RESUMO
LESSONS LEARNED: Palbociclib monotherapy demonstrated minimal clinical activity in patients with previously treated gastroesophageal cancers. Further clinical evaluation of palbociclib monotherapy is not warranted in gastroesophageal cancers, but improved understanding of resistance mechanisms may permit rational combination approaches. BACKGROUND: Dysregulation of the cell cycle is a hallmark of cancer. Progression through the G1/S transition requires phosphorylation of retinoblastoma (RB) by cyclin-dependent kinases (CDKs) 4 and 6, which are regulated by cyclins D and E. Amplifications of cyclin D loci and activating mutations in CDKs are frequent molecular aberrations in gastroesophageal malignancies. We conducted a phase II trial of the CDK4/6 inhibitor palbociclib as an initial test of efficacy. METHODS: Patients with previously treated metastatic gastroesophageal cancers with intact RB nuclear expression by immunohistochemistry were treated with 125 mg daily of palbociclib for days 1-21 of 28-day cycles. The primary endpoint was overall response rate. RESULTS: We screened 29 patients and enrolled 21 patients: 5 with gastric adenocarcinoma, 3 with gastroesophageal junction adenocarcinoma, 8 with esophageal adenocarcinoma, and 5 with esophageal squamous cell carcinoma. All 29 tumors screened had intact nuclear RB expression, and four treated patients tested positive for CCND1 overexpression. No objective responses were seen. Median progression-free survival was 1.8 months, and median overall survival was 3.0 months. All recurrent grade 3 or 4 toxicities were hematologic, with neutropenia in eight patients (38%), anemia in four patients (19%), and thrombocytopenia in two patients (10%). CONCLUSION: Palbociclib has limited single-agent activity in gastroesophageal tumors.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Piperazinas/efeitos adversos , Piridinas , Neoplasias Gástricas/tratamento farmacológicoRESUMO
BACKGROUND: Alterations in the retinoblastoma pathway in germ cell tumors (GCTs) have been described. In the phase 1 trials of the selective cyclin-dependent kinase 4/6 inhibitor palbociclib, 3 patients with unresectable, growing, mature teratoma syndrome achieved prolonged disease stabilization. The authors conducted an open-label, phase 2 study to determine the efficacy and safety of palbociclib in patients with incurable, refractory, retinoblastoma protein (pRB)-expressing GCTs. METHODS: Patients who had incurable, refractory GCTs that demonstrated pRB expression by immunohistochemistry received oral palbociclib 125 mg daily for 21 days followed by a 7-day break. The primary endpoint was the 24-week progression-free survival (PFS) rate. A 24-week PFS rate ≥15% was considered promising, and a PFS rate ≤5% was not considered promising. RESULTS: Thirty patients received treatment, and 29 were evaluable for the primary endpoint. The estimated 24-week PFS rate was 28% (90% exact confidence interval, 15%-44%). Patients who had teratoma and teratoma with malignant transformation had significantly better PFS than patients who had nonteratomatous GCTs. Toxicity was manageable and was principally hematologic. CONCLUSIONS: Treatment with palbociclib was associated with a favorable 24-week PFS rate in patients with refractory, pRB-expressing GCTs. Benefit was mainly observed in patients who had unresectable teratomas and teratomas with malignant transformation.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Proteína do Retinoblastoma/metabolismo , Teratoma/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Adulto , Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Piperazinas/farmacologia , Piridinas/farmacologia , Teratoma/metabolismo , Teratoma/mortalidade , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/mortalidade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Vascular endothelial growth factor and platelet-derived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis. PATIENTS AND METHODS: We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks. RESULTS: A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks could be safely combined with imatinib 800 mg daily. Common toxicities included fatigue, nausea, vomiting, edema, proteinuria, and anemia, but were not commonly severe. A total of 23 patients with metastatic melanoma (48% with American Joint Commission on Cancer stage M1c; median age, 63 years) were enrolled in the first stage of phase II. The 16-week progression-free survival rate was 35%, leading to termination of phase II after the first stage. In the small subset of patients who remained on study with lesions evaluable by DCE-MRI, significant decreases in tumor vascular permeability were noted, despite early disease progression using the Response Evaluation Criteria In Solid Tumors. CONCLUSION: Bevacizumab and imatinib can be safely combined at the maximum doses used for each agent. We did not observe significant clinical activity with this regimen in melanoma patients.
