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Melanoma: HELP
Articles by Lawrence E. Flaherty
Based on 17 articles published since 2008
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Between 2008 and 2019, Lawrence Flaherty wrote the following 17 articles about Melanoma.
 
+ Citations + Abstracts
1 Clinical Trial Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). 2017

Agarwala, Sanjiv S / Lee, Sandra J / Yip, Waiki / Rao, Uma N / Tarhini, Ahmad A / Cohen, Gary I / Reintgen, Douglas S / Evans, Terry L / Brell, Joanna M / Albertini, Mark R / Atkins, Michael B / Dakhil, Shaker R / Conry, Robert M / Sosman, Jeffrey A / Flaherty, Lawrence E / Sondak, Vernon K / Carson, William E / Smylie, Michael G / Pappo, Alberto S / Kefford, Richard F / Kirkwood, John M. ·Sanjiv S. Agarwala, Saint Luke's University Hospital, Easton · Uma N. Rao, Ahmad A. Tarhini, Terry L. Evans, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · Sandra J. Lee, and Waiki Yip, Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA · Gary I. Cohen, Greater Baltimore Medical Center, Baltimore, MD · Douglas S. Reintgen, Lakeland Regional Cancer Center, Lakeland · Vernon K. Sondak, H. Lee Moffitt Cancer Center, Tampa, FL · Joanna M. Brell, MetroHealth Medical Center, Cleveland · William E. Carson, The Ohio State University Comprehensive Cancer Center, Columbus, OH · Mark R. Albertini, University of Wisconsin Hospital, Madison, WI · Michael B. Atkins, Georgetown Medical Center, Washington, DC · Shaker R. Dakhil, Cancer Center of Kansas, Wichita, KS · Robert M. Conry, University of Alabama at Birmingham, Birmingham, AL · Jeffrey A. Sosman, Vanderbilt University, Nashville · Alberto S. Pappo, Saint Jude Children's Research Hospital Oncology, Memphis, TN · Lawrence E. Flaherty, Wayne State University/Karmanos Cancer Institute, Detroit, MI · Michael G. Smylie, Cross Cancer Institute, Edmonton, Canada · and Richard F. Kefford, Sydney West Area Health Service, Westmead, Australia. ·J Clin Oncol · Pubmed #28135150.

ABSTRACT: Purpose To test the efficacy of 4 weeks of intravenous (IV) induction with high-dose interferon (IFN) as part of the Eastern Cooperative Oncology Group regimen compared with observation (OBS) in patients with surgically resected intermediate-risk melanoma. Patients and Methods In this intergroup international trial, eligible patients had surgically resected cutaneous melanoma in the following categories: (1) T2bN0, (2) T3a-bN0, (3) T4a-bN0, and (4) T1-4N1a-2a (microscopic). Patients were randomly assigned to receive IFN α-2b at 20 MU/m

2 Clinical Trial Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933. 2015

Lee, Sylvia M / Moon, James / Redman, Bruce G / Chidiac, Tarek / Flaherty, Lawrence E / Zha, Yuanyuan / Othus, Megan / Ribas, Antoni / Sondak, Vernon K / Gajewski, Thomas F / Margolin, Kim A. ·Seattle Cancer Care Alliance/University of Washington, Seattle, WA. · SWOG Statistical Center, Seattle, WA. · University of Michigan, Ann Arbor, MI. · Columbus CCOP/Mid-Ohio Onc/Hem Inc, Columbus, OH. · Wayne State University/Karmanos Cancer Institute, Detroit, MI. · University of Chicago, Chicago, IL. · UCLA Medical Center, Los Angeles, CA. · H. Lee Moffitt Cancer Center, Tampa, FL. ·Cancer · Pubmed #25250858.

ABSTRACT: BACKGROUND: Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma. METHODS: Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 patients and with continuation of enrollment if 4 or more of the 32 patients responded. RESULTS: Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and there were 8 patients with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of interleukin-2, a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition. CONCLUSIONS: RO4929097 showed minimal clinical activity against metastatic melanoma in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in melanoma, the results do not support further investigation of RO4929097 with this dose and schedule.

