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1.
Cancer ; 129(10): 1537-1546, 2023 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-36882377

RESUMEN

BACKGROUND: The nucleoside FF-10502-01, structurally similar to but with different biologic effects than gemcitabine, shows promising activity both alone and combined with cisplatin in preclinical gemcitabine-resistant tumor models. We conducted an open-label, single-arm, 3 + 3 first-in-human trial to explore the safety, tolerability, and antitumor activity of FF-10502-01 in patients with solid tumors. METHODS: Patients with inoperable metastatic tumors refractory to standard therapies were enrolled. Escalating intravenous FF-10502-01 doses (8-135 mg/m2 ) were administered weekly for 3 weeks in 28-day cycles until progressive disease or unacceptable toxicity was observed. Three expansion cohorts were subsequently evaluated. RESULTS: A phase 2 dose of 90 mg/m2 was determined after evaluating 40 patients. Dose-limiting toxicities included hypotension and nausea. Phase 2a enrolled patients with cholangiocarcinoma (36), gallbladder cancer (10), and pancreatic/other tumors (20). Common adverse events were grade 1-2 rash, pruritus, fever, and fatigue. Grade 3 or 4 hematologic toxicities were observed at low incidences, including thrombocytopenia (5.1%) and neutropenia (2%). Confirmed partial responses (PRs) occurred in five patients with gemcitabine-refractory tumors, including three with cholangiocarcinoma and one each with gallbladder and urothelial cancer. Median progression-free and overall survival rates in patients with cholangiocarcinoma were 24.7 and 39.1 weeks, respectively. Prolonged progression-free survival in patients with cholangiocarcinoma was associated with BAP1 and PBRM1 mutations. CONCLUSION: FF-10502-01 was well tolerated with manageable side effects and limited hematologic toxicity. Durable PRs and disease stabilizations were observed in heavily pretreated biliary tract patients who had received prior gemcitabine. FF-10502-01 is distinct from gemcitabine and may represent an effective therapy.


Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias de la Vesícula Biliar , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Conductos Biliares Intrahepáticos , Colangiocarcinoma/tratamiento farmacológico , Desoxicitidina , Gemcitabina
2.
Blood Adv ; 8(10): 2527-2535, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38502195

RESUMEN

ABSTRACT: FLT3 tyrosine kinase inhibitors (TKIs) have clinical efficacy for patients with FLT3-mutated AML (acute myeloid leukemia), but their impact is limited by resistance in the setting of monotherapy and by tolerability problems when used in combination therapies. FF-10101 is a novel compound that covalently binds to a cysteine residue near the active site of FLT3, irreversibly inhibiting receptor signaling. It is effective against most FLT3 activating mutations, and, unlike other inhibitors, is minimally vulnerable to resistance induced by FLT3 ligand. We conducted a phase 1 dose escalation study of oral FF-10101 in patients with relapsed and/or refractory AML, the majority of whom harbored FLT3-activating mutations and/or had prior exposure to FLT3 inhibitors. Fifty-four participants enrolled in cohorts receiving doses ranging from 10 to 225 mg per day and 50 to 100 mg twice daily (BID). The dose limiting toxicities were diarrhea and QT prolongation. Among 40 response-evaluable participants, the composite complete response rate was 10%, and the overall response rate (including partial responses) was 12.5%, including patients who had progressed on gilteritinib. Overall, 56% of participants had prior exposure to FLT3 inhibitors. The recommended phase 2 dose was 75 mg BID. FF-10101 potentially represents a next-generation advance in the management of FLT3-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03194685.