Assuntos
Antineoplásicos/uso terapêutico , Bevacizumab/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Bevacizumab/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein-expressing, advanced breast cancer. PATIENTS AND METHODS: This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28-day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase II dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose. RESULTS: Twenty-seven patients enrolled. Although there was only 1 DLT (grade 3 alanine aminotransferase/aspartate aminotransferase at 125 mg), neutropenia (NTP) requiring dose modification in cycle 1 (C1) resulted in an RP2D of 75 mg palbociclib/80 mg/m2 paclitaxel. During C1, the most common adverse event was NTP, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy were also observed in 8 patients each (29.6%). The clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes. CONCLUSIONS: Alternating sequential palbociclib/paclitaxel in patients with Rb+ advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb+ breast cancer regardless of subtype; efficacy trials are warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etiologia , Neoplasias da Mama/terapia , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Retratamento , Resultado do TratamentoAssuntos
Antineoplásicos/uso terapêutico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Segunda Neoplasia Primária/tratamento farmacológico , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Teratoma/tratamento farmacológico , Adulto , Progressão da Doença , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/patologia , Segunda Neoplasia Primária/metabolismo , Proteína do Retinoblastoma/metabolismo , Teratoma/metabolismo , Adulto JovemRESUMO
PURPOSE: Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin. EXPERIMENTAL DESIGN: Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.v. infusion and CA4P was given 60 minutes later as a 10-minute infusion. RESULTS: Sixteen patients with solid tumors received 40 cycles of therapy at CA4P doses of 27 and 36 mg/m(2) together with carboplatin at area under the concentration-time curve (AUC) values of 4 and 5 mg min/mL. The dose-limiting toxicity of thrombocytopenia halted the dose escalation phase of the study. Four patients were treated at an amended dose level of CA4P of 36 mg/m(2) and carboplatin AUC of 4 mg min/mL although grade 3 neutropenia and thrombocytopenia were still observed. Three lines of evidence are adduced to suggest that a pharmacokinetic interaction between the drugs results in greater thrombocytopenia than anticipated: the carboplatin exposure (as AUC) was greater than predicted; the platelet nadirs were lower than predicted; and the deviation of the carboplatin exposure from predicted was proportional to the AUC of CA4, the active metabolite of CA4P. Patient benefit included six patients with stable disease lasting at least four cycles. CONCLUSION: This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia. Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/metabolismo , Neutropenia/induzido quimicamente , Estilbenos/administração & dosagem , Estilbenos/efeitos adversos , Estilbenos/farmacocinética , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
BACKGROUND: Unresectable mature teratoma is an incurable disease associated with significant morbidity. Given the rarity of the disease, long-term outcomes for patients receiving systemic therapy have not been well described. PATIENTS AND METHODS: The present study was a retrospective analysis with long-term follow-up data of the patient cohort with unresectable mature teratoma treated in the nonrandomized phase II study of palbociclib for the treatment of metastatic, retinoblastoma protein-expressing refractory germ cell tumors. Patient clinical data were obtained from the medical records and by communication with the enrolled patients and referring medical providers. Major medical events for the treatment of germ cell tumor, including before, during, and after study treatment, were recorded. The major clinical events of interest included the initiation of systemic therapy, radiation therapy, surgical debulking, or other invasive procedures. The study endpoints included the prestudy period and study period clinical event rates, event-free survival, and radiographic progression-free survival. RESULTS: Long-term follow-up data were obtained for 12 patients with unresectable mature teratoma. The median prestudy period follow-up period was 19.7 months, and the median study follow-up period was 38.0 months. The median number of palbociclib treatment cycles was 11. The prestudy major clinical event rate was 2.27 events annually (95% confidence interval [CI], 1.66-3.13 events), and the study period event rate was 0.62 events annually (95% CI, 0.36-1.09 events). The median progression-free survival was 5.3 months (95% CI, 1.8-22.6 months), and the median event-free survival duration was 16.2 months (95% CI, 3.0-24.3 months). CONCLUSION: Unresectable mature teratoma is associated with significant long-term cumulative morbidity. The initiation of palbociclib might result in a clinically meaningful delay in disease-related major clinical events. These findings lend further support to the therapeutic activity of cyclin-dependent kinase 4/6 inhibition in this incurable patient population.
