- ICH GCP
- Registro de ensayos clínicos de EE. UU.
- Ensayo clínico NCT00703625
Phase I Study of Docetaxel and Temsirolimus in Resistant Solid Malignancies
Rationale:
The Mammalian Target of Rapamycin (mTOR) is a large polypeptide serine/threonine kinase of 289 kDa; kinases have been shown to be important regulators of cancer cell cycle, proliferation, invasion, and angiogenesis, and mTOR has been shown to have a key role in the signaling of malignant cell growth, proliferation, differentiation, migration, and survival. Inhibition of mTOR would result in arrest of cell growth in the G1 phase of the cell cycle.
Temsirolimus (CCI-779) is a soluble ester analogue of rapamycin (sirolimus) which has shown impressive in vitro and in vivo cytostatic activity in selectively inhibiting mTOR. In animal models, temsirolimus has demonstrated an impressive cytostatic effect on a wide variety of cancer cells. In vitro, it inhibited the growth of human T-cell leukemia, glioblastoma, melanoma, prostate, breast, renal cell, and pancreatic cells, all of which showed particular sensitivity to temsirolimus, with significant growth inhibition at concentrations of less that 0.01micrometers. In Phase I trials, temsirolimus has been investigated as a single agent on a weekly schedule as well as daily for 5 days every other week, and evidence of activity was observed over the entire dose range (15 - 220 mg/m2) in patients with both breast and renal cancer. There was no apparent relationship between exposure and clinical benefit, suggesting that the inhibition of mTOR may be achieved at doses well below dose levels that result in dose limiting toxicities. Major tumor responses were noted in Phase I trials in patients previously treated with lung, breast, renal as well as neuroendocrine tumors. Minor responses were noted in soft tissue sarcoma, endometrial, and cervical carcinoma.
Docetaxel is a taxane analog which is active against many solid tumors including breast, non-small cell lung, prostate, gastric, ovarian, head and neck, and pancreatic cancers, soft tissue sarcoma, and melanoma. It has been shown in several Phase III studies to have clinically significant activity in several solid tumors.
We propose treating patients with resistant solid malignancies with docetaxel and temsirolimus. In a study using human breast cancer cell lines, mTOR inhibition with rapamycin had a synergistic cytotoxic effect with paclitaxel. Given the novel mechanism of action of mTOR inhibitors and known synergistic activity of an mTOR inhibitor, rapamycin, with a taxane, paclitaxel, in vitro, we envision that this regimen would be highly active in patients with solid tumor malignancies.
Objectives:
Primary
- To define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of temsirolimus in combination with pegylated liposomal doxorubicin in patients with resistant solid malignancies.
- To determine the incidence and severity of other toxicities of temsirolimus in combination with pegylated liposomal doxorubicin in patients with resistant solid malignancies.
Secondary
- To assess the pharmacokinetic profile of temsirolimus in combination with pegylated liposomal doxorubicin.
- To determine any anti-tumor activity and response to the combination of temsirolimus and pegylated liposomal doxorubicin in treatment of patients with resistant solid malignancies.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Tipo de estudio
Inscripción (Actual)
Fase
- Fase 1
Contactos y Ubicaciones
Ubicaciones de estudio
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Missouri
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St. Louis, Missouri, Estados Unidos, 63110
- Washington University School of Medicine
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion and Exclusion Criteria:
- Patients must have a histologically or cytologically proven solid malignancy which is resistant to conventional therapy or for which no effective therapy is known.
- Patients with measurable or non-measurable disease are eligible for entry to this study. In addition, patients without measurable or non-measurable disease are also eligible.
- Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Neuropathy must have recovered to grade 1. No chemotherapy or radiotherapy may be given within 4 weeks prior to the start of protocol treatment.
- Patients must be ≥18 years old.
- ECOG 0-2 at study entry.
- Patients must have a life expectancy of greater than 8 weeks.
- Required Laboratory Values:
- absolute neutrophil count ≥1,500/mm3
- platelets ≥100,000/mm3
- hemoglobin ≥9.0 g/dL
- total bilirubin ≤1.5 x ULN
- AST(SGOT)/ALT(SGPT) ≤1.5 x ULN (≤2.5 x ULN for patients with liver metastases
- alkaline phosphatase ≤2.5 x ULN
- creatinine ≤1.5 x ULN OR
- creatinine clearance ≥60 mL/min/1.732 for patients with creatinine levels above 2.0 mg/dl
- serum cholesterol ≤350 mg/dL /9.0 mmol/L (fasting)
- triglycerides ≤400 mg/dL (fasting)*
- albumin ≥3.0 mg/dL
- PT/INR ≤1.5, unless the patient is on full dose warfarin or stable dose of LMW heparin with a therapeutic INR of >1.5 - ≤3
- Patients cannot be receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, carbamazepine, phenobarbital) nor any other CYP3A4 inducer such as rifampin or St. John's wort, as these may decrease temsirolimus levels.
- Patients with known hypersensitivity reactions to macrolide antibiotics (such as erythromycin, clarithromycin, and azithromycin) are not eligible for this trial.
- For all sexually active patients, the use of adequate contraception (hormonal or barrier method of birth control) will be required prior to study entry and for the duration of study participation. Non-pregnant status will be determined in all women of childbearing potential. Pregnant and nursing women are not eligible.
- Patients must not have active CNS disease.
- Patients must have recovered from uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia.
- Patients must have signed a Washington University, Human Research Protection Office (HRPO) approved informed consent. The patient should not have any serious medical or psychiatric illness that would prevent either the giving of informed consent or the receipt of treatment.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: No aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: Cohort 1
Temsirolimus IV 15 mg weekly Docetaxel 60 mg/m2 IV once every three weeks. |
Otros nombres:
Otros nombres:
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Experimental: Cohort 2
Temsirolimus IV 25 mg weekly Docetaxel IV 60 mg/m2 once every 3 weeks |
Otros nombres:
Otros nombres:
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Experimental: Cohort 1A
Temsirolimus IV 15 mg weekly Docetaxel IV 50 mg/m2 every 3 weeks. |
Otros nombres:
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Periodo de tiempo |
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Definir la dosis máxima tolerada (MTD) y las toxicidades limitantes de la dosis (DLT) de temsirolimus en combinación con doxorrubicina liposomal pegilada en pacientes con neoplasias malignas sólidas resistentes.
Periodo de tiempo: Después de completar el ciclo 1 por todos los pacientes
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Después de completar el ciclo 1 por todos los pacientes
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Determinar la incidencia y la gravedad de otras toxicidades de temsirolimus en combinación con doxorrubicina liposomal pegilada en pacientes con neoplasias malignas sólidas resistentes.
Periodo de tiempo: 30 días después de la finalización del tratamiento
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30 días después de la finalización del tratamiento
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
---|---|---|
To assess the pharmacokinetic profile of temsirolimus in combination with pegylated liposomal doxorubicin.
Periodo de tiempo: Through cycle 2 day 8
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cycle 1 day 1, cycle 2 day 1 (pre-dose, 0.5 hours before end of temsirolimus infusion, 1.5 hours after start of temsirolimus infusion, