RESUMO
BACKGROUND: Tarloxotinib, a hypoxia-activated prodrug of an irreversible pan-ErbB tyrosine kinase inhibitor, represents a novel therapeutic which exploits the tumor-specific hypoxic environment as a mechanism for tumor-specific targeting. This study evaluated the safety and activity of tarloxotinib in recurrent or metastatic (R/M) cutaneous (CSCC) or head and neck squamous cell carcinoma (HNSCC). METHODS: This was a phase II two-stage multi-centre study for patients with R/M HNSCC or CSCC. All patients received tarloxotinib 150 mg/m2 on days 1,8,15 and 22 in a 28-day cycle. Stage 1 enrolled patients in three cohorts: p16-negative HNSCC, p16-positive oropharyngeal SCC, and CSCC. In order for a cohort to proceed to stage 2 a minimum response rate of 5% was required. RESULTS: 30 patients were enrolled: 23% were female with median age of 63.3 years. The median duration of follow-up was 20 weeks. The median progression-free survival was 2.0 months (95%CI 1.8-3.4) and median overall survival 5.7 months (95%CI 3.6-8.0). Treatment was well tolerated. The objective response rate was 3% with one patient with CSCC having a partial response. CONCLUSIONS: Hypoxia-activated prodrugs represent a novel approach to cancer treatment, however, no clinically meaningful benefit for tarloxotinib in R/M HNSCC or CSCC was identified in this study. TRIAL REGISTRATION NUMBER: NCT02449681 (May 20, 2015).
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Pró-Fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/patologia , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Hipóxia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Pró-Fármacos/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológicoRESUMO
Medullary thyroid cancer (MTC) accounts for ~4% of all thyroid malignancies. MTC derives from the neural crest and secretes calcitonin (CTN) and carcinoembryonic antigen (CEA). Unlike differentiated thyroid cancer, MTC does not uptake iodine and I-131 RAI (radioactive iodine) treatment is ineffective. Patients with metastatic disease are candidates for FDA-approved agents with either vandetanib or cabozantinib; however, adverse effects limit their use. There are ongoing trials exploring the role of less toxic immunotherapies in patients with MTC. We present a 61-year-old male with the diagnosis of MTC and persistent local recurrence despite multiple surgeries. He was started on sunitinib, but ultimately its use was limited by toxicity. He then presented to the National Cancer Institute (NCI) and was enrolled on a clinical trial with heat-killed yeast-CEA vaccine (NCT01856920) and his calcitonin doubling time improved in 3 months. He then came off vaccine for elective surgery. After surgery, his calcitonin was rising and he enrolled on a phase I trial of avelumab, a programmed death-ligand 1 (PD-L1) inhibitor (NCT01772004). Thereafter, his calcitonin decreased > 40% on 5 consecutive evaluations. His tumor was subsequently found to express PD-L1. CEA-specific T cells were increased following vaccination, and a number of potential immune-enhancing changes were noted in the peripheral immunome over the course of sequential immunotherapy treatment. Although calcitonin declines do not always directly correlate with clinical responses, this response is noteworthy and highlights the potential for immunotherapy or sequential immunotherapy in metastatic or unresectable MTC.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Vacinas Anticâncer/administração & dosagem , Antígeno Carcinoembrionário/administração & dosagem , Carcinoma Neuroendócrino/tratamento farmacológico , Saccharomyces cerevisiae/imunologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Vacinas de DNA/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Neuroendócrino/imunologia , Carcinoma Neuroendócrino/patologia , Quimioterapia Combinada , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
