RESUMO
OBJECTIVE: This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. METHODS: Patients with histologic diagnosis of endometrial cancer (1-2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2-4, 9-11, 16-18, and 23-25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1-3, 8-10, 15-17, and 22-24. RESULTS: Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58-1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43-1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. CONCLUSIONS: Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02725268.
Assuntos
Neoplasias do Endométrio , Paclitaxel , Humanos , Feminino , Paclitaxel/efeitos adversos , Resultado do Tratamento , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/etiologia , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
PURPOSE: This phase II study investigated daily or weekly sapanisertib (a selective dual inhibitor of mTOR complexes 1 and 2) in combination with fulvestrant. PATIENTS AND METHODS: Postmenopausal women with estrogen receptor-positive (ER+)/HER2-negative (HER2-) advanced or metastatic breast cancer following progression during/after aromatase inhibitor treatment were randomized to receive fulvestrant 500 mg (28-day treatment cycles), fulvestrant plus sapanisertib 4 mg daily, or fulvestrant plus sapanisertib 30 mg weekly, until progressive disease, unacceptable toxicity, consent withdrawal, or study completion. RESULTS: Among 141 enrolled patients, baseline characteristics were balanced among treatment arms, including prior cyclin-dependent kinase-4/6 (CDK4/6) inhibitor treatment in 33% to 35% of patients. Median progression-free survival (PFS; primary endpoint) was 3.5 months in the single-agent fulvestrant arm, compared with 7.2 months for fulvestrant plus sapanisertib daily [HR, 0.77; 95% confidence interval (CI), 0.47-1.26] and 5.6 months for fulvestrant plus sapanisertib weekly (HR, 0.88; 95% CI, 0.53-1.45). The greatest PFS benefits were seen in patients who had previously received CDK4/6 inhibitors. The most common adverse events were nausea, vomiting, and hyperglycemia, all occurring more frequently in the combination therapy arms. Treatment discontinuation due to adverse events occurred more frequently in the two combination therapy arms than with single-agent fulvestrant (32% and 36% vs. 4%, respectively). CONCLUSIONS: Fulvestrant plus sapanisertib daily/weekly resulted in numerically longer PFS in patients with ER+/HER2- advanced or metastatic breast cancer, compared with single-agent fulvestrant. The combination was associated with increased toxicity. Further development of sapanisertib using these dosing schedules in this setting is not supported by these data.
Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Feminino , Fulvestranto , Humanos , Pós-Menopausa , Pirazóis , Pirimidinas , Receptor ErbB-2/uso terapêutico , Receptores de EstrogênioRESUMO
PURPOSE: This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer. PATIENTS AND METHODS: Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16). RESULTS: Overall, 118 patients enrolled in phase IB (n = 24) and II (n = 94). Five patients in phase IB experienced dose-limiting toxicities, at sapanisertib doses of 5 mg every day (n = 4) and 4 mg every day (n = 1); sapanisertib 4 mg every day was the MTD in combination with exemestane or fulvestrant. In phase II, in everolimus-sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%, respectively. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between AKT1 mutation status and best treatment response (complete + partial response; P = 0.0262). CONCLUSIONS: Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausal women with pretreated everolimus-sensitive or everolimus-resistant breast cancer.
Assuntos
Neoplasias da Mama , Androstadienos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Fulvestranto , Humanos , Pirazóis , Pirimidinas , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêutico , Receptores de Estrogênio , Receptores de ProgesteronaRESUMO
BACKGROUND: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. METHODS: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). RESULTS: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. CONCLUSIONS: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01058707.
Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
PURPOSE: Recommended phase II dose (RP2D) determination for combination therapy regimens is a constrained optimization problem of maximizing antitumor activity within the constraint of clinical tolerability to provide a wide therapeutic index. A methodology for addressing this problem was developed and tested using clinical and preclinical data from combinations of the investigational drugs TAK-117, a PI3Kα inhibitor, and TAK-228, a TORC1/2 dual inhibitor. EXPERIMENTAL DESIGN: Utilizing free fraction-corrected average concentrations, [Formula: see text] and [Formula: see text], which are the primary pharmacokinetic predictors of single-agent preclinical antitumor activity, a preclinical exposure-efficacy surface was characterized, allowing for nonlinear interactions between growth rate inhibition of the agents on a MDA-MB-361 cell line xenograft model. Logistic regression was used to generate an exposure-effect surface for [Formula: see text] and [Formula: see text] versus clinical toxicity outcomes [experiencing a dose-limiting toxicity (DLT)] in single-agent and combination dose-escalation studies. A maximum tolerated exposure curve was defined at which DLT probability was 25%; predicted antitumor activity along this curve was used to determine optimal RP2D. RESULTS: The toxicity constraint curve determined from early clinical data predicted that any clinically tolerable combination was unlikely to result in greater antitumor activity than either single-agent TAK-117 or TAK-228 administered at their respective MTDs. Similar results were obtained with 10 other cell lines, with one agent or the other predicted to outperform the combination. CONCLUSIONS: This methodology represents a general, principled way of evaluating and selecting optimal RP2D combinations in oncology. The methodology will be retested upon availability of clinical data from TAK-117/TAK-228 combination phase II studies.See related commentary by Mayawala et al., p. 6564.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Modelos Teóricos , Neoplasias/tratamento farmacológico , Algoritmos , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Terapia Combinada , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Humanos , Camundongos , Neoplasias/patologia , Índice Terapêutico , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Sapanisertib (TAK-228) is an investigational, orally available, potent and highly selective mTORC1/2 inhibitor demonstrating promise in numerous malignancies. This phase I study (NCT02412722) evaluated the safety, tolerability, pharmacokinetics and antitumour activity of single-agent TAK-228 (milled capsules), administered daily (QD) or weekly (QW) and in combination with paclitaxel in patients with advanced solid tumours. Pharmacokinetic comparisons of milled versus unmilled TAK-228 and the impact of food were also investigated. METHODS: Patients were enrolled to receive: TAK-228 QD, TAK-228 3 days/week plus paclitaxel 80 mg/m2 days 1, 8, 15 (TAK-228+P) or TAK-228 QW (all 28-day cycles); starting TAK228 doses were 4, 6 and 20 mg, respectively. RESULTS: Sixty-one adults were enrolled. Maximum tolerated doses for milled TAK-228 were 3 mg (TAK-228 QD), 6 mg (TAK-228+P) and 30 mg (TAK-228 QW). Most patients reported ≥1 adverse event (AE); there were no meaningful differences in drug-related AEs across regimens or doses. Three on-study deaths occurred, all considered unrelated to study drugs. TAK-228 pharmacokinetics did not differ between unmilled/milled capsules or with/without paclitaxel. However, TAK-228 Cmax decreased by ~40% in fed versus fasted patients. Objective response rates were 12% (TAK-228 QD), 18% (TAK-228+P) and 0% (TAK-228 QW). One patient receiving TAK-228+P had a complete response; three patients receiving TAK-228+P and two patients receiving TAK-228 QD had partial responses. CONCLUSIONS: Milled TAK-228 was well tolerated with signs of antitumour activity; administration did not reduce overall exposure (area under the plasma concentration-time curve) but reduced Cmax, which is expected when dosed in the fed state. These promising findings warrant further investigation. TRIAL REGISTRATION NUMBER: NCT02412722.