Asunto(s)
Leucemia Mieloide Aguda , Inhibidores de Proteínas Quinasas , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Persona de Mediana Edad , Femenino , Masculino , Adulto , Anciano , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Recurrencia , Mutación , Resultado del Tratamiento , Resistencia a Antineoplásicos/efectos de los fármacos , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/efectos adversos , Adulto Joven
3.
Clin Cancer Res ; 26(22): 5830-5842, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-32816889

RESUMEN

PURPOSE: 90Y-FF-21101 is an Yttrium-90-conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors. PATIENTS AND METHODS: The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5-25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months. RESULTS: 111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity. CONCLUSIONS: The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Cadherinas/antagonistas & inhibidores , Neoplasias/radioterapia , Radioinmunoterapia , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Cadherinas/genética , Cadherinas/inmunología , Antígeno Carcinoembrionario/genética , Adhesión Celular/efectos de los fármacos , Fraccionamiento de la Dosis de Radiación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoglobulinas/inmunología , Radioisótopos de Indio/administración & dosificación , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Bazo/efectos de los fármacos , Testículo/efectos de los fármacos , Radioisótopos de Itrio/administración & dosificación
4.
J Pain Res ; 10: 2413-2424, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29062240

RESUMEN

BACKGROUND: Oliceridine (TRV130), a novel µ-receptor G-protein pathway selective (µ-GPS) modulator, was designed to improve the therapeutic window of conventional opioids by activating G-protein signaling while causing low ß-arrestin recruitment to the µ receptor. This randomized, double-blind, patient-controlled analgesia Phase IIb study was conducted to investigate the efficacy, safety, and tolerability of oliceridine compared with morphine and placebo in patients with moderate to severe pain following abdominoplasty (NCT02335294; oliceridine is an investigational agent not yet approved by the US Food and Drug Administration). METHODS: Patients were randomized to receive postoperative regimens of intravenous oliceridine (loading/patient-controlled demand doses [mg/mg]: 1.5/0.10 [regimen A]; 1.5/0.35 [regimen B]), morphine (4.0/1.0), or placebo with treatment initiated within 4 hours of surgery and continued as needed for 24 hours. RESULTS: Two hundred patients were treated (n=39, n=39, n=83, and n=39 in the oliceridine regimen A, oliceridine regimen B, morphine, and placebo groups, respectively). Patients were predominantly female (n=198 [99%]) and had a mean age of 38.2 years, weight of 71.2 kg, and baseline pain score of 7.7 (on 11-point numeric pain rating scale). Patients receiving the oliceridine regimens had reductions in average pain scores (model-based change in time-weighted average versus placebo over 24 hours) of 2.3 and 2.1 points, respectively (P=0.0001 and P=0.0005 versus placebo); patients receiving morphine had a similar reduction (2.1 points; P<0.0001 versus placebo). A lower prevalence of adverse events (AEs) related to nausea, vomiting, and respiratory function was observed with the oliceridine regimens than with morphine (P<0.05). Other AEs with oliceridine were generally dose-related and similar in nature to those observed with conventional opioids; no serious AEs were reported with oliceridine. CONCLUSION: These results suggest that oliceridine may provide effective, rapid analgesia in patients with moderate to severe postoperative pain, with an acceptable safety/tolerability profile and potentially wider therapeutic window than morphine.

5.
Pain ; 157(1): 264-272, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26683109

RESUMEN

Efficacy of conventional opioids can be limited by adverse events (AEs). TRV130 is a structurally novel biased ligand of the µ-opioid receptor that activates G protein signaling with little ß-arrestin recruitment. In this phase 2, randomized, placebo- and active-controlled study, we investigated the efficacy and tolerability of TRV130 in acute pain after bunionectomy. We used an adaptive study design in which 144 patients experiencing moderate-to-severe acute pain after bunionectomy were randomized to receive double-blind TRV130, placebo, or morphine in a pilot phase. After pilot phase analysis, 195 patients were randomized to receive double-dummy TRV130 0.5, 1, 2, or 3 mg every 3 hours (q3h); placebo; or morphine 4 mg q4h intravenously. The primary end point was the time-weighted average change in numeric rating scale pain intensity over the 48-hour treatment period. Secondary end points included stopwatch and categorical assessments of pain relief. Safety and tolerability were also assessed. TRV130 2 and 3 mg q3h, and morphine 4 mg q4h produced statistically greater mean reductions in pain intensity than placebo over 48 hours (P < 0.005). TRV130 at 2 and 3 mg produced significantly greater categorical pain relief than morphine (P < 0.005) after the first dose, with meaningful pain relief occurring in under 5 minutes. TRV130 produced no serious AEs, with tolerability similar to morphine. These results demonstrate that TRV130 rapidly produces profound analgesia in moderate-to-severe acute pain, suggesting that G-protein-biased µ-opioid receptor activation is a promising target for development of novel analgesics.