LESSONS LEARNED: Vandetanib at a dose of 300 mg orally every day plus bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 could be administered safely.Assessing outcomes in 17 patients with medullary thyroid cancer, investigators considered the combination to be more difficult to administer than single-agent vandetanib and that achieving better outcomes was unlikely. Consequently, a planned phase II study was terminated early. BACKGROUND: The proto-oncogene RET (REarranged during Transfection) has a critical role in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib (V), a multitargeted tyrosine kinase inhibitor approved for the treatment of MTC, is thought to inhibit RET in MTC. Supported by preclinical studies demonstrating that bortezomib (B) administration lowered RET mRNA and protein levels, we conducted a phase I study in advanced solid tumors of vandetanib in combination with bortezomib. The goal was to establish an RP2D (recommended phase II dose) for the combination of vandetanib plus bortezomib, a regimen envisioned as a dual strategy for targeting RET in MTC. METHODS: Patients with advanced solid tumors were treated with escalating doses of bortezomib or vandetanib to assess the safety and tolerability of daily oral vandetanib and intravenous (IV) bortezomib administered on days 1, 4, 8, and 11 of a 28-day cycle. Intrapatient dose escalation was allowed. RESULTS: Twenty-two patients were enrolled and received escalating mg/m2 bortezomib and mg vandetanib (number of patients) at initial doses of 1 and 100 (3), 1.3 and 100 (6), 1.3 and 200 (6), and 1.3 and 300 (7), respectively. Patients received a median of four cycles of bortezomib/vandetanib (range: 1-10), with 13 patients escalating to 1.3/200 and 10 to 1.3/300. G3 toxicities occurring in more than one patient included hypertension (24%), fatigue (19%), thrombocytopenia (10%), diarrhea (10%), and arthralgia (10%). There were no drug-related G4/5 toxicities. There was one dose-limiting toxicity, G3 thrombocytopenia, at bortezomib/vandetanib doses of 1.3/200 in cycle 2 that resolved without intervention. Four patients with a diagnosis of MTC (27%) had a partial response (PR). CONCLUSION: The MTD of the combination was established as bortezomib, 1.3 mg/m2 IV days 1, 4, 8, and 11 with vandetanib 300 mg p.o. daily. RECIST responses were observed in patients with a diagnosis of MTC.
Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Piperidinas/uso terapêutico , Quinazolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Carcinoma Neuroendócrino/dietoterapia , Feminino , Humanos , Masculino , Piperidinas/farmacologia , Proto-Oncogene Mas , Quinazolinas/farmacologia , Neoplasias da Glândula Tireoide/dietoterapiaRESUMO
BACKGROUND: Anaplastic thyroid cancer (ATC), a rare highly vascularized tumor, has a dismal outcome. We conducted an open-label study of doublet carboplatin/paclitaxel chemotherapy with or without fosbretabulin in patients with ATC. METHODS: Patients were randomly assigned in a 2:1 ratio to 6 cycles of paclitaxel 200 mg/m(2) followed by carboplatin AUC 6 on day 1 every 3 weeks (CP), or these drugs were given on day 2 after fosbretabulin 60 mg/m(2) (CP/fosbretabulin) on days 1, 8 and 15. After 6 cycles, patients on the fosbretabulin arm without progression could continue to receive fosbretabulin on days 1 and 8 of a 3-week schedule until progression. The primary end point was overall survival (OS). RESULTS: Eighty patients were assigned (planned, 180) when enrollment was stopped due to rarity of disease and very low accrual. Median OS was 5.2 months [95% confidence interval (CI) 3.1, 9.0] for the CP/fosbretabulin arm (n=55; hazard ratio 0.73 [95% CI 0.44, 1.21]) and 4.0 months [95% CI 2.8, 6.2] for the CP arm (n=25; p=0.22 [log rank test]). One-year survival for CP/fosbretabulin versus CP was 26% versus 9%, respectively. There was no significant difference in progression-free survival between the two arms. Grade 1-2 hypertension and grade 3-4 neutropenia were more common with CP/fosbretabulin. There were no significant adverse cardiovascular side effects. CONCLUSIONS: Although the study did not meet statistical significance in improvement in OS with the addition of fosbretabulin to carboplatin/paclitaxel, it represents the largest prospective randomized trial ever conducted in ATC. The regimen is well tolerated, with AEs and deaths primarily related to ATC and disease progression.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estilbenos/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Estilbenos/efeitos adversos , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND: Anaplastic thyroid cancer (ATC) is an aggressive neoplasm for which a paucity of data exist about the relative role of operative procedures in disease management. METHODS: The FACT trial was a randomized, controlled phase 2/3 trial assessing the safety and efficacy of carboplatin/paclitaxel with CA4P (experimental arm) or without CA4P (control arm) in ATC, 2007-11. Patients were permitted to have had an operation before enrollment, which was stratified on the basis of exposure to operation. A subpopulation of patients who had a cancer-related operation (thyroidectomy) was compared with those who did not, and 1-year and median survival were estimated. RESULTS: A total of 80 patients were enrolled; 55% had undergone a cancer-related operation, of whom 70% had near-total/total thyroidectomy. Baseline characteristics for operative and nonoperative patients were not substantially different. Median survival for patients who had cancer-related operation was 8.2 months in the CA4P arm versus 4.0 months in the control arm, resulting in a hazard ratio of 0.66 (P = .25) and a suggested associated reduction in risk of death of 35%. 