RESUMO
Purpose To evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). Patients and Methods After real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index [IPI] score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m2 intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP). Results After a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP ( P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2-year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade ≥ 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%). Conclusion Outcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Rituximab , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto JovemRESUMO
Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/efeitos adversos , Bortezomib/efeitos adversos , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Anti-Inflamatórios/administração & dosagem , Dexametasona/administração & dosagem , Esquema de Medicação , Humanos , Doenças do Sistema Nervoso Periférico/prevenção & controle , Estudos RetrospectivosRESUMO
This population analysis described the pharmacokinetics of bortezomib after twice-weekly, repeat-dose, intravenous administration in pediatric patients participating in 2 clinical trials: the phase 2 AALL07P1 (NCT00873093) trial in relapsed acute lymphoblastic leukemia and the phase 3 AAML1031 (NCT01371981) trial in de novo acute myelogenous leukemia. The sources of variability in the pharmacokinetic parameters were characterized and quantified to support dosing recommendations. Patients received intravenous bortezomib 1.3 mg/m2 twice-weekly, on days 1, 4, and 8 during specific blocks or cycles of both trials and on day 11 of block 1 of study AALL07P1, in combination with multiagent chemotherapy. Blood samples were obtained and the plasma was harvested on day 8 over 0-72 hours postdose to measure bortezomib concentrations by liquid chromatography-tandem mass spectrometry. Concentration-time data were analyzed by nonlinear mixed-effects modeling. Covariates were examined using forward addition (P < .01)/backward elimination (P < .001). Data were included from 104 patients (49%/51% acute lymphoblastic leukemia/acute myelogenous leukemia; 60%/40% aged 2-11 years/12-16 years). Bortezomib pharmacokinetics were described by a 3-compartment model with linear elimination. Body surface area adequately accounted for variability in clearance (exponent 0.97), supporting body surface area-based dosing. Stratified visual predictive check simulations verified that neither age group nor patient population represented sources of meaningful pharmacokinetic heterogeneity not accounted for by the final population pharmacokinetic model. Following administration of 1.3 mg/m2 intravenous bortezomib doses, body surface area-normalized clearance in pediatric patients was similar to that observed in adult patients, thereby indicating that this dose achieves similar systemic exposures in pediatric patients.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Bortezomib/administração & dosagem , Bortezomib/farmacocinética , Leucemia Mieloide Aguda/metabolismo , Modelos Biológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Antineoplásicos/sangue , Superfície Corporal , Bortezomib/sangue , Criança , Pré-Escolar , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangueRESUMO
Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median Tmax was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2-22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46-97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned.
Assuntos
Antineoplásicos , Neoplasias do Colo/tratamento farmacológico , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases , Piridonas , Pirimidinonas , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Uveais/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias do Colo/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/sangue , Feminino , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Masculino , Dose Máxima Tolerável , Melanoma/metabolismo , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/efeitos adversos , Piridonas/farmacocinética , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/metabolismo , Resultado do Tratamento , Neoplasias Uveais/metabolismo , Adulto JovemRESUMO
PURPOSE: Since the pioneering work of Salmon and Durie, quantitative measures of tumor burden in multiple myeloma have been used to make clinical predictions and model tumor growth. However, such quantitative analyses have not yet been performed on large datasets from trials using modern chemotherapy regimens. EXPERIMENTAL DESIGN: We analyzed a large set of tumor response data from three randomized controlled trials of bortezomib-based chemotherapy regimens (total sample size n = 1,469 patients) to establish and validate a novel mathematical model of multiple myeloma cell dynamics. RESULTS: Treatment dynamics in newly diagnosed patients were most consistent with a model postulating two tumor cell subpopulations, "progenitor cells" and "differentiated cells." Differential treatment responses were observed with significant tumoricidal effects on differentiated cells and less clear effects on progenitor cells. We validated this model using a second trial of newly diagnosed patients and a third trial of refractory patients. When applying our model to data of relapsed patients, we found that a hybrid model incorporating both a differentiation hierarchy and clonal evolution best explains the response patterns. CONCLUSIONS: The clinical data, together with mathematical modeling, suggest that bortezomib-based therapy exerts a selection pressure on myeloma cells that can shape the disease phenotype, thereby generating further inter-patient variability. This model may be a useful tool for improving our understanding of disease biology and the response to chemotherapy regimens. Clin Cancer Res; 22(16); 4206-14. ©2016 AACR.
Assuntos
Diferenciação Celular , Evolução Clonal , Modelos Teóricos , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/patologia , Diferenciação Celular/genética , Ensaios Clínicos como Assunto , Evolução Clonal/genética , Humanos , Modelos Estatísticos , Mieloma Múltiplo/terapia , Reprodutibilidade dos TestesRESUMO
The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies.