3 Clinical Trial Southwest Oncology Group S0008: a phase III trial of high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of cancer and leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. 2014

Flaherty, Lawrence E / Othus, Megan / Atkins, Michael B / Tuthill, Ralph J / Thompson, John A / Vetto, John T / Haluska, Frank G / Pappo, Alberto S / Sosman, Jeffrey A / Redman, Bruce G / Moon, James / Ribas, Antoni / Kirkwood, John M / Sondak, Vernon K. ·Lawrence E. Flaherty, Wayne State University, Detroit · Bruce G. Redman, University of Michigan, Ann Arbor, MI · Megan Othus, James Moon, Southwest Oncology Group Statistical Center · John A. Thompson, Seattle Cancer Care Alliance, Seattle, WA · Michael B. Atkins, Georgetown University Hospital, Washington DC · Ralph J. Tuthill, Cleveland Clinic Foundation, Cleveland, OH · John T. Vetto, Oregon Health & Science University/Knight Cancer Institute, Portland, OR · Frank G. Haluska, Tufts-New England Medical Center, Boston, MA · Alberto S. Pappo, Texas Children's Cancer Center, Houston, TX · Jeffrey A. Sosman, Vanderbilt University School of Medicine Nashville, TN · Antoni Ribas, University of California Los Angeles, Los Angeles, CA · John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · Vernon K. Sondak, H. Lee Moffitt Cancer Center, Tampa, FL. ·J Clin Oncol · Pubmed #25332243.

ABSTRACT: PURPOSE: High-dose interferon (IFN) for 1 year (HDI) is the US Food and Drug Administration-approved adjuvant therapy for patients with high-risk melanoma. Efforts to modify IFN dose and schedule have not improved efficacy. We sought to determine whether a shorter course of biochemotherapy would be more effective. PATIENTS AND METHODS: S0008 (S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma) was an Intergroup phase III trial that enrolled high-risk patients (stage IIIA-N2a through IIIC-N3), randomly assigning them to receive either HDI or biochemotherapy consisting of dacarbazine, cisplatin, vinblastine, interleukin-2, IFN alfa-2b (IFN-α-2b) and granulocyte colony-stimulating factor given every 21 days for three cycles. Coprimary end points were relapse-free survival (RFS) and overall survival (OS). RESULTS: In all, 432 patients were enrolled. Grade 3 and 4 adverse events occurred in 57% and 7% of HDI patients and 36% and 40% of biochemotherapy patients, respectively. At a median follow-up of 7.2 years, biochemotherapy improved RFS (hazard ratio [HR], 0.75; 95% CI, 0.58 to 0.97; P = .015), with a median RFS of 4.0 years (95% CI, 1.9 years to not reached [NR]) versus 1.9 years for HDI (95% CI, 1.2 to 2.8 years) and a 5-year RFS of 48% versus 39%. Median OS was not different (HR, 0.98; 95% CI, 0.74 to 1.31; P = .55), with a median OS of 9.9 years (95% CI, 4.62 years to NR) for biochemotherapy versus 6.7 years (95% CI, 4.5 years to NR) for HDI and a 5-year OS of 56% for both arms. CONCLUSION: Biochemotherapy is a shorter, alternative adjuvant treatment for patients with high-risk melanoma that provides statistically significant improvement in RFS but no difference in OS and more toxicity compared with HDI.

4 Clinical Trial Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. 2014

Ribas, Antoni / Gonzalez, Rene / Pavlick, Anna / Hamid, Omid / Gajewski, Thomas F / Daud, Adil / Flaherty, Lawrence / Logan, Theodore / Chmielowski, Bartosz / Lewis, Karl / Kee, Damien / Boasberg, Peter / Yin, Ming / Chan, Iris / Musib, Luna / Choong, Nicholas / Puzanov, Igor / McArthur, Grant A. ·Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA. · University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. · New York University Medical Center, New York, NY, USA. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · University of Chicago, Chicago, IL, USA. · Hematology/Oncology Division, University of California, San Francisco, CA, USA. · Karmanos Cancer Institute, Detroit, MI, USA. · Indiana University, Indianapolis, IN, USA. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. · Genentech, South San Francisco, CA, USA. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Electronic address: grant.mcarthur@petermac.org. ·Lancet Oncol · Pubmed #25037139.

ABSTRACT: BACKGROUND: Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma. METHODS: We undertook a phase 1b study in patients with advanced BRAF(V600)-mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803. FINDINGS: 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1-17·5). INTERPRETATION: The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing. FUNDING: F Hoffmann-La Roche/Genentech.

