCT and mBT for stage IV melanoma. Expression of five melanoma-associated CTC biomarkers (MART-1, GalNAc-T, PAX-3, MAGE-A3, and Mitf) was assessed by quantitative real-time reverse transcriptase-PCR, and correlated with treatment response and disease outcome. RESULTS: The number of positive CTC biomarkers decreased overall during induction BCT (P < 0.0001). CTC biomarker detection after two cycles of BCT was correlated with treatment response (P = 0.005) and overall survival (P = 0.001): an increase in the number of CTC biomarkers was associated with poor response (P = 0.006) and overall survival (P < 0.0001). Multivariate analyses with the use of a Cox proportional hazards model identified the change in CTC biomarkers after two cycles of BCT as an independent prognostic factor for disease progression (risk ratio, 12.6; 95% confidence interval, 4.78-33.4; P < 0.0001) and overall survival (risk ratio, 6.11; 95% confidence interval, 2.37-15.7; P = 0.0005). CONCLUSION: Serial monitoring of CTC during induction BCT may be useful for predicting therapeutic efficacy and disease outcome in patients receiving BCT and mBT for stage IV melanoma.