Assuntos
Antineoplásicos/uso terapêutico , Benzoxazóis/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Benzoxazóis/farmacologia , Monitoramento de Medicamentos , Feminino , Humanos , Linfoma não Hodgkin/diagnóstico , Masculino , Dose Máxima Tolerável , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Complexos Multiproteicos/antagonistas & inibidores , Gradação de Tumores , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Recidiva , Retratamento , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/diagnósticoRESUMO
PURPOSE: The US community-based, phase IIIB UPFRONT trial was designed to compare three frontline bortezomib-based regimens in transplantation-ineligible patients with myeloma. PATIENTS AND METHODS: Patients (N = 502) were randomly assigned 1:1:1 to 24 weeks (eight 21-day cycles) of induction with bortezomib-dexamethasone (VD; n = 168; intravenous bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11 plus oral dexamethasone 20 mg, days 1, 2, 4, 5, 8, 9, 11, and 12 [cycles 1 to 4], or 1, 2, 4, and 5 [cycles 5 to 8]), bortezomib-thalidomide-dexamethasone (VTD; n = 167; bortezomib and dexamethasone as before plus oral thalidomide 100 mg, days 1 to 21), or bortezomib-melphalan-prednisone (VMP; n = 167; bortezomib as before plus oral melphalan 9 mg/m(2) and oral prednisone 60 mg/m(2), days 1 to 4, every other cycle), followed by 25 weeks (five 35-day cycles) of bortezomib maintenance (1.6 mg/m(2), days 1, 8, 15, and 22). The primary end point was progression-free survival. RESULTS: After 42.7 months' median follow-up, median progression-free survival with VD, VTD, and VMP was 14.7, 15.4, and 17.3 months, respectively; median overall survival was 49.8, 51.5, and 53.1 months, with no significant differences among treatments for either end point (global P = .46 and P = .79, respectively, Wald test). Overall response rates were 73% (VD), 80% (VTD), and 70% (VMP). Adverse events were more common with VTD than VD or VMP. Bortezomib maintenance was feasible without producing cumulative toxicity. CONCLUSION: Although all bortezomib-containing regimens produced good outcomes, VTD and VMP did not appear to offer an advantage over VD in transplantation-ineligible patients with myeloma treated in US community practice.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Serviços de Saúde Comunitária , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do TratamentoRESUMO
This non-comparative phase II study (ClinicalTrials.gov: NCT00715208) evaluated bortezomib in place of vincristine in established rituximab-chemotherapy regimens in relapsed/refractory follicular (FL) or marginal zone lymphoma (MZL). Patients were allocated (physician/patient preference) to receive six 21-d cycles of: bortezomib 1·6 mg/m(2) (days 1, 8), rituximab 375 mg/m(2) (day 1), cyclophosphamide 1000 mg/m(2) (day 1) and prednisone 100 mg (days 1-5; VR-CP; 47 FL, 1 MZL patients); or bortezomib, rituximab, prednisone per VR-CP, cyclophosphamide 750 mg/m(2) and doxorubicin 50 mg/m(2) (day 1; VR-CAP; 4 FL, 2 MZL, 1 chronic lymphocytic leukaemia patients). With VR-CP, the response rate was 77%, with a 27% complete response rate. After a median follow-up of 10·9 months, 40% of patients had relapsed/progressed or died. Median duration of response and progression-free survival was 21·9 and 14·9 months, respectively. Common drug-related grade ≥3 adverse events were neutropenia (25%), thrombocytopenia (6%) and lymphopenia (6%). Thirteen (27%) patients reported peripheral neuropathy (one grade 3). With VR-CAP, one FL patient achieved complete response and three FL and two MZL patients achieved partial responses. Three patients reported drug-related grade 1/2 peripheral neuropathy. Weekly bortezomib and rituximab represents an active, feasible treatment platform in FL. VR-CP was active and well tolerated in patients with relapsed/refractory FL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Bortezomib , Ciclofosfamida/administração & dosagem , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Quimioterapia de Manutenção/métodos , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Pirazinas/administração & dosagem , Recidiva , Rituximab , Resultado do TratamentoRESUMO
BACKGROUND/OBJECTIVE: Kisspeptin-54, an endogenous naturally occurring ligand of the G protein-coupled receptor-54, stimulates GnRH-gonadotropin secretion and suppresses metastases in animal models of cancer but is subject to rapid degradation and inactivation. TAK-448 is an investigational oligopeptide analog of the fully active 10-amino acid C terminus of kisspeptin-54. This phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of TAK-448 in healthy subjects and patients with prostate cancer (PC). DESIGN: Healthy subjects aged 50 years or older received TAK-448 sc as a single-bolus or 2-hour infusion (0.01-6 mg/d; part A) and as a 14-day sc administration (0.01-1 mg/d; part B). In a subsequent, open-label, phase 1 study in PC patients aged 40-78 years, TAK-448 was given as a 1-month depot formulation. RESULTS: Eighty-two healthy subjects received TAK-448; 30 received placebo. Grades 1-2 adverse events were reported in 26% of subjects during TAK-448 treatment. All dosing regimens resulted in dose-proportional exposures. The maximum observed plasma concentration occurred after 0.25-0.5 hours, and median terminal elimination half-life was 1.4-5.3 hours. T increased approximately 1.3- to 2-fold by 48 hours after a single bolus or 2 hour injections, whereas during the 14-day infusion, at doses above 0.1 mg/d, T dropped to below-baseline values by 60 hours and reached a subsequently sustained below-castration level by day 8. In PC patients, T decreased to less than 20 ng/dL in four of five patients dosed with 12 or 24 mg TAK-448 sc-depot injections. The prostate-specific antigen decreased greater than 50% in all patients dosed with 24 mg. CONCLUSIONS: Continuous TAK-448 infusion was well tolerated by healthy males and resulted in sustained T suppression. Depot injection in patients with PC similarly reduced T and resulted in prostate-specific antigen responses.
