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1.
Support Care Cancer ; 27(4): 1497-1507, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30392112

RESUMEN

INTRODUCTION: Increasing numbers of metastatic melanoma (MM) patients are receiving immunotherapy treatment, including pembrolizumab, and the impact on their well-being is underexplored. OBJECTIVES: To assess the feasibility of a multimodal supportive care program to MM patients being treated with pembrolizumab. METHODS: This pre-post-test feasibility cohort study recruited MM participants treated with pembrolizumab: (i) supportive care intervention with usual care and (ii) usual care. The intervention comprised comprehensive medical assessment by supportive care physician (SCP), exercise physiologist (EP), and dietitian then a tailored supportive care program. Programs included exercise, dietary advice, non-invasive complementary therapies, and psychology consultation. Outcome measures included adherence, patient-reported symptoms, anxiety and depression, and toxicity. Descriptive data are reported. RESULTS: We recruited 28 participants: 13 intervention and 15 control; three did not complete the study. Most were male, with median age 66 (range 42-85) years. All intervention participants completed baseline assessments with SCP, EP, and dietitian. Two missed follow-up with EP or dietitian. Symptoms most troubling at baseline were as follows: fatigue (n = 6), sleep (n = 6), general aches and pains (n = 5), and memory (n = 4). All intervention participants were prescribed 16 exercise sessions; 8 (50%) completed all; overall exercise adherence was 85%. Integrative therapies were accessed by 85% (11) participants. Immunotherapy-related adverse event rates were low and SCP consultation identified symptoms not captured by CTCAE 4.0. CONCLUSIONS: A holistic supportive care intervention tailored to individual needs is feasible. The symptom burden in MM patients was low. Further investigation of the intervention is warranted, focused on populations with higher symptom burden to improve outcomes.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Melanoma/terapia , Cuidados Paliativos/métodos , Aceptación de la Atención de Salud , Percepción , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Terapia Combinada/métodos , Dietoterapia , Terapia por Ejercicio , Estudios de Factibilidad , Femenino , Humanos , Inmunoterapia/métodos , Masculino , Melanoma/patología , Melanoma/psicología , Persona de Mediana Edad , Manipulaciones Musculoesqueléticas , Metástasis de la Neoplasia , Aceptación de la Atención de Salud/estadística & datos numéricos , Proyectos Piloto , Calidad de Vida , Medición de Riesgo
2.
Invest New Drugs ; 36(5): 886-894, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29766337

RESUMEN

Background The MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF) also known as scatter factor, are associated with tumourigenesis and metastasis by promotion of scattering, proliferation, angiogenesis, motility and invasion. ASLAN-002 is a potent inhibitor of MET as well as related kinases. A phase I dose escalation study was conducted to determine the safety and pharmacokinetics of ASLAN-002 in patients with advanced cancer. Methods Patients with advanced or metastatic solid tumours, who had progressed on standard therapy or for whom standard therapy was not known, were administered ASLAN-002 orally. The starting dose was 100 mg once daily (QD) with subsequent cohorts to receive doses of 200 mg QD, 300 mg QD, 450 mg QD, 600 mg QD, 300 mg twice daily (BID), 450 mg BID, and 600 mg BID. Results Forty patients were included across 7 dose cohorts. Cohort 8 (600 mg BID) was not opened due to the lack of appreciable pharmacokinetic (PK) differences between 300 mg BID and 450 mg BID and higher incidences of grade 3 or 4 adverse events (AE) in Cohort 7 (450 mg BID). Fifteen patients (37.5%) experienced a grade 3 or 4 AE. The most commonly reported AEs were nausea (55%), fatigue (47.5%) and constipation (30%). One dose limiting toxicity (DLT) of atrial fibrillation was observed with 450 mg BID. Conclusions ASLAN-002 is well tolerated at 300 mg BID and is the recommended dose for future phase II studies (RP2D). Clinical Trials Registry Number: NCT01721148 .


Asunto(s)
Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Fatiga/inducido químicamente , Fatiga/metabolismo , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Náusea/inducido químicamente , Náusea/metabolismo , Neoplasias/metabolismo
3.
Lancet Oncol ; 18(9): 1202-1210, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28729151

RESUMEN

BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. FUNDING: Merck & Co, Inc.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/secundario , Anciano , Australia , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Ipilimumab , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Nueva Zelanda , Resultado del Tratamiento , Estados Unidos
5.
J Oncol Pharm Pract ; 19(4): 365-8, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23235917

RESUMEN

Glioblastoma multiforme is an aggressive malignant brain tumor. The monoclonal antibody, bevacizumab, is active in recurrent disease via inhibition of angiogenesis. Proteinuria and renal thrombotic microangiopathy are known complications. We report a case of a patient developing acute renal failure with biopsy-proven interstitial nephritis while receiving bevacizumab for recurrent disease. The patient was otherwise well with a history of controlled hypertension. Renal function improved with discontinuation of bevacizumab and the administration of corticosteroid therapy.


Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Nefritis Intersticial/inducido químicamente , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab , Biopsia , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Nefritis Intersticial/diagnóstico , Nefritis Intersticial/fisiopatología
7.
Ocul Immunol Inflamm ; 26(4): 628-631, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-27892777

RESUMEN

PURPOSE: To report the diagnosis of acute VKH-like syndrome as a complication from dabrafenib (a serine/threonine inhibitor of BRAF V600) and trametinib (a MEK inhibitor). In combination, these targeted agents have been shown to prolong overall survival and progression free survival in BRAF mutant metastatic melanoma. METHODS: Retrospective medical chart review including radiologic and ophthalmologic investigations. RESULTS: A patient with metastatic melanoma being treated with dabrafenib and trametinib for 2 months presented with 1 week of visual blurring. He had developed bilateral optic disc swelling and uveitis that responded to pulsed steroid therapy. CONCLUSIONS: VKH-like syndrome is a rare but serious complication of targeted therapy that should be considered when evaluating a patient with visual disturbances on dabrafenib and trametinib therapy.


Asunto(s)
Imidazoles/uso terapéutico , Melanoma/complicaciones , Disco Óptico/patología , Oximas/uso terapéutico , Papiledema/etiología , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Neoplasias Cutáneas/complicaciones , Uveítis/etiología , Antineoplásicos/uso terapéutico , Supervivencia sin Enfermedad , Quimioterapia Combinada , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/secundario , Persona de Mediana Edad , Papiledema/diagnóstico , Papiledema/tratamiento farmacológico , Neoplasias Cutáneas/patología , Tomografía de Coherencia Óptica , Uveítis/diagnóstico , Uveítis/tratamiento farmacológico
8.
J Skin Cancer ; 2018: 9602540, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29610684

RESUMEN

Immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 antibodies) are a standard of care for advanced melanoma. Novel toxicities comprise immune-related adverse events (irAE). With increasing use, irAE require recognition, practical management strategies, and multidisciplinary care. We retrospectively evaluated the incidence, kinetics, and management of irAE in 41 patients receiving anti-PD-1 antibody therapy (pembrolizumab) for advanced melanoma. 63% received prior anti-CTLA-4 antibody therapy (ipilimumab). IrAE occurred in 54%, most commonly dermatological (24%), rheumatological (22%), and thyroid dysfunction (12%). Thyroiditis was characterised by a brief asymptomatic hyperthyroid phase followed by a symptomatic hypothyroid phase requiring thyroxine replacement. Transplant rejection doses of methylprednisolone were necessary to manage refractory hepatotoxicity. A bullous pemphigoid-like skin reaction with refractory pruritus responded to corticosteroids and neuropathic analgesia. Disabling grade 3-4 oligoarthritis required sulfasalazine therapy in combination with steroids. The median interval between the last dose of anti-CTLA-4 antibody and the first dose of anti-PD-1 therapy was 2.0 months (range: 0.4 to 22.4). Toxicities may occur late; this requires vigilance and multidisciplinary management which may allow effective anticancer therapy to continue. Management algorithms for thyroiditis, hypophysitis, arthralgia/arthritis, colitis, steroid-refractory hepatitis, and skin toxicity are discussed.

9.
Emerg Med Australas ; 29(2): 245-251, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28093870

RESUMEN

When a patient receiving anti-cancer treatment presents acutely unwell, an understanding of associated side effects of their therapy is critical. This review will discuss the approach to patients receiving anti-cancer treatment with immunotherapy presenting with autoimmune toxicities in the emergency setting. These toxicities are commonly referred to as immune-related adverse events (irAE). IrAE might consist of, but are not limited to, dermatologic, gastrointestinal (diarrhoea, colitis), hepatic, endocrine (thyroid dysfunction, hypophysitis, adrenal crisis), renal, ocular and pulmonary toxicity. General principles of managing these irAE in the acute setting will be outlined. Steroid therapy is a critical component of the treatment algorithm, being administered at high doses and for prolonged periods to switch off immune over-activation. Prompt intervention might prevent multi-organ failure and fatality, and allow patients to remain on effective anti-cancer therapy.


Asunto(s)
Autoinmunidad/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/terapia , Medicina de Emergencia/métodos , Inmunoterapia/efectos adversos , Neoplasias/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Colitis/etiología , Diarrea/etiología , Humanos , Inmunoterapia/métodos , Ipilimumab , Neoplasias/inmunología , Nivolumab , Prurito/etiología
10.
Clin J Oncol Nurs ; 21(4): E93-E98, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28738040

RESUMEN

BACKGROUND: Targeted therapy and immunotherapy agents for advanced melanoma are associated with novel toxicities. Melanoma clinical nurse consultants (CNCs) provide multifaceted clinical care.
. OBJECTIVES: The objective was to evaluate the type of support, excluding clinic and inpatient care, provided by CNCs for patients not enrolled in a clinical trial.
. METHODS: A prospective review of CNC support provided during a 12-week period was conducted.
. FINDINGS: From May to August 2015, 105 patients attended clinic, and 72 received CNC support. Initial patient encounters with CNCs were documented (n = 150), as well as additional interactions (n = 291). The most common problem identified per initial encounter was symptom/drug toxicity. The most common therapy-related concern was related to anti-programmed cell death protein 1 immunotherapy and BRAF plus MEK inhibition. CNC interventions commonly involved clinical advice and counseling and care coordination.


