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Melanoma: HELP
Articles by John J. Nemunaitis
Based on 9 articles published since 2008
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Between 2008 and 2019, John Nemunaitis wrote the following 9 articles about Melanoma.
 
+ Citations + Abstracts
1 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.

2 Clinical Trial Safety and Activity of Varlilumab, a Novel and First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors. 2017

Burris, Howard A / Infante, Jeffrey R / Ansell, Stephen M / Nemunaitis, John J / Weiss, Geoffrey R / Villalobos, Victor M / Sikic, Branimir I / Taylor, Matthew H / Northfelt, Donald W / Carson, William E / Hawthorne, Thomas R / Davis, Thomas A / Yellin, Michael J / Keler, Tibor / Bullock, Timothy. ·Howard A. Burris and Jeffrey R. Infante, Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN · Stephen M. Ansell, Mayo Clinic, Rochester, MN · John J. Nemunaitis, Mary Crowley Cancer Research Center, Dallas, TX · Geoffrey R. Weiss and Timothy Bullock, University of Virginia, Charlottesville, VA · Victor M. Villalobos and Branimir I. Sikic, Stanford Cancer Institute, Stanford, CA · Matthew H. Taylor, Oregon Health & Science University, Portland, OR · Donald W. Northfelt, Mayo Clinic, Scottsdale, AZ · William E. Carson III, The Ohio State University, Columbus, OH · Thomas R. Hawthorne, Thomas A. Davis, Michael J. Yellin, and Tibor Keler, Celldex Therapeutics, Hampton, NJ. ·J Clin Oncol · Pubmed #28463630.

ABSTRACT: Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity-grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation-chemokine induction, T-cell stimulation, regulatory T cell depletion-was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.

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 Phase 1b study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma. 2015

Hong, David S / Kurzrock, Razelle / Falchook, Gerald S / Andresen, Corina / Kwak, Jennifer / Ren, Min / Xu, Lucy / George, Goldy C / Kim, Kevin B / Nguyen, Ly M / O'Brien, James P / Nemunaitis, John. ·The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Sarah Cannon Research Institute at HealthONE, Denver, CO, USA. · Former employees of Eisai Inc., Woodcliff Lake, NJ, USA. · Eisai Inc., Oncology, Woodcliff Lake, NJ, USA. · Mary Crowley Cancer Research Center, Dallas, TX, USA. ·Oncotarget · Pubmed #26503473.

ABSTRACT: OBJECTIVE AND METHODS: In this phase 1b study, patients with stage 4 or unresectable stage 3 melanoma were treated with escalating doses of lenvatinib (once daily) and temozolomide (TMZ) (days 1-5) in 28-day cycles, to determine the maximum tolerated dose (MTD) of the combination. Dose Level (DL)1: lenvatinib 20 mg, TMZ 100 mg/m2; DL2: lenvatinib 24 mg, TMZ 100 mg/m2; DL3: lenvatinib 24 mg, TMZ 150 mg/m2. Adverse events (AEs) were recorded and tumor response assessed per RECIST 1.0. RESULTS: Dose-limiting toxicity occurred in 1 of 32 treated patients (DL1); MTD was not reached. The highest dose administered was lenvatinib 24 mg + TMZ 150 mg/m2. Most common treatment-related AEs included fatigue (56.3%), hypertension (53.1%), and proteinuria (46.9%). Overall objective response rate was 18.8% (6 patients), all partial response; (DL1, n = 1; DL3, n = 5). Stable disease (SD) ≥ 16 weeks was observed in 28.1% of patients (DL1 and DL2, n = 1 each; DL3, n = 7); 12.5% of patients had SD ≥ 23 weeks. Single and repeat-dose pharmacokinetics of lenvatinib were comparable across cycles and with concomitant TMZ administration. CONCLUSIONS: Lenvatinib 24 mg/day + TMZ 150 mg/m2/day (days 1-5) demonstrated modest clinical activity, an acceptable safety profile, and was administered without worsening of either lenvatinib- or TMZ-related toxicities in this patient group.