Assuntos
Drogas em Investigação/administração & dosagem , Kisspeptinas/administração & dosagem , Orquiectomia , Neoplasias da Próstata/sangue , Testosterona/sangue , Adulto , Idoso , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Esquema de Medicação , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Saúde , Humanos , Kisspeptinas/efeitos adversos , Kisspeptinas/farmacocinética , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Placebos , Neoplasias da Próstata/metabolismoRESUMO
Various translocations and mutations have been identified in myeloma, and certain aberrations, such as t(4;14) and del17, are linked with disease prognosis. To investigate mutational prevalence in myeloma and associations between mutations and patient outcomes, we tested a panel of 41 known oncogenes and tumor suppressor genes in tumor samples from 133 relapsed myeloma patients participating in phase 2 or 3 clinical trials of bortezomib. DNA mutations were identified in 14 genes. BRAF as well as RAS genes were mutated in a large proportion of cases (45.9%) and these mutations were mutually exclusive. New recurrent mutations were also identified, including in the PDGFRA and JAK3 genes. NRAS mutations were associated with a significantly lower response rate to single-agent bortezomib (7% vs 53% in patients with mutant vs wild-type NRAS, P = .00116, Bonferroni-corrected P = .016), as well as shorter time to progression in bortezomib-treated patients (P = .0058, Bonferroni-corrected P = .012). However, NRAS mutation did not impact outcome in patients treated with high-dose dexamethasone. KRAS mutation did not reduce sensitivity to bortezomib or dexamethasone. These findings identify a significant clinical impact of NRAS mutation in myeloma and demonstrate a clear example of functional differences between the KRAS and NRAS oncogenes.
Assuntos
Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Mieloma Múltiplo/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas/genética , Pirazinas/uso terapêutico , Proteínas ras/genética , Bortezomib , Estudos de Coortes , Relação Dose-Resposta a Droga , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Prognóstico , Proteínas Proto-Oncogênicas p21(ras) , Análise de SobrevidaRESUMO
The incidence of herpes zoster (HZ) in patients with non-Hodgkin lymphoma (NHL) receiving bortezomib-based therapy has not been well studied. We reviewed data from two phase II trials in which bortezomib was administered to 236 patients, median age 65 years, with relapsed/refractory mantle cell or indolent NHL. HZ occurred in 24 patients (10.2%) overall, with a comparable incidence in NHL histologic subgroups. Median time to HZ was 39 (range, 11-206) days. In total, 71% of patients who developed HZ were aged ≥ 65 years, compared to 48% without HZ (p = 0.03). Patients with HZ were more likely to have had received ≥ 2 lines of therapy (63% vs. 47%, p = 0.16). Six (25%) of the patients who developed HZ had received purine analogs, compared with 34 (16%) patients without HZ (p = 0.27). As the occurrence of HZ may complicate the course of indolent or mantle cell NHL in patients receiving bortezomib-based therapies, these patients, especially the elderly, should be strongly considered for antiviral prophylaxis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Herpes Zoster/complicações , Linfoma de Células B/complicações , Linfoma de Células B/tratamento farmacológico , Linfoma de Célula do Manto/complicações , Linfoma de Célula do Manto/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Bortezomib , Feminino , Herpes Zoster/etiologia , Humanos , Linfoma de Células B/patologia , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pirazinas/administração & dosagem , Recidiva , Fatores de RiscoRESUMO
PURPOSE: The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. EXPERIMENTAL DESIGN: Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m(2) standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m(2), respectively, up to a 1.3 mg/m(2) maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. RESULTS: Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC(0-tlast)) or C(max) compared with patients with normal function. Mean dose-normalized AUC(0-tlast) was increased by approximately 60% on day 8 in patients with moderate or severe impairment. CONCLUSIONS: Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m(2).