Assuntos
Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Teratoma/tratamento farmacológico , Adolescente , Adulto , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Metástase Neoplásica , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Teratoma/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
IMPORTANCE: Palbociclib (PD0332991) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive, ERBB2-negative (formerly HER2 or HER2/neu) breast cancer in the first-line metastatic setting. OBJECTIVE: Herein we describe the preclinical and translational data and early- and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types. We discuss the pharmacodynamics, pharmacokinetics, toxic effects, and clinical response rates. EVIDENCE REVIEW: On March 1, 2015, we conducted a review of the literature describing the development of palbociclib. We used the PubMed search terms "PD0332991," "palbociclib," and "CDK4/6 inhibitor" to find all published articles of interest, without limitation as to publication date. FINDINGS: Palbociclib is a potent and specific oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein-expressing tumors. Phase 1 trials have demonstrated safety, and phase 2 trials have shown single-agent activity in mantle-cell lymphoma, breast cancer, liposarcoma, and teratoma with reversible neutropenia as the main toxic effect. Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy-naïve and endocrine therapy-resistant metastatic settings. CONCLUSIONS AND RELEVANCE: Palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Humanos , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
PURPOSE: Combretastatin A4 (CA4) phosphate (CA4P) inhibits microtubule polymerization and is toxic to proliferating endothelial cells in vitro. It causes reversible vascular shutdown in established tumors in vivo, consistent with an antivascular mechanism of action. The present study investigated escalating doses of CA4P administered intravenously to patients with advanced cancer. PATIENTS AND METHODS: Patients with solid malignancies and good performance status received CA4P as a 10-minute infusion daily for 5 days repeated every 3 weeks. Pharmacokinetic sampling was performed during cycle 1. Patients receiving >/= 52 mg/m2/d had serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies to measure changes in tumor perfusion with CA4P treatment. RESULTS: Thirty-seven patients received 133 treatment cycles. CA4P dose levels ranged from 6 mg/m2 to 75 mg/m2 daily. Severe pain at sites of known tumor was dose limiting at 75 mg/m2. Dose-limiting cardiopulmonary toxicity (syncope and dyspnea or hypoxia) was noted as well in two patients treated at 75 mg/m2. Other toxicities included hypotension, ataxia, dyspnea, nausea or vomiting, headache, and transient sensory neuropathy. Plasma CA4P and CA4 area under the concentration-time curve and maximal concentration values increased linearly with dose. Tumor perfusion, as measured by the first-order rate constant of gadolinium plasma to tissue transfer during DCE-MRI studies, was found to decrease in eight of 10 patients. Relationships were also demonstrated between perfusion changes and pharmacokinetic indices. A partial response was observed in a patient with metastatic soft tissue sarcoma, and 14 patients exhibited disease stability for a minimum of two cycles. CONCLUSION: Doses of CA4P on a daily times five schedule of 52 to 65 mg/m2 were reasonably well-tolerated. The 52 mg/m2 dose is recommended for further study based on cumulative phase I experience with CA4P. Antitumor efficacy was observed, and the use of DCE-MRI provided a valuable noninvasive measure of the vascular effects of CA4P treatment.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Estilbenos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/farmacocinética , Área Sob a Curva , Meios de Contraste , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Neovascularização Patológica/patologia , Estilbenos/farmacocinética , Tomografia Computadorizada de Emissão , Resultado do TratamentoRESUMO
BMS-184476 is a 7-methylthiomethyl ether derivative of paclitaxel that displays potency superior to paclitaxel against tumor cells in culture and human tumor xenografts. It also inhibits the growth of paclitaxel-resistant human tumor cell lines with multidrug resistance mediated by either P-glycoprotein or mutated tubulin. Given the known synergy between taxanes and cisplatin in vitro and their clinical activity in combination, we performed a Phase I trial of BMS-184476 as a 1-h i.v. infusion followed by cisplatin every 21 days. Twenty-seven patients with a variety of solid tumors and good performance status received 116 cycles of therapy at BMS-184476 doses of 40-60 mg/m(2) together with cisplatin at 75 mg/m(2). The early observation of hypersensitivity reactions required prophylactic premedication in all patients. At the planned highest dose of BMS-184476 (60 mg/m(2)) and cisplatin (75 mg/m(2)), we observed dose-limiting toxicity in the form of neutropenia and diarrhea. Also at this level, five patients experienced grade 3 or worse nausea and vomiting. Aggressive prophylactic