Asunto(s)
Consultores , Inmunoterapia , Melanoma/terapia , Enfermeras Clínicas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
11.
Int J Rheum Dis ; 20(9): 1277-1285, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28480561

RESUMEN

AIM: Sarcoidosis is a multisystem granulomatous disease. This condition has a documented association with the diagnosis of melanoma and can be induced in melanoma patients receiving anti-neoplastic therapy. We evaluated a case series of melanoma patients who developed immunotherapy-induced sarcoidosis. METHODS: Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated with anti-programmed cell death (PD)-1 antibody therapy at two institutions developed biopsy-proven sarcoidosis. We used mass cytometry to determine expression of the relevant chemokine receptors (CR) by peripheral blood mononuclear cells for two of the three patients who developed sarcoidosis and 13 melanoma patients who did not. Blood samples were collected before receiving PD-1 checkpoint inhibitor therapy. RESULTS: Immunophenotypic analysis demonstrated abnormally high numbers of circulating Th17.1 (CCR6+ CCR4- CXCR3+ CCR10- ) cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15 melanoma patients, including both the patients who developed sarcoidosis during the course of therapy. CONCLUSION: Our findings support prior literature implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we demonstrate these findings in patients with melanoma prior to administration of checkpoint therapy and before the onset of clinically symptomatic sarcoidosis. The identification of elevated Th17.1 cells in melanoma patients who have not developed sarcoidosis may reflect the established association between melanoma and sarcoidosis. With some patients receiving these agents over a prolonged period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Inmunofenotipificación , Inmunoterapia/efectos adversos , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Sarcoidosis Pulmonar/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Células Th17/efectos de los fármacos , Corticoesteroides/uso terapéutico , Adulto , Anciano , Biomarcadores/sangre , Biopsia , Femenino , Humanos , Masculino , Melanoma/sangre , Melanoma/inmunología , Melanoma/secundario , Persona de Mediana Edad , Estadificación de Neoplasias , Fenotipo , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Receptor de Muerte Celular Programada 1/inmunología , Sarcoidosis Pulmonar/sangre , Sarcoidosis Pulmonar/diagnóstico , Sarcoidosis Pulmonar/tratamiento farmacológico , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Células Th17/inmunología , Células Th17/metabolismo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
12.
Target Oncol ; 8(2): 153-5, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23430346

RESUMEN

Spinal metastases from glioblastoma are extremely rare and may be misdiagnosed leading to a delay in investigation and treatment. Patient outcomes are poor with a high morbidity and mortality. Metastases are seen in the context of increasing survival due to improvements in glioblastoma therapies. We report a case of a patient developing a thoracic spinal cord metastasis while receiving anti-angiogenesis therapy with bevacizumab.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Glioblastoma/secundario , Neoplasias de la Médula Espinal/tratamiento farmacológico , Neoplasias de la Médula Espinal/secundario , Adulto , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Bevacizumab , Neoplasias Encefálicas/patología , Glioblastoma/patología , Humanos , Masculino , Neoplasias de la Médula Espinal/patología
13.
J Bone Oncol ; 2(4): 145-53, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26909285

RESUMEN

UNLABELLED: Postmenopausal women on aromatase inhibitors (AI) are at risk of aromatase inhibitor-associated bone loss (AIBL) and fractures. In 2005 Osteoporosis Australia proposed an algorithm for bisphosphonate intervention. Three hundred and three postmenopausal women with early breast cancer (EBC) were enrolled (osteoporotic, n=25; osteopaenic, n=146; normal bone mineral density (BMD), n=126). Weekly alendronate (70 mg) treatment efficacy as triggered by the algorithm in preventing bone loss was evaluated. All patients received anastrozole (1 mg daily), calcium and vitamin D. RESULTS: All osteoporotic patients received alendronate at baseline. Eleven out of the 146 (7.5%) osteopaenic patients commenced alendronate within 18 months of participation and eleven commenced after. One hundred and twenty four out of the 146 (84.9%) osteopaenic patients and all 126 with normal baseline BMD did not trigger the algorithm. At three years, lumbar spine mean BMD increased (15.6%, p<0.01) in the osteoporotic group. BMD in the osteopaenic group with early intervention significantly increased at three years (6.3%, p=0.02). No significant change was seen in the late intervention group. No change was observed in those with osteopaenia without alendronate. There was a significant drop in lumbar spine (-5.4%) and hip (-4.5%) mean BMD, in the normal BMD group, none of whom received alendronate. Fracture data will be presented. CONCLUSION: In postmenopausal women with endocrine-responsive EBC, BMD improved over time when a bisphosphonate is administered with anastrozole in osteoporotic patients using an osteoporosis schedule. Subjects with normal baseline BMD experienced the greatest BMD loss, although none became osteoporotic.

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