RESUMEN
BACKGROUND: A sequential approach, synchronizing cell-cycle specific chemotherapy during VEGFR-TKI treatment breaks, may improve the therapeutic index of this combination therapy. In this study we investigate the safety/tolerability and pharmacodynamic effects of docetaxel used in sequential combination with the novel VEGFR-TKI X-82. METHODS: Patients with advanced solid malignancies underwent 21-day treatment cycles with X-82 administered daily on days 1-14, a treatment break on days 15-20, and docetaxel administered on day 21. Randomization was 1:1 to either a low-dose X-82 (200 mg) or high-dose X-82 (400 mg) arm. Patients were scheduled to undergo four 3'-deoxy-3'-18F-fluorothymidine (FLT) PET/CT scans to assess changes in tumor cell proliferation. PET standardized uptake values (SUV) were summarized for tumors and changes were assessed using mixed effects models. RESULTS: 14 patients were enrolled and treated with median 3.5 cycles (range 0-12). Three patients in the high-dose cohort (50%) and three patients in the low-dose cohort (38%) experienced at least one grade 3 adverse event during the study (infections, cytopenias, electrolyte abnormalities, and vascular complications). Four patients with 13 metastatic tumors underwent FLT PET/CT scanning. During the cycle 1 X-82 exposure period, tumor SUVmax decreased by - 11% (p = 0.04). After administration of docetaxel and the cycle 2 X-82 exposure period, tumor SUVmax decreased - 44% (p = 0.03). CONCLUSIONS: The sequential combination of X-82 and docetaxel was safe and led to diminished FLT uptake. Further, decrease in FLT uptake during cycle 2 (X-82 plus docetaxel) was greater than in cycle 1 (X-82 alone), suggesting sequential chemotherapy enhances the pharmacodynamic effect of therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Didesoxinucleósidos , Docetaxel/administración & dosificación , Docetaxel/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Oxindoles/administración & dosificación , Oxindoles/efectos adversos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Radiofármacos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods This open-label phase I study used a 3 + 3 dose escalation design. Patients (pts) were treated with escalating doses of tivantinib (120-360 mg tablets orally twice daily) and temsirolimus (20 mg IV weekly) followed by dose expansion at the MTD. Separate cohorts were planned for extensive (normal) and poor tivantinib metabolizers based on CYP2C19 genotypes. Cycles were 28 days besides cycle 1 that was 35 days to allow for PK analysis. Results Twenty-nine pts. [median age 58 (range 28-77)] were enrolled (21 in dose escalation and 8 in dose expansion). All were extensive CYP2C19 metabolizers. The most common types of cancer were colorectal, ovarian and non-small cell lung. Sixteen out of 21 and 6 out of 8 pts. were evaluable for DLT evaluation per protocol in the dose escalation and dose expansion phases, respectively. Pts remained on study for a median of 71 days (range 18-296). The MTD and RP2D was tivantinib 240 mg twice daily and temsirolimus 20 mg weekly. DLTs included grade (gr) 4 neutropenia (2 pts.; 1 with gr 3 febrile neutropenia), gr 3 abdominal pain (1 pt) and gr 2 mucositis resulting in inadequate drug delivery. The most common treatment related AEs grade ≥ 2 included: anemia (gr 2 in 9 pts., gr 3 in 3 pts), fatigue (gr 2 in 10 pts), anorexia (gr 2 in 9 pts), hypoalbuminemia (gr 2 in 6 pts., gr 3 in 2 pts), hypophosphatemia (gr 2 in 2 pts., gr 3 in 5 pts) and nausea (gr 2 in 6 pts., gr 3 in 1 pt). One pt. with ovarian cancer had a confirmed partial response and remained on study for 10 months, a second patient with ovarian cancer had stable disease and remained on study for 6 months and a third pt. with squamous cell carcinoma of the tongue had stable disease and remained on study for 7 months. Pharmacokinetic analysis showed that there is no interaction in the plasma concentrations between tivantinib and temsirolimus. Conclusions The combination of tivantinib with temsirolimus appears to be well tolerated with evidence of clinical activity.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirrolidinonas/uso terapéutico , Quinolinas/uso terapéutico , Sirolimus/análogos & derivados , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Citocromo P-450 CYP2C19/metabolismo , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/farmacocinética , Pirrolidinonas/efectos adversos , Pirrolidinonas/sangre , Pirrolidinonas/farmacocinética , Quinolinas/efectos adversos , Quinolinas/sangre , Quinolinas/farmacocinética , Sirolimus/efectos adversos , Sirolimus/sangre , Sirolimus/farmacocinética , Sirolimus/uso terapéuticoRESUMEN
This study explores the imaging and therapeutic properties of a novel radiopharmaceutical, (131)I-CLR1404. Phase 1a data demonstrated safety and tumor localization by SPECT-CT. This 1b study assessed safety, imaging characteristics, and possible antineoplastic properties and provided further proof-of-concept of phospholipid ether analogues' retention within tumors. A total of 10 patients received (131)I-CLR1404 in an adaptive dose-escalation design. Imaging characteristics were consistent with prior studies, showing tumor uptake in primary tumors and metastases. At doses of 31.25 mCi/m(2) and greater, DLTs were thrombocytopenia and neutropenia. Disease-specific studies are underway to identify cancers most likely to benefit from (131)I-CLR1404 monotherapy.
Asunto(s)
Yodobencenos/uso terapéutico , Neoplasias/tratamiento farmacológico , Éteres Fosfolípidos/uso terapéutico , Adulto , Anciano , Descubrimiento de Drogas , Femenino , Humanos , Yodobencenos/administración & dosificación , Yodobencenos/farmacología , Masculino , Persona de Mediana Edad , Neoplasias/radioterapia , Éteres Fosfolípidos/administración & dosificación , Éteres Fosfolípidos/farmacología , RecurrenciaRESUMEN
PURPOSE: Potential cytochrome P-450 (CYP) drug-drug interactions in adults with metastatic solid tumors and their effect on eligibility for Phase I clinical trials were characterized. METHODS: This study included adult patients with metastatic solid tumors seen by a medical oncologist from January 2008 through July 2011. The medications used by these patients were identified. Each medication's potential for interacting with CYP isozymes was also characterized. Medication changes required to meet Phase I trial eligibility criteria were also reviewed. RESULTS: Data from 1773 patients were analyzed: 1489 were not enrolled in a Phase I trial and 284 were enrolled in a Phase I trial. Polypharmacy was significantly more prevalent in the group enrolled in a Phase I trial compared with those not enrolled (95% versus 80%, p < 0.001). The majority of patients not enrolled in a Phase I trial were taking at least one CYP isozyme inhibitor (87%) and at least one CYP isozyme inducer (45%). In a separate analysis, four Phase I trials were evaluated. Of 295 screened patients, 3.2% could not enroll due to concurrent medications. Charts from 74 enrolled patients revealed 655 concurrent medications93 medications required further review for eligibility involving 51 (69%) of patients. Of the 93 medications, 38 (41%) were stopped and 41 (44%) were changed for the study. CONCLUSION: Polypharmacy and the use of medications that interact with CYP isoyzmes were common in adult patients with metastatic solid tumors. Patients enrolling in Phase I studies often require medication changes to meet eligibility requirements.
Asunto(s)
Antineoplásicos/farmacología , Ensayos Clínicos Fase I como Asunto/métodos , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Selección de Paciente , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Inductores de las Enzimas del Citocromo P-450/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Polifarmacia , Prevalencia , Adulto JovenRESUMEN
PURPOSE: Rapid disease progression associated with increased tumor proliferation has been observed during withdrawal of anti-angiogenic therapy. We characterize the dynamics of withdrawal flare for axitinib. METHODS: Thirty patients with metastatic solid malignancies received axitinib for 2 weeks, followed by a 1-week drug holiday. Twenty patients suitable for PET imaging received scans with (18)F-3'deoxy-3'fluoro-L-thymidine (FLT), a marker of proliferation. Plasma VEGF and axitinib pharmacokinetic levels were also assessed at specified time points. RESULTS: During axitinib withdrawal, significant increases in both SUVmax (+22 %; p = 0.006) and SUVmean (+20 %; p = 0.001) were observed. Significant increases relative to peak axitinib concentration were observed at day 2 withdrawal for SUVmax and SUVmean, with no further significant increase from day 2 to day 7 of withdrawal. No significant change in SUVmax or SUVmean was observed during the treatment period, relative to baseline. VEGF concentration significantly increased when on drug (p < 0.001) and decreased back to a level indistinguishable from baseline by day 7 of drug washout (p = 0.448). No correlation between change in VEGF and change in imaging metrics was observed. CONCLUSIONS: A significant increase in tumor proliferation was observed during withdrawal of axitinib therapy, and this flare occurred within 2 days of axitinib withdrawal. An exploratory analysis indicated that this flare may be associated with poor clinical outcome.
Asunto(s)
Didesoxinucleósidos , Imidazoles/administración & dosificación , Indazoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Adulto , Anciano , Axitinib , Progresión de la Enfermedad , Femenino , Radioisótopos de Flúor , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Indazoles/efectos adversos , Indazoles/farmacocinética , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Neoplasias/sangre , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Tomografía de Emisión de Positrones/métodos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Radiofármacos , Síndrome de Abstinencia a Sustancias/sangre , Síndrome de Abstinencia a Sustancias/diagnóstico por imagen , Síndrome de Abstinencia a Sustancias/etiología , Síndrome de Abstinencia a Sustancias/metabolismo , Tomografía Computarizada por Rayos X/métodos , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND: Sunitinib treatment results in a compensatory increase in plasma VEGF levels. Acute withdrawal of sunitinib results in a proliferative withdrawal flare, primarily due to elevated VEGF levels. Concurrent sunitinib plus bevacizumab is poorly tolerated with high (37 %) incidence of microangiopathic hemolytic anemia (MAHA). We evaluated a sequential design administering bevacizumab during the sunitinib treatment break to suppress the sunitinib withdrawal flare. METHODS: Patients with no prior VEGF treatment were enrolled in this study. All patients had target lesions amenable to serial FLT PET/CT imaging. Sunitinib 37.5 mg was given on days 1-28 every 6 weeks with bevacizumab 5 mg/kg on day 29. If safe and tolerable, sunitinib increased to 50 mg. FLT PET/CT scans would be obtained at baseline (D1), week 4, and week 6 to evaluate pharmacodynamics of the sequential combination. Sunitinib pharmacokinetics and total, free, and bound VEGF levels were obtained on each cycle at D1, pre-bevacizumab (D29), 4 h post-bevacizumab (D29H4), and day 42 (D42). RESULTS: Six patients enrolled in the safety cohort of sunitinib 37.5 mg plus bevacizumab (see Table). One patient experienced grade 1 MAHA, and after discussion with the Cancer Therapy Evaluation Program (CTEP), the trial was closed to further accrual. No imaging scans were obtained due to early closure. Total and free VEGF levels during cycle 1 Cycle 1 Total VEGF (pg/mL) Mean ± SD Free VEGF (pg/mL) Mean ± SD D1 80 ± 70 51 ± 47 D29 150 ± 62 103 ± 35 D29H4 10 ± 12 2 ± 5 D42 177 ± 34 97 ± 18 CONCLUSIONS: Subclinical MAHA was seen despite using sequential sunitinib with low-dose bevacizumab, and this combination was not feasible for further development. As predicted, VEGF levels increased during sunitinib exposure followed by a rapid decline after bevacizumab. Due to the long half-life of bevacizumab, we expected VEGF ligand suppression through D42, but instead observed a complete rebound in total/free VEGF levels by D42. The increase in VEGF at D42 was unexpected based on sunitinib alone and contrary to the hypothesis that we would block VEGF flare with low-dose bevacizumab. VEGF ligand production may increase as a result of bevacizumab, implying a robust host compensatory mechanism to VEGF signaling pathway inhibition. A greater understanding of the compensatory mechanism would aid future sequencing strategies of new agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/metabolismo , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Carcinoma de Células Renales/patología , Estudios de Cohortes , Esquema de Medicación , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Indoles/farmacocinética , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Pirroles/administración & dosificación , Pirroles/efectos adversos , Pirroles/farmacocinética , SunitinibRESUMEN
PURPOSE: This phase I trial sought to define the toxicity, maximally tolerated dose (MTD) and pharmacodynamics of a combination of bortezomib and doxorubicin in patients with advanced malignancies. PATIENTS AND METHODS: Twenty-six patients were treated with bortezomib intravenously on days 1, 4, 8 and 11, with doxorubicin also administered intravenously on days 1 and 8, both in a 21-day cycle. Dosing ranged from 1.0 mg/m(2) of bortezomib with 15 mg/m(2) of doxorubicin to 1.5 mg/m(2) of bortezomib with 20 mg/m(2) of doxorubicin. Pharmacodynamic studies performed included assessment of levels of 20S proteasome activity and ubiquitin-protein conjugates. RESULTS: The combination of bortezomib and doxorubicin was generally well tolerated. There were two dose limiting toxicities (DLT) at dose cohort 3 (1.3 mg/m(2) bortezomib, 20 mg/m(2) doxorubicin) and 2 DLT at dose cohort 3a (1.5 mg/m(2) bortezomib, 15 mg/m(2) doxorubicin). DLT seen included neutropenia, thrombocytopenia, and neuropathy. In addition, one patient developed grade 3 central nervous system toxicity in cycle 2 (not a DLT). One patient with hormone refractory prostate cancer had a partial response. Proteasome inhibition in whole blood was demonstrated and an increase in ubiquitin-protein conjugates was observed in peripheral blood mononuclear cells of most patients. CONCLUSIONS: Bortezomib and doxorubicin can be administered safely. The recommended phase II dose for this 21-day cycle is bortezomib 1.3 mg/m(2 )intravenously on days 1, 4, 8 and 11, and doxorubicin 20 mg/m(2) intravenously on days 1 and 8. This combination may be of special interest in multiple myeloma, given the activity of both drugs in that disease.