treatment eliminated the gastrointestinal toxicity. Mild to moderate peripheral neuropathy was infrequent, as was alopecia. Patient benefits included three partial responses in patients with mesothelioma, esophageal cancer, and head and neck cancer, and two additional minor responses. Plasma pharmacokinetic data are available for 23 patients treated at 40-60 mg/m(2). The mean maximum plasma concentrations and areas under the curves increased in a dose-related manner. The pharmacokinetics of BMS-184476 appeared independent of dose. The mean (+/- SE) values for clearance, volume of distribution at steady state, and the apparent terminal half-lives of the three dose groups during cycle 1 were 243 +/- 5 ml/min/m(2), 423 +/- 58 l/m(2), and 32.2 +/- 4.5 h, respectively. BMS-184476 60 at mg/m(2) with cisplatin at 75 mg/m(2) with appropriate supportive therapy is the dose recommended for further evaluation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Terapia de Salvação , Taxoides/administração & dosagemRESUMO
The cryptophycin analogue LY355703 is a potent inhibitor of microtubule polymerization that displays in vitro and in vivo activity in cell lines and tumor xenografts displaying the multidrug-resistant phenotype. In a Phase I trial, 25 patients received LY355703 as a 2-h i.v. infusion on day 1 and day 8 repeated every 3 weeks. Doses were escalated from 0.1 to 2.22 mg/m2 using a modified continual reassessment method. Neurological toxicity was found to be dose-limiting at 1.84 and 2.22 mg/m2. Among four patients treated at these doses, two had grade 4 constipation/ileus, one with severe myalgias, and one had grade 3 motor neuropathy. These findings were reversible. The 1.5 mg/m2 dose level was well tolerated. An amended twice-weekly schedule was pursued in 11 patients in an attempt to improve dose intensity and avoid dose-limiting neurotoxicity. Doses of >0.75 mg/m2 on a day 1, 4, 8, and 11 schedule every 21 days were not tolerated as a result of nausea/constipation, suggesting that LY335703 toxicity is not schedule dependent and is related to cumulative dose. LY355703 plasma concentrations measured by liquid chromatography with tandem mass spectrometry were evaluated using a population pharmacokinetic model. LY355703 was eliminated rapidly with a short terminal half-life that ranged from 0.8 to 3.9 h. Interpatient variability with respect to plasma clearance and volume of distribution, including covariates, was moderate at 32% and 39%, respectively. Maximum plasma concentration and area under the plasma concentration-time curve were linear over the dose range studied. A patient with non-small cell lung cancer previously treated with taxanes experienced a partial response lasting 4 months, and five patients had stable disease lasting > or =3 months. LY355703 at a dose of 1.5 mg/m2 is recommended for Phase II evaluation on a days 1 and 8 schedule. Twice-weekly dosing did not allow improvement in dose intensity or tolerability.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Depsipeptídeos , Lactamas/farmacocinética , Lactamas/uso terapêutico , Lactonas/farmacocinética , Lactonas/uso terapêutico , Neoplasias/tratamento farmacológico , Peptídeos Cíclicos/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Lactamas/administração & dosagem , Lactonas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Modelos Químicos , Modelos Teóricos , Transplante de Neoplasias , Fenótipo , Fatores de TempoRESUMO
PURPOSE: The G1-S checkpoint of the cell cycle is frequently dysregulated in breast cancer. Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a phase II, single-arm trial of palbociclib in advanced breast cancer. EXPERIMENTAL DESIGN: Eligible patients had histologically confirmed, metastatic breast cancer positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1 to 21 of a 28-day cycle. Primary objectives were tumor response and tolerability. Secondary objectives included progression-free survival (PFS) and assessment of Rb expression/localization, KI-67, p16 loss, and CCND1 amplification. RESULTS: Thirty-seven patients were enrolled; 84% hormone-receptor (HR)(+)/Her2(-), 5% HR(+)/Her2(+), and 11% HR(-)/Her2(-), with a median of 2 prior cytotoxic regimens. Two patients had partial response (PR) and 5 had stable disease ≥ 6 months for a clinical benefit rate (CBR = PR + 6moSD) of 19% overall, 21% in HR(+), and 29% in HR(+)/Her2(-) who had progressed through ≥2 prior lines of hormonal therapy. Median PFS overall was 3.7 months [95% confidence interval (CI), 1.9-5.1], but significantly longer for those with HR(+) versus HR(-) disease (P = 0.03) and those who had previously progressed through endocrine therapy for advanced disease (P = 0.02). Grade 3/4 toxicities included neutropenia (51%), anemia (5%), and thrombocytopenia (22%). Twenty-four percent had treatment interruption and 51% had dose reduction, all for cytopenias. No biomarker identified a sensitive tumor population. CONCLUSIONS: Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant, HR(+), Rb-positive breast cancer. Cytopenias were uncomplicated and easily managed with dose reduction.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Proteína do Retinoblastoma/metabolismo , Retratamento , Resultado do TratamentoRESUMO
From the results of recent studies, it is likely that multimodality therapy with chemotherapy and radiation treatment may improve the overall outcome of locally advanced upper gastrointestinal (GI) malignancies, including esophageal, gastric, pancreatic, and biliary tract carcinomas. However, more effective, more optimal, and less toxic chemotherapy regimen(s) with concomitant radiotherapy are needed beyond the concurrent continuous-infusion fluorouracil (5-FU) with radiation that is commonly applied in general practice. Epirubicin (Ellence), cisplatin, and irinotecan (Camptosar) are all active cytotoxic chemotherapy agents in upper GI cancers. Two phase I studies were designed to test the tolerability of the combination of radiotherapy with infusional 5-FU, epirubicin, and cisplatin (ECF) or 5-FU, irinotecan, and epirubicin (EIF) in the treatment of locally advanced upper GI malignancies.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Relação Dose-Resposta a Droga , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante , Resultado do Tratamento , Trato Gastrointestinal Superior/fisiopatologiaRESUMO
Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dacarbazina/análogos & derivados , Hidroxicloroquina/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autofagia/efeitos dos fármacos , Dacarbazina/efeitos adversos , Dacarbazina/farmacocinética , Dacarbazina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/farmacocinética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Temozolomida , Resultado do TratamentoRESUMO
PURPOSE: Multimodality therapy with chemotherapy and radiation treatment may improve disease control and overall outcome of locally advanced upper gastrointestinal (UGI) malignancies including esophageal, gastric, pancreatic, and biliary tract carcinomas. However, more effective and less toxic chemotherapy regimens with concomitant radiotherapy are needed beyond concurrent continuous-infusion fluorouracil (CIFU) with radiation that is commonly applied in general practice. Epirubicin, cisplatin, and irinotecan are active cytotoxic chemotherapy agents in UGI cancers. METHODS: Two parallel phase I studies were designed to test the tolerability (dose-limited toxicity [DLT] and maximum tolerable dose [MTD]) of the combination of radiotherapy concurrently with CIFU, epirubicin, and cisplatin (ECF/radiation) or CIFU, epirubicin, and irinotecan (EIF/radiation) in the treatment of locally advanced upper GI malignancies. CIFU was administered through a portable infusion pump for 5 1/2 weeks during radiation treatment (50.4 Gy-a dose of 45 Gy in 25 fractions of 1.8 Gy, with additional comedown of 5.4 Gy). Epirubicin, cisplatin, or irinotecan were administered intravenously each week for 5 weeks (days 1, 8, 15, 22, and 29). RESULTS: The MTDs recommended for further studies are: 5-fluorouracil 200 mg/m²/day CI, weekly cisplatin 20 mg/m² and epirubicin 10 mg/m² for ECF/radiation combination; 5-fluorouracil 200 mg/m²/day CI, weekly irinotecan 30 mg/m² and epirubicin 10 mg/m² for EIF/radiation regimen. The DLTs are neutropenia, diarrhea/dehydration, and mucositis as expected. CONCLUSIONS: Both regimens are safe with expected toxicities, and the efficacy of both regimens was encouraging. Further larger scale studies should be considered.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cisplatino/administração & dosagem , Terapia Combinada , Relação Dose-Resposta a Droga , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/radioterapia , Humanos , Infusões Intravenosas , Irinotecano , Masculino , Dose Máxima Tolerável , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The investigation of angiogenesis inhibitors is of particular interest in renal cell carcinoma (RCC), in which dysregulated blood vessel formation has been correlated with shortened survival. Sorafenib is a novel RAF and VEGF receptor tyrosine kinase inhibitor. We conducted this study to (a) determine if sorafenib is anti-angiogenic, and (b) to relate anti-angiogenic effect to outcome. RESULTS: Four patients achieved partial response by WHO criteria (ORR 24%). Median time to progression (TTP) was 12.9 months. K(trans) decreased significantly during treatment with sorafenib (60.3% decline, 95% CI 46.1-74.6%). The percent decline in K(trans) and change in tumor size by CT scan were significantly associated with progression-free survival (p = 0.01 and 0.05, respectively). In addition, K(trans) at baseline was also significantly associated with progress-free survival (p = 0.02). PATIENTS AND METHODS: Seventeen patients with metastatic RCC underwent dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI was used to calculate the gadolinium exchange constant between blood and tumor interstitial tissue, K(trans). CONCLUSIONS: In patients with RCC, inhibition of tumor vascular permeability by sorafenib was associated with improved outcome. Moreover, baseline tumor vascular permeability, expected to be a poor prognosis factor, was a predictive marker of favorable response to therapy.