5 Clinical Trial Adjuvant vaccine immunotherapy of resected, clinically node-negative melanoma: long-term outcome and impact of HLA class I antigen expression on overall survival. 2014

Carson, William E / Unger, Joseph M / Sosman, Jeffrey A / Flaherty, Lawrence E / Tuthill, Ralph J / Porter, Mark J / Thompson, John A / Kempf, Raymond A / Othus, Megan / Ribas, Antoni / Sondak, Vernon K. ·Division of Surgical Oncology, The Ohio State University, Columbus, Ohio. william.carson@osumc.edu. · SWOG Statistical Center, Seattle, Washington. · Vanderbilt University, Nashville, Tennessee. · Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. · Cleveland Clinic Foundation, Cleveland, Ohio. · Division of Surgical Oncology, The Ohio State University, Columbus, Ohio. · Seattle Cancer Care Alliance, Seattle, Washington. · Los Angeles County Department of Health Services, University of Southern California, Los Angeles, California. · University of California Los Angeles, Los Angeles, California. · H. Lee Moffitt Cancer Center, Tampa, Florida. ·Cancer Immunol Res · Pubmed #24994597.

ABSTRACT: Associations between HLA class I antigen expression and the efficacy of a melanoma vaccine (Melacine; Corixa Corp.) were initially described in stage IV melanoma. Similar associations were observed in S9035, a phase III adjuvant trial evaluating Melacine for 2 years compared with observation in patients with stage II melanoma. This report provides long-term results. The effects of treatment on relapse-free survival (RFS) and overall survival (OS) were evaluated, and prespecified analyses investigated associations between treatment and HLA expression. Multivariable analyses were adjusted for tumor thickness, ulceration and site, method of nodal staging, and sex. P = 0.01 was considered statistically significant in subset analyses to account for multiple comparisons. For the entire study population of 689 patients, there were no significant differences in RFS or OS by treatment arm. HLA serotyping was performed on 553 (80%) patients (vaccine, 294; observation, 259). Among the subpopulation with HLA-A2 and/or HLA-Cw3 serotype, vaccine arm patients (n = 178) had marginally improved RFS (adjusted P = 0.02) and significantly improved OS compared with observation arm patients (n = 145), with 10-year OS of 75% and 63%, respectively [hazard ratio (HR), 0.62; 99% confidence interval (CI), 0.37-1.02; P = 0.01]. There was no impact of HLA-A2 and/or HLA-Cw3 expression on observation arm patients. An analysis of mature data from S9035 indicates a significant OS benefit from adjuvant vaccine therapy for patients with HLA-A2- and/or HLA-Cw3-expressing melanoma. The possibility of interactions between HLA type and outcome should be considered in future immunotherapy trials. Further investigations of melanoma-associated antigens present in Melacine and presented by HLA-A2 and HLA-Cw3 may be warranted.

6 Clinical Trial A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States. 2014

Flaherty, Lawrence / Hamid, Omid / Linette, Gerald / Schuchter, Lynn / Hallmeyer, Sigrun / Gonzalez, Rene / Cowey, C Lance / Pavlick, Anna / Kudrik, Fred / Curti, Brendan / Lawson, David / Chapman, Paul B / Margolin, Kim / Ribas, Antoni / McDermott, David / Flaherty, Keith / Cranmer, Lee / Hodi, F Stephen / Day, Bann-Mo / Linke, Rolf / Hainsworth, John. ·From the *Karmanos Cancer Center, Wayne State University, Detroit, MI; †The Angeles Clinic and Research Institute, Los Angeles, CA; ‡Washington University, St Louis, MO; §University of Pennsylvania, Philadelphia, PA; ∥Oncology Specialists S.C., Park Ridge, IL; ¶University of Colorado Cancer Center, Aurora, CO; #Baylor Sammons Cancer Center, Texas Oncology, PA, Dallas, TX; **NYU Medical Center, New York, NY; ††South Carolina Oncology Associates, Columbia, SC; ‡‡Providence Portland Medical Center, Portland, OR; §§Winship Cancer Institute, Emory University, Atlanta, GA; ∥∥Memorial Sloan Kettering Cancer Center, New York, NY; ¶¶Seattle Cancer Care Alliance, Seattle, WA; ##UCLA School of Medicine, Los Angeles, CA; ***Beth Israel Deaconess Medical Center and †††Massachusetts General Hospital, Boston, MA; ‡‡‡University of Arizona Cancer Center, Tucson, AZ; §§§Dana Farber Cancer Institute, Boston, MA; ∥∥∥Genentech, San Francisco, CA; ¶¶¶The SFJ Pharma Group, Pleasanton, CA; and ###Sarah Cannon Research Institute, Nashville, TN. ·Cancer J · Pubmed #24445759.

ABSTRACT: PURPOSE: This open-label, multicenter study was designed to allow access to vemurafenib for patients with metastatic melanoma, bridging the time between end of enrollment in the phase III registration trial (December 2010) and commercial availability following US Food and Drug Administration approval of vemurafenib for the treatment of unresectable or metastatic BRAF-mutated melanoma (August 2011). PATIENTS AND METHODS: Eligible patients had metastatic melanoma with a BRAF mutation (detected by the cobas 4800 BRAF V600 Mutation Test). Unlike previous vemurafenib trials, patients with poor performance status (PS) and treated brain metastases were permitted. Enrolled patients received oral vemurafenib 960 mg twice daily. RESULTS: Of 374 patients enrolled at 29 US sites (December 2010 to October 2011), 371 patients received vemurafenib and were followed up for a median of 2.8 months (the study had a prespecified end upon vemurafenib approval and commercial availability). At baseline, most patients (75%) had stage M1c disease, and 19% had an Eastern Cooperative Oncology Group PS of 2 or 3; 72% of patients had received prior systemic therapy for metastatic melanoma, 27% received prior ipilimumab, and 29% radiotherapy for prior brain metastases. Because reassessment data to confirm response were not available for most patients, point estimates of objective response rate (ORR) are reported. Among 241 efficacy-evaluable patients, the ORR was 54% (median time to response, 1.9 months). The ORR in non-central nervous system sites in patients with previously treated brain metastases (n = 68) was 53%. The ORR in prior ipilimumab-treated patients (n = 68) was 52%. For patients with PS of 0 or 1 (n = 210) and 2 or 3 (n = 31), the ORRs were 55%, and 42%, respectively. The safety profile observed was consistent with that reported in previous studies. The number of patients with grade 3 or 4 treatment-related adverse events was higher in patients with PS 2 or 3 than in those with PS 0 or 1 (10% vs. 5%, respectively). Adverse events requiring a dose reduction (at least 1 level) occurred in 11% of patients, and 9 patients (2%) experienced events leading to vemurafenib withdrawal, including 2 with repeated QT interval prolongation. DISCUSSION: This study confirmed the established rapid and high tumor response rate achievable with vemurafenib in BRAF mutation-positive metastatic melanoma. Several groups not included in previous studies, including patients with previously treated brain metastases, Eastern Cooperative Oncology Group PS 2 to 3, or previous ipilimumab treatment had benefitted from vemurafenib similar to the overall population. No new safety signals were detected.

7 Clinical Trial Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. 2013

Flaherty, Keith T / Lee, Sandra J / Zhao, Fengmin / Schuchter, Lynn M / Flaherty, Lawrence / Kefford, Richard / Atkins, Michael B / Leming, Philip / Kirkwood, John M. ·Massachusetts General Hospital, 55 Fruit St, Yawkey 9E, Boston, MA 02114, USA. kflaherty@partners.org ·J Clin Oncol · Pubmed #23248256.

ABSTRACT: PURPOSE: The primary objective of this study was to determine whether carboplatin, paclitaxel, and sorafenib (CPS) improve overall survival (OS) compared with carboplatin and paclitaxel (CP) in chemotherapy-naive patients with metastatic melanoma. PATIENTS AND METHODS: In this double-blind, randomized, placebo-controlled phase III study, all patients received carboplatin at area under the [concentration-time] curve 6 and paclitaxel 225 mg/m(2) intravenously once every 21 days with random assignment to sorafenib 400 mg orally twice per day on days 2 through 19 every 21 days or placebo. The primary end point was OS, and secondary end points included progression-free survival, objective tumor response, and toxicity. RESULTS: In all, 823 patients were enrolled over 34 months. At final analysis, the median OS was 11.3 months (95% CI, 9.8 to 12.2 months) for CP and 11.1 months (95% CI, 10.3 to 12.3 months) for CPS; the difference in the OS distribution was not statistically significant by the stratified log-rank test, stratified on American Joint Committee on Cancer (AJCC) stage, Eastern Cooperative Oncology Group (ECOG) performance status, and prior therapy (P = .878). Median progression-free survival was 4.9 months for CPS and 4.2 months for CP (P = .092, stratified log-rank test). Response rate was 20% for CPS and 18% for CP (P = .427). More patients on the CPS arm had grade 3 or higher toxicities (84% v 78%; P = .027), with increased rash, hand-foot syndrome, and thrombocytopenia accounting for most of the difference. CONCLUSION: Sorafenib does not improve OS when given in combination with CP for chemotherapy-naive patients with metastatic melanoma. This study establishes benchmark end points for the CP regimen in first-line therapy of metastatic melanoma.

8 Clinical Trial Randomized phase II trial of sorafenib with temsirolimus or tipifarnib in untreated metastatic melanoma (S0438). 2012

Margolin, Kim A / Moon, James / Flaherty, Lawrence E / Lao, Christopher D / Akerley, Wallace L / Othus, Megan / Sosman, Jeffrey A / Kirkwood, John M / Sondak, Vernon K. ·University of Washington, SWOG Statistical Center, Seattle, WA98109., USA. kmargoli@seattlecca.org ·Clin Cancer Res · Pubmed #22228638.

ABSTRACT: PURPOSE: Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by intrinsic and acquired resistance. The mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate 2 molecularly targeted drug combinations in patients with untreated metastatic melanoma. EXPERIMENTAL DESIGN: This randomized phase II study enrolled patients between May 2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400 mg every morning, 200 mg every night daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate, and toxicity for the 2 regimens. RESULTS: On arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) was 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS was 7 months, with 1 patient achieving PR. CONCLUSIONS: The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates.

9 Clinical Trial A phase 2 trial of complete resection for stage IV melanoma: results of Southwest Oncology Group Clinical Trial S9430. 2011

Sosman, Jeffrey A / Moon, James / Tuthill, Ralph J / Warneke, James A / Vetto, John T / Redman, Bruce G / Liu, P Y / Unger, Joseph M / Flaherty, Lawrence E / Sondak, Vernon K. ·Vanderbilt University School of Medicine, Department of Medicine, Nashville, Tennessee, USA. jeff.sosman@vanderbilt.edu ·Cancer · Pubmed #21455999.

ABSTRACT: BACKGROUND: On the basis of retrospective experience at individual centers, it appears that patients with stage IV melanoma who undergo complete resection have a favorable outcome compared with patients with disseminated stage IV disease. The Southwest Oncology Group (SWOG) performed a prospective trial in patients with metastatic melanoma who were enrolled before complete resection of their metastatic disease and provided prospective outcomes in the cooperative group setting. METHODS: Based on their physical examination and radiologic imaging studies, patients with a stage IV melanoma judged amenable to complete resection underwent surgery within 28 days of enrollment. All eligible patients were followed with scans (computed tomography or positron emission tomography) every 6 months until relapse and death. RESULTS: Seventy-seven patients were enrolled from 18 different centers. Of those, 5 patients were ineligible; 2 had stage III disease alone; and 3 had no melanoma in their surgical specimen. In addition, 8 eligible patients had incompletely resected tumor. Therefore, the primary analysis included 64 completely resected patients. Twenty patients (31%) had visceral disease. With a median follow-up of 5 years, the median relapse-free survival was 5 months (95% CI, 3-7 months) whereas median overall survival was 21 months (95% CI, 16-34 months). Overall survivals at 3 and 4 years were 36% and 31%, respectively. CONCLUSIONS: In a prospective multicenter setting, appropriately selected patients with stage IV melanoma achieved prolonged overall survival after complete surgical resection. Although median relapse-free survival was only 5 months, patients could still frequently undergo subsequent surgery for isolated recurrences. This patient population is appropriate for aggressive surgical therapy and for trials evaluating adjuvant therapy.

10 Clinical Trial A study of paclitaxel, carboplatin, and bortezomib in the treatment of metastatic malignant melanoma: a phase 2 consortium study. 2010

Croghan, Gary A / Suman, Vera J / Maples, William J / Albertini, Mark / Linette, Gerald / Flaherty, Lawrence / Eckardt, John / Ma, Cynthia / Markovic, Svetomir N / Erlichman, Charles. ·Department of Medical Oncology, Melanoma Study Group, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. croghan.gary@mayo.edu ·Cancer · Pubmed #20564112.

ABSTRACT: BACKGROUND: Chemotherapy has not been reported to have a significant impact on survival for patients with metastatic melanoma. Bortezomib was shown to have additive/synergistic effects with several chemotherapeutic agents, including paclitaxel and platinum. A phase 1 trial of this 3-drug combination reported that 6 of 28 patients treated with bortezomib followed by paclitaxel and carboplatin achieved a partial response (including 2 of 5 patients with metastatic melanoma). METHODS: A 2-stage phase 2 clinical trial was conducted to assess the antitumor activity of this 3-agent combination in patients with metastatic melanoma who had received at most 1 prior chemotherapy for metastatic disease. Treatment included bortezomib at a dose of 1.3 mg/m2 intravenously on Days 1, 4, and 8; paclitaxel at a dose of 175 mg/m2; and carboplatin at an area under the concentration (AUC) of 6 on Day 2 of a 21-day cycle. The primary endpoint of this trial was tumor response rate (TRR). RESULTS: Seventeen eligible patients were enrolled. A median of 4 cycles were administered (range, 1-7 cycles). Three patients discontinued treatment due to persistent grade 4 (based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neutropenia with grade 3 leukopenia (2 patients) or grade 4 pulmonary embolism (1 patient). Grade>or=3 toxicities included neutropenia (71%), leukopenia (41%), thrombocytopenia (29%), and arthralgia (12%). Two partial responses were observed (TRR, 11.8%). Four patients had stable disease at >12 weeks. The median progression-free survival was 3.2 months, and the median overall survival was 7.0 months. CONCLUSIONS: Due to insufficient clinical efficacy, this trial did not proceed to second-stage accrual. The combination of paclitaxel, carboplatin, and bortezomib demonstrated limited clinical benefit and was associated with significant toxicity.

11 Clinical Trial Phase 2 trial of combination thalidomide plus temozolomide in patients with metastatic malignant melanoma: Southwest Oncology Group S0508. 2010

Clark, Joseph I / Moon, James / Hutchins, Laura F / Sosman, Jeffrey A / Kast, W Martin / Da Silva, Diane M / Liu, P Y / Thompson, John A / Flaherty, Lawrence E / Sondak, Vernon K. ·Cardinal Bernardin Cancer Center, Loyola University Medical Center, Division of Hematology/Oncology, 2160 South First Avenue, Maywood, IL 60153, USA. jclark@lumc.edu ·Cancer · Pubmed #19918923.

ABSTRACT: BACKGROUND: In limited institution phase 2 studies, thalidomide and temozolomide has yielded response rates (RRs) up to 32% for advanced melanoma, leading to the use of this combination as "standard" by some. We conducted a multicenter phase 2 trial to better define the clinical efficacy of thalidomide and temozolomide and the immune modulatory effects of thalidomide, when combined with temozolomide, in patients with metastatic melanoma. METHODS: Patients must have had stage IV cutaneous melanoma, no active brain metastases, Zubrod PS 0-1, up to 1 prior systemic therapy excluding thalidomide, temozolomide, or dacarbazine, adequate organ function, and given informed consent. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included overall survival (OS), RR, toxicities, and assessment of relationships between biomarkers and clinical outcomes. Patients received thalidomide (200 mg/d escalated to 400 mg/d for patients <70, or 100 mg/d escalated to 250 mg/d for patients > or =70) plus temozolomide (75 mg/m(2)/d x 6 weeks, and then 2 weeks rest). RESULTS: Sixty-four patients were enrolled; 2 refused treatment. The 6-month PFS was 15% (95% confidence interval [CI], 6%-23%), the 1-year OS was 35% (95% CI, 24%-47%), and the RR was 13% (95% CI, 5%-25%), all partial. One treatment-related death occurred from myocardial infarction; 3 other grade 4 events occurred, including pulmonary embolism, neutropenia, and central nervous system (CNS) ischemia. There was no significant correlation between biomarkers and PFS or OS. CONCLUSIONS: This combination of thalidomide and temozolomide does not appear to have a clinical benefit that exceeds dacarbazine alone. We would not recommend it further for phase 3 trials or for standard community use.