1-year survival was 33.3% in the CA4P arm versus 7.7% in the control arm. CONCLUSION: In this largest prospective study ever conducted in ATC, thyroidectomy followed by CA4P combination regimen showed a nonsignificant trend toward improvement in patient survival.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Estilbenos/uso terapêutico , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia , Idoso , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide/mortalidadeAssuntos
Neoplasias Ósseas/complicações , Neoplasias Ósseas/secundário , Fraturas Ósseas/epidemiologia , Hipercalcemia/epidemiologia , Compressão da Medula Espinal/epidemiologia , Neoplasias da Glândula Tireoide/patologia , Conservadores da Densidade Óssea/uso terapêutico , Fraturas Ósseas/prevenção & controle , Humanos , Hipercalcemia/prevenção & controle , Incidência , Fatores de Risco , Compressão da Medula Espinal/prevenção & controleRESUMO
Gastrointestinal stromal tumors (GIST) are the most common type of sarcoma in the gastrointestinal tract. Surgery is the primary treatment modality, but many patients suffer disease recurrence or metastasis. Fortunately, the management of advanced GIST has been revolutionized by the use of small molecule kinase inhibitors that target the underlying pathogenetic mutant kinases found in the vast majority of cases. Approximately 85% of GISTs have oncogenic mutations in KIT, allowing for constitutive kinase activation that is responsible for cellular proliferation and survival. About 5 to 7% of GISTs have activating mutations of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase. The progression-free and overall survival of patients with advanced disease is greatly improved by treatment with the kinase inhibitors imatinib and sunitinib. However, the emergence of drug-resistant tumor clones limits the long-term benefit of these drugs in most patients. Resistance to these kinase inhibitors is associated with distinctive clinical and molecular features, with the development of secondary mutations of the oncogenic kinase being the most common mechanism. We review the molecular basis of GIST response and/or resistance to TKIs, and discuss strategies to prevent and/or overcome drug resistance. These concepts are directly relevant to the development of targeted molecular therapy for other solid tumors. (Clin Cancer Res 2009;15(24):7510-8).
RESUMO
Radioiodine (RAI) ablation following thyroidectomy is standard of care treatment for patients with intermediate or high risk differentiated thyroid cancer. Traditionally, this has been achieved by forgoing thyroid hormone replacement postoperatively, allowing endogenous thyroid stimulating hormone (TSH) levels to rise. This rise in TSH provides the stimulus for RAI uptake by the thyroid remnant, but is associated with clinical hypothyroidism and its associated morbidities. Recombinant human TSH (rhTSH, thyrotropin alfa [Thyrogen(®)], Genzyme Corporation, Cambridge, MA, USA) was developed to provide TSH stimulation without withdrawal of thyroid hormone and clinical hypothyroidism. Phase III studies reported equivalent detection of recurrent or residual disease when rhTSH was used compared with thyroid hormone withdrawal (THW). These trials led to its approval as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without RAI imaging in the surveillance of patients with differentiated thyroid cancer. Recently, rhTSH was given an indication for adjunctive preparation for thyroid remnant ablation after phase III studies demonstrated comparable outcomes for rhTSH preparation when compared with THW. Importantly, rhTSH stimulation has been found to be safe, well tolerated, and to result in improved quality of life. Here, we review the efficacy and tolerability studies leading to the approval for the use of rhTSH in well-differentiated thyroid cancer management.