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Inibidores da Angiogênese/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Neovascularização Patológica/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Idoso , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Projetos Piloto , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sorafenibe , Análise de SobrevidaRESUMO
PURPOSE: The cell-surface molecule CD40 activates antigen-presenting cells and enhances immune responses. CD40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective CD40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study. PATIENTS AND METHODS: Patients with advanced solid tumors received single doses of CP-870,893 intravenously. The primary objective was to determine safety and the maximum-tolerated dose (MTD). Secondary objectives included assessment of immune modulation and tumor response. RESULTS: Twenty-nine patients received CP-870,893 in doses from 0.01 to 0.3 mg/kg. Dose-limiting toxicity was observed in two of seven patients at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). MTD was estimated as 0.2 mg/kg. The most common adverse event was cytokine release syndrome (grade 1 to 2) which included chills, rigors, and fever. Transient laboratory abnormalities affecting lymphocytes, monocytes, platelets, D-dimer and liver function tests were observed 24 to 48 hours after infusion. Four patients with melanoma (14% of all patients and 27% of melanoma patients) had objective partial responses at restaging (day 43). CP-870,893 infusion resulted in transient depletion of CD19+ B cells in blood (93% depletion at the MTD for < 1 week). Among B cells remaining in blood, we found a dose-related upregulation of costimulatory molecules after treatment. CONCLUSION: The CD40 agonist mAb CP-870,893 was well tolerated and biologically active, and was associated with antitumor activity. Further studies of repeated doses of CP-870,893 alone and in combination with other antineoplastic agents are warranted.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígenos CD40/agonistas , Neoplasias/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Fígado/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/imunologiaRESUMO
PURPOSE: BAY 43-9006 (sorafenib) is an inhibitor of Raf kinase, the vascular endothelial growth factor (VEGF) receptor-2, and angiogenesis in tumor xenografts. The current study investigated the incidence, severity, and mechanism of blood pressure (BP) elevation in patients treated with BAY 43-9006. PATIENTS AND METHODS: Twenty patients received BAY 43-9006 400 mg orally twice daily. BP and heart rate were measured at baseline and then every 3 weeks for 18 weeks. VEGF, catecholamines, endothelin I, urotensin II, renin, and aldosterone were measured at baseline and after 3 weeks of therapy. We assessed vascular stiffness at baseline, after 3 to 6 weeks of therapy, and again after 9 to 10 months of therapy. RESULTS: Fifteen (75%) of 20 patients experienced an increase of > or = 10 mmHg in systolic BP (SBP), and 12 (60%) of 20 patients experienced an increase of > or = 20 mmHg in SBP compared with their baseline value, with a mean change of 20.6 mmHg (P < .0001) after 3 weeks of therapy. There were no statistically significant changes in humoral factors, although there was a statistically significant inverse relationship between decreases in catecholamines and increases in SBP, suggesting a secondary response to BP elevation. Measures of vascular stiffness increased significantly during the period of observation. CONCLUSION: Treatment with BAY 43-9006 is associated with a significant and sustained increase in BP. The lack of significant change in circulating factors suggests that these humoral factors had little role in the increase in BP.
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Benzenossulfonatos/efeitos adversos , Hipertensão/induzido quimicamente , Piridinas/efeitos adversos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/administração & dosagem , Piridinas/uso terapêutico , SorafenibeRESUMO
BACKGROUND: The authors performed a dose escalation study of cisplatin and the novel deoxycytidine analog, tezacitabine, to determine the maximum tolerated dose of the combination. METHODS: Twenty-three patients with advanced cancer and good performance status were accrued to 3 dose levels of tezacitabine (150-270 mg/m(2)) and cisplatin (50 mg/m(2)). Using a 28-day treatment cycle, both drugs were administered on Days 1 and 15. RESULTS: Hematologic toxicity was the most frequently observed side effect and was dose limiting. Grade 3 or 4 neutropenia and thrombocytopenia complicated 75% and 31% of all cycles, respectively. Nonhematologic toxicities were mild. Among 18 evaluable patients, 2 with upper gastrointestinal tract tumors achieved partial responses and 4 had stable disease. CONCLUSIONS: Based on dose-limiting neutropenia and thrombocytopenia at the highest dose level, the recommended Phase II doses are 200 mg/m(2) of tezacitabine and 50 mg/m(2) of cisplatin.