12 Clinical Trial 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 by the Eastern Cooperative Oncology Group. 2008

Atkins, Michael B / Hsu, Jessie / Lee, Sandra / Cohen, Gary I / Flaherty, Lawrence E / Sosman, Jeffrey A / Sondak, Vernon K / Kirkwood, John M / Anonymous2430615. ·Beth Israel Deaconess Medical Center; Dana-Farber Cancer Institute, Boston, MA 02215, USA. matkins@bidmc.harvard.edu ·J Clin Oncol · Pubmed #19001327.

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 significantly longer for BCT than for CVD (4.8 v 2.9 months; P = .015), although this did not translate into an advantage in either median overall survival (9.0 v 8.7 months) or the percentage of patients alive at 1 year (41% v 36.9%). More patients experienced grade 3 or worse toxic events with BCT than CVD (95% v 73%; P = .001). CONCLUSION: Although BCT produced slightly higher response rates and longer median progression-free survival than CVD alone, this was not associated with either improved overall survival or durable responses. Considering the extra toxicity and complexity, this concurrent BCT regimen cannot be recommended for patients with metastatic melanoma.

13 Clinical Trial Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma. 2008

Sosman, Jeffrey A / Carrillo, Carole / Urba, Walter J / Flaherty, Lawrence / Atkins, Michael B / Clark, Joseph I / Dutcher, Janet / Margolin, Kim A / Mier, James / Gollob, Jarod / Kirkwood, John M / Panka, David J / Crosby, Nancy A / O'Boyle, Kevin / LaFleur, Bonnie / Ernstoff, Marc S. ·Vanderbilt-Ingram Cancer Center Vanderbilt, University Medical Center, Section of Hematology/Oncology, 777 Preston Research Bldg, Nashville, TN 37232-6307, USA. jeff.sosman@vanderbilt.edu ·J Clin Oncol · Pubmed #18467720.

ABSTRACT: 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 >or= 30 months. Immune studies including assays of CD3-zeta 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.

14 Article Cancer Site and Adverse Events Induced by Immune Checkpoint Inhibitors: A Retrospective Analysis of Real-life Experience at a Single Institution. 2019

Sukari, Ammar / Nagasaka, Misako / Alhasan, Roba / Patel, Dhaval / Wozniak, Antoinette / Ramchandren, Radhakrishnan / Vaishampayan, Ulka / Weise, Amy / Flaherty, Lawrence / Jang, Hyejeong / Kim, Seongho / Gadgeel, Shirish. ·Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, U.S.A. sukaria@karmanos.org. · Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, U.S.A. · Department of Advanced Medical Innovation, St. Marianna University Graduate School of Medicine, Kawasaki, Japan. · Department of Hematology and Oncology, Michigan State University, Lansing, MI, U.S.A. · Department of Oncology, University of Pittsburgh, Pittsburgh, PA, U.S.A. · Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, U.S.A. ·Anticancer Res · Pubmed #30711957.

ABSTRACT: BACKGROUND: Data on the characteristics of patients who are likely to experience adverse events, both immune-related and non-immune-related, from programmed cell death-1 (PD1) inhibitors are limited. PATIENTS AND METHODS: Data from patients who received ≥1 dose of single-agent PD1 inhibitor between August 3, 2011 and August 31, 2016 were obtained from our Institution's pharmacy database. AEs were graded using Common Terminology Criteria for Adverse Events version 4. RESULTS: One hundred and eighty-two patients received at least one dose of single-agent PD1 inhibitor prior to data cut-off. After excluding 14 patients with uncommon malignancies, the total number of patients were 168. The median age was 63 (range=24-92) years. There were 87 (52%) cases of non-small cell lung cancer (NSCLC), 35 (21%) of renal cell carcinoma (RCC), 12 (7%) of melanoma, 18 (11%) of Hodgkin's lymphomas, eight (5%) of head and neck squamous cell carcinoma (HNSCC) and eight (5%) of small cell lung cancer. Considering grade 2 or more AEs, 30 (18%) patients had kidney injury, 34 (20%) hypothyroidism, 36 (21%) transaminitis, 20 (12%) pneumonitis, and 18 (11%) colitis. Patients with RCC had higher odds of experiencing grade 2 or more kidney injury than patients with other primary tumor types (adjusted p=0.025), whereas patients with Hodgkin's lymphoma and HNSCC had higher odds of grade 2 hypothyroidism (adjusted p=0.005). Patients with NSCLC had higher risk of death with pneumonitis than those whose primary cancer was not NSCLC (adjusted p=0.005). DISCUSSION: The increased odds of patients with Hodgkin's lymphoma and HNSCC experiencing grade 2 or more hypothyroidism may be related to previous radiation exposure. Most patients with RCC had undergone nephrectomy, making them more susceptible to acute kidney injury. When pneumonitis occurred in patients with primary NSCLC, the overall survival was significantly worse. The duration of PD1 therapy was significantly associated with onset of pneumonitis (p=0.007). CONCLUSION: The site of primary tumor or metastasis may help predict the most common AEs in patients treated with PD1 inhibitors.