Asunto(s)
Dolor Agudo/tratamiento farmacológico , Analgésicos Opioides/uso terapéutico , Receptores Opioides mu/agonistas , Compuestos de Espiro/uso terapéutico , Tiofenos/uso terapéutico , Dolor Agudo/etiología , Adolescente , Adulto , Anciano , Método Doble Ciego , Femenino , Hallux Valgus/cirugía , Humanos , Masculino , Persona de Mediana Edad , Morfina/uso terapéutico , Procedimientos Ortopédicos/efectos adversos , Resultado del Tratamiento , Adulto Joven
6.
Ther Innov Regul Sci ; 49(5): 756-766, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30227035

RESUMEN

BACKGROUND: Conventional opioids provide powerful analgesia but also produce efficacy-limiting adverse effects, limiting their clinical utility (CU). TRV130 is being evaluated to determine whether CU can be expanded by way of increased efficacy, decreased adverse effects, or some combination thereof. METHODS: This phase 2 study of TRV130 blends traditional objectives with novel design features aimed toward the specific strategic goal of optimizing the attributes of TRV130 efficacy and tolerability compared with the conventional opioid, morphine. The adaptive maximizing design (AMD) was developed to maximize assignment of future patients to doses that demonstrate maximum balance between efficacy and tolerability (ie, CU) assessed via a CU function. RESULTS: Our evaluation of the AMD performance characteristics reveals that the AMD has a strong capacity to estimate the TRV130 dose-regimens with maximum CU, assign more patients to the TRV130 dose-regimens with maximum CU, and, conversely, assign fewer patients to doses away from the those with maximum or near-maximum CU. CONCLUSIONS: Based on this evaluation of performance characteristics of the AMD versus a traditional study design, the AMD was selected for this proof-of-concept and dose-regimen finding study of TRV130.

7.
J Clin Pharmacol ; 54(3): 351-7, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24122908

RESUMEN

TRV130 is a G protein-biased ligand at the µ-opioid receptor. In preclinical studies it was potently analgesic while causing less respiratory depression and gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. A first-in-human study was conducted with ascending doses of TRV130 to explore its tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers. TRV130 was well-tolerated over the dose range 0.15 to 7 mg administered intravenously over 1 hour. TRV130 geometric mean exposure and Cmax were dose-linear, with AUC0-inf of 2.52 to 205.97 ng h/mL and Cmax of 1.04 to 102.36 ng/mL across the dose range tested, with half-life of 1.6-2.7 hours. A 1.5 mg dose of TRV130 was also well-tolerated when administered as 30, 15, 5, and 1 minute infusions. TRV130 pharmacokinetics were modestly affected by CYP2D6 phenotype: clearance was reduced by 53% in CYP2D6 poor metabolizers.TRV130 caused dose- and exposure-related pupil constriction, confirming central compartment µ-opioid receptor engagement. Marked pupil constriction was noted at 2.2, 4, and 7 mg doses. Nausea and vomiting observed at the 7 mg dose limited further dose escalation. These findings suggest that TRV130 may have a broad margin between doses causing µ-opioid receptor-mediated pharmacology and doses causing µ-opioid receptor-mediated intolerance.