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacocinética , Hepatopatias/complicações , Neoplasias/tratamento farmacológico , Pirazinas/efeitos adversos , Pirazinas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/sangue , Bortezomib , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/metabolismo , Pirazinas/administração & dosagem , Pirazinas/sangueRESUMO
Overexpression of the Bcl-2 family of genes results in increased transcription of anti-apoptotic proteins. In vitro data suggest that this may enhance acquired chemoresistance and correlate with extramedullary invasion. This has led to pursuing the Bcl-2 family of proteins as therapeutic targets in several malignant disorders, including multiple myeloma (MM). The impact of novel therapeutic agents such as bortezomib on these molecular markers is not known. We investigated the association between the expression of anti-apoptotic members of the Bcl-2 family and the efficacy of bortezomib in patients with relapsed/refractory MM. Gene expression data generated prospectively from large clinical trials were utilized. Hypothesis testing using a multisample test for equivalence was performed. The association between Bcl-2 expression levels and clinical response was negated in bortezomib-treated patients (p = 0.014), while not so in dexamethasone-treated patients (p = 0.92). Similar results were noted for variant 2 of the Mcl-1 gene (p = 0.003). Results for Bcl-xl did not meet the level of significance. Thus, the importance of the Bcl-2 family of proteins as prognostic markers in MM should be reassessed in the novel therapeutic agent era. Our data suggest that bortezomib may overcome the prognostic effect conferred by overexpression of some of the anti-apoptotic Bcl-2 family of genes in patients with relapsed/refractory MM.
Assuntos
Ácidos Borônicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Genes bcl-2/genética , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Pirazinas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Ácidos Borônicos/farmacologia , Bortezomib , Ensaios Clínicos como Assunto/estatística & dados numéricos , Análise por Conglomerados , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes bcl-2/efeitos dos fármacos , Humanos , Análise em Microsséries , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Prognóstico , Pirazinas/farmacologia , Recidiva , Falha de Tratamento , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
BACKGROUND: In multiple myeloma, expression of cancer testis antigens may provide prognostic markers and potential targets for immunotherapy. Expression at relapse has not yet been evaluated for a large panel of cancer testis antigens which can be classified by varying expression in normal tissue: restricted to testis, expressed in testis and brain and not restricted but selectively expressed in testis. DESIGN AND METHODS: Evaluation of cancer testis antigen expression was made in newly diagnosed multiple myeloma cases (HOVON-65/GMMG-HD4 trial; n = 320) and in relapse cases (APEX, SUMMIT, CREST trials; n = 264). Presence of expression using Affymetrix GeneChips was determined for 123 cancer testis antigens. Of these 87 had a frequency of more than 5% in the newly diagnosed and relapsed patients, and were evaluated in detail. RESULTS: Tissue restriction was known for 58 out of 87 cancer testis antigens. A significantly lower frequency of presence calls in the relapsed compared to newly diagnosed cases was found for 3 out of 13 testis restricted genes, 2 out of 7 testis/brain restricted genes, and 17 out of 38 testis selective genes. MAGEC1, MAGEB2 and SSX1 were the most frequent testis-restricted cancer testis antigens in both data sets. Multivariate analysis demonstrated that presence of MAGEA6 and CDCA1 were clearly associated with shorter progression free survival, and presence of MAGEA9 with shorter overall survival in the set of newly diagnosed cases. In the set of relapse cases, presence of CTAG2 was associated with shorter progression free survival and presence of SSX1 with shorter overall survival. CONCLUSIONS: Relapsed multiple myeloma reveals extensive cancer testis antigen expression. Cancer testis antigens are confirmed as useful prognostic markers in newly diagnosed multiple myeloma patients and in relapsed multiple myeloma patients. The HOVON-65/GMMG-HD4 trial is registered under Dutch trial register n. NTR-213. CREST, SUMMIT and APEX trials were registered under ns. M34100-024, M34100-025 and NCT00049478/NCT00048230, respectively.