15 Article High frequency of brain metastases after adjuvant therapy for high-risk melanoma. 2017

Samlowski, Wolfram E / Moon, James / Witter, Merle / Atkins, Michael B / Kirkwood, John M / Othus, Megan / Ribas, Antoni / Sondak, Vernon K / Flaherty, Lawrence E. ·Comprehensive Cancer Centers of Nevada/Southern Nevada CCOP, Las Vegas, Nevada. · SWOG Statistical Center, Seattle, Washington. · Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC. · University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · UCLA Medical Center, Los Angeles, California. · H Lee Moffitt Cancer Center, Tampa, Florida. · Wayne State University/Karmanos Cancer Institute, Detroit, Michigan. ·Cancer Med · Pubmed #28994212.

ABSTRACT: The incidence of CNS progression in patients with high-risk regional melanoma (stages IIIAN2a-IIIC) is not well characterized. Data from the S0008 trial provided an opportunity to examine the role of CNS progression in treatment failure and survival. All patients were surgically staged. Following wide excision and full regional lymphadenectomy, patients were randomized to receive adjuvant biochemotherapy (BCT) or high-dose interferon alfa-2B (HDI). CNS progression was retrospectively identified from data forms. Survival was measured from date of CNS progression. A total of 402 eligible patients were included in the analysis (BCT: 199, HDI: 203). Median follow-up (if alive) was over 7 years (range: 1 month to 11 years). The site of initial progression was identifiable in 80% of relapsing patients. CNS progression was a component of systemic melanoma relapse in 59/402 patients (15% overall). In 34/402 patients (9%) CNS progression represented the initial site of treatment failure. CNS progression was a component of initial progression in 27% of all patients whose melanoma relapsed (59/221). The risk of CNS progression was highest within 3 years of randomization. The difference in CNS progression rates between treatment arms was not significant (BCT = 25, HDI = 34, P = 0.24). Lymph node macrometastases strongly associated with CNS progression (P = 0.001), while ulceration and head and neck primaries were not significant predictors. This retrospective analysis of the S0008 trial identified a high brain metastasis rate (15%) in regionally advanced melanoma patients. Further studies are needed to establish whether screening plus earlier treatment would improve survival following CNS progression.

16 Article Targeted therapies: Improved outcomes for patients with metastatic melanoma. 2011

Sondak, Vernon K / Flaherty, Lawrence E. ·Department of Cutaneous Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. vernon.sondak@moffitt.org ·Nat Rev Clin Oncol · Pubmed #21788973.

ABSTRACT: Recently published phase III trials involving interleukin-2, ipilimumab and vemurafenib redefine 'standard-of-care' for metastatic melanoma and demonstrate improved survival compared with dacarbazine. All three therapies are potential first-line options for patients with metastatic melanoma, with optimal treatment strategies evolving based on tumor mutation status, disease burden, performance status and comorbidities.

17 Article Adjuvant therapy of melanoma: is pegylated interferon alfa-2b what we've been waiting for? 2008

Sondak, Vernon K / Flaherty, Lawrence E. ·H Lee Moffitt Cancer Center and University of South Florida College of Medicine, Tampa, FL 33612, USA. vernon.sondak@moffi tt.org ·Lancet · Pubmed #18620932.

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