5 Clinical Trial Phase I Dose-Escalation Study of the Multikinase Inhibitor Lenvatinib in Patients with Advanced Solid Tumors and in an Expanded Cohort of Patients with Melanoma. 2015

Hong, David S / Kurzrock, Razelle / Wheler, Jennifer J / Naing, Aung / Falchook, Gerald S / Fu, Siqing / Kim, Kevin B / Davies, Michael A / Nguyen, Ly M / George, Goldy C / Xu, Lucy / Shumaker, Robert / Ren, Min / Mink, Jennifer / Bedell, Cynthia / Andresen, Corina / Sachdev, Pallavi / O'Brien, James P / Nemunaitis, John. ·The University of Texas MD Anderson Cancer Center, Houston, Texas. dshong@mdanderson.org. · The University of Texas MD Anderson Cancer Center, Houston, Texas. · Sarah Cannon Research Institute at HealthONE, Denver, Colorado. · Eisai Inc., Oncology, Woodcliff Lake, New Jersey. · Former employees of Eisai Inc., Woodcliff Lake, New Jersey. · Mary Crowley Cancer Research Center, Dallas, Texas. ·Clin Cancer Res · Pubmed #26169970.

ABSTRACT: PURPOSE: This "3+3" phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors. EXPERIMENTAL DESIGN: Ascending doses of lenvatinib were administered per os twice daily in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort. RESULTS: Seventy-seven patients were treated in 3 cohorts: 18 with intermittent twice-daily dosing (7 days on, 7 days off) of 0.1-3.2 mg; 33 with twice-daily dosing of 3.2-12 mg; and 26 with twice-daily dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg per os twice daily. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (uPR, n = 3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD ≥23 weeks was 40.3% (n = 31). Responses (PR/uPR) by disease were as follows: melanoma, 5 of 29 patients (includes 1 patient with NRAS mutation); thyroid, 3 of 6 patients; pancreatic, 1 of 2 patients; lung, 1 of 1 patients; renal, 1 of 1 patients; endometrial, 1 of 4 patients; and ovarian, 1 of 5 patients. AUC(0-24) and C(max) increased dose proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P = 0.041 and P = 0.03, respectively). CONCLUSIONS: The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients.

6 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.

7 Clinical Trial Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma. 2009

Eager, Robert M / Cunningham, C Casey / Senzer, Neil N / Stephenson, Joe / Anthony, Stephen P / O'Day, Steven J / Frenette, Gary / Pavlick, Anna C / Jones, Barry / Uprichard, Margaret / Nemunaitis, John. ·Mary Crowley Cancer Research Centers, Dallas, TX, USA. eager.rm@gmail.com ·BMC Cancer · Pubmed #19643020.

ABSTRACT: BACKGROUND: Metastatic melanoma is an incurable disease with an average survival of less than one year. Talabostat is a novel dipeptidyl peptidase inhibitor with immunostimulatory properties. METHODS: This phase II, open label, single arm study was conducted to evaluate the safety and efficacy of 75-100 mg/m2 cisplatin combined with 300-400 mcg talabostat bid for 6, 21-day cycles. The primary endpoint was overall response. The rate of complete responses, duration of overall objective response, progression-free survival (PFS), and overall survival were the secondary endpoints. RESULTS: Six objective partial responses were recorded in the 74 patients (8.1%) in the intention-to-treat population. Five of these responses involved the 40 evaluable patients (12.5%). Thirty-one percent of patients reported SAEs to the combination of talabostat and cisplatin. CONCLUSION: Acceptable tolerability was observed in the intention-to-treat population and antitumor activity was observed in 12.5% of evaluable patients, which is not greater than historical expectation with cisplatin alone.

8 Article Cancer targeting vaccines: surrogate measures of activity. 2013

Nemunaitis, John. ·Mary Crowley Cancer Research Centers, Dallas, TX USA. jnemunaitis@marycrowley.org ·Hum Vaccin Immunother · Pubmed #23442594.