Asunto(s)
Analgésicos , Compuestos de Espiro , Tiofenos , Administración Intravenosa , Adulto , Analgésicos/administración & dosificación , Analgésicos/efectos adversos , Analgésicos/farmacocinética , Analgésicos/farmacología , Estudios Cruzados , Método Doble Ciego , Voluntarios Sanos , Humanos , Ligandos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Receptores Opioides mu/metabolismo , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/efectos adversos , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Tiofenos/farmacocinética , Tiofenos/farmacología , Vómitos/inducido químicamente , Adulto Joven
8.
Pain ; 155(9): 1829-1835, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24954166

RESUMEN

Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating µ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116 seconds latency vs 75 seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (-15.9 for morphine versus -7.3, -7.6, and -9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.


Asunto(s)
Analgésicos Opioides/efectos adversos , Morfina/efectos adversos , Dolor/tratamiento farmacológico , Compuestos de Espiro/efectos adversos , Tiofenos/efectos adversos , Adolescente , Adulto , Analgesia , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Estudios Cruzados , Mareo/inducido químicamente , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Cefalea/inducido químicamente , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Morfina/administración & dosificación , Morfina/uso terapéutico , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/uso terapéutico , Tiofenos/administración & dosificación , Tiofenos/uso terapéutico , Vómitos/inducido químicamente , Adulto Joven
9.
J Clin Pharmacol ; 53(9): 892-9, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23813302

RESUMEN

TRV027 is a novel ß-arrestin biased peptide ligand of the angiotensin II type 1 receptor (AT1R). The compound antagonizes G protein coupling while simultaneously stimulating ß-arrestin-mediated signaling. In preclinical studies, TRV027 reversibly reduced blood pressure while preserving renal function in a dog tachypaced heart failure model and stimulating cardiomyocyte contractility in vitro. This profile suggests that TRV027 may have unique benefits in acute heart failure, a condition associated with renin-angiotensin system activation. A first-time-in-human study was conducted with ascending doses of TRV027 to explore its tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers. Subjects' salt intake was restricted to stimulate RAS activation. In this study TRV027 was safe and well tolerated with a short-half-life (ranging between 2.4 and 13.2 minutes) and dose-proportional increases in systemic exposure. Consistent with the pre-clinical findings, TRV027 reduced blood pressure to a greater degree in subjects with RAS activation, measured as elevated plasma renin activity, than in those with normal PRA levels. This study in sodium-restricted healthy subjects suggests that TRV027 will successfully target a core mechanism of acute heart failure pathophysiology. Further clinical studies with TRV027 in patients with heart failure are underway.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antihipertensivos/farmacología , Oligopéptidos/farmacología , Adulto , Bloqueadores del Receptor Tipo 1 de Angiotensina II/sangre , Antihipertensivos/sangre , Presión Sanguínea/efectos de los fármacos , Estudios Cruzados , Dieta Hiposódica , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oligopéptidos/sangre , Renina/sangre
10.
Ren Fail ; 24(5): 609-14, 2002 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12380906

RESUMEN

Pruritus is a common complaint among end stage renal disease patients and has been associated with poor outcome. We characterized this problem at our outpatient hemodialysis unit. Seventy patients were surveyed over a two-day period. A visual analog scale was used to evaluate the intensity of itching. Location of itching and temporal relationship to dialysis was assessed by questionnaire. Laboratory parameters were evaluated to differentiate between those who itched and those who did not itch. Seventy percent of patients reported pruritus either during and/or between hemodialysis sessions. Itch intensity ranged from mild to severe. Forty-five percent of patients itched in three or more areas with the back and legs most commonly reported. Laboratory parameters were unable to differentiate between patients who itched and those who did not itch. Itching remains a common problem in hemodialysis patients. New treatments for patients resistant to standard therapies are needed.


Asunto(s)
Instituciones de Atención Ambulatoria/estadística & datos numéricos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Prurito/epidemiología , Prurito/etiología , Diálisis Renal/estadística & datos numéricos , Uremia/complicaciones , Uremia/epidemiología , Adulto , Anciano , Femenino , Humanos , Fallo Renal Crónico/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Prurito/terapia , Índice de Severidad de la Enfermedad , Factores de Tiempo , Uremia/terapia
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