ABSTRACT: Recent FDA approval of sipuleucel-T and Ipilimumab as indicated immunologic therapy in patients with advanced prostate cancer and melanoma, respectively, has established a foothold for broader utilization of vaccine based technology in managing cancer.  Despite difficulty of cell harvest and processing with sipuleucel-T and modest toxicity to Ipilimumab, when matched up with the appropriate cancer patient these immunologic approaches have provided significant benefit and have stimulated exciting forward progress in the development of new potent and less toxic (more targeted) vaccines.  However, surrogate measures of activity to optimally define more sensitive subset populations and to determine length of treatment time in order to optimize management with other treatment options remain elusive.  Key clinically tested vaccines under development which demonstrate correlation of patient benefit to induced immune responsiveness will be discussed.  Results suggest with some vaccines correlation of patient benefit and surrogate measures of activity actually do exist.  Examples will be discussed.

9 Article In vivo safety and antitumor efficacy of bifunctional small hairpin RNAs specific for the human Stathmin 1 oncoprotein. 2011

Phadke, Anagha P / Jay, Chris M / Wang, Zhaohui / Chen, Salina / Liu, Shengnan / Haddock, Courtney / Kumar, Padmasini / Pappen, Beena O / Rao, Donald D / Templeton, Nancy S / Daniels, Egeenee Q / Webb, Craig / Monsma, David / Scott, Stephanie / Dylewski, Dawna / Frieboes, Hermann B / Brunicardi, Francis Charles / Senzer, Neil / Maples, Phillip B / Nemunaitis, John / Tong, Alex W. ·Gradalis, Inc., Dallas, TX 75201, USA. ·DNA Cell Biol · Pubmed #21612405.

ABSTRACT: Bifunctional small hairpin RNAs (bi-shRNAs) are functional miRNA/siRNA composites that are optimized for posttranscriptional gene silencing through concurrent mRNA cleavage-dependent and -independent mechanisms (Rao et al., 2010 ). We have generated a novel bi-shRNA using the miR30 scaffold that is highly effective for knockdown of human stathmin (STMN1) mRNA. STMN1 overexpression well documented in human solid cancers correlates with their poor prognosis. Transfection with the bi-shSTMN1-encoding expression plasmid (pbi-shSTMN1) markedly reduced CCL-247 human colorectal cancer and SK-Mel-28 melanoma cell growth in vitro (Rao et al., 2010 ). We now examine in vivo the antitumor efficacy of this RNA interference-based approach with human tumor xenografted athymic mice. A single intratumoral (IT) injection of pbi-shSTMN1 (8 μg) reduced CCL-247 tumor xenograft growth by 44% at 7 days when delivered as a 1,2-dioleoyl-3-trimethyl-ammoniopropane:cholesterol liposomal complex. Extended growth reductions (57% at day 15; p < 0.05) were achieved with three daily treatments of the same construct. STMN1 protein reduction was confirmed by immunoblot analysis. IT treatments with pbi-shSTMN1 similarly inhibited the growth of tumorgrafts derived from low-passage primary melanoma (≥70% reduction for 2 weeks) and abrogated osteosarcoma tumorgraft growth, with the mature bi-shRNA effector molecule detectable for up to 16 days after last injection. Antitumor efficacy was evident for up to 25 days posttreatment in the melanoma tumorgraft model. The maximum tolerated dose by IT injection of >92 μg (Human equivalent dose [HED] of >0.3 mg/kg) in CCL-247 tumor xenograft-bearing athymic mice was ∼10-fold higher than the extrapolated IC(50) of 9 μg (HED of 0.03 mg/kg). Healthy, immunocompetent rats were used as biorelevant models for systemic safety assessments. The observed maximum tolerated dose of <100 μg for intravenously injected pbi-shSTMN1 (mouse equivalent of <26.5 μg; HED of <0.09 mg/kg) confirmed systemic safety of the therapeutic dose, hence supporting early-phase assessments of clinical safety and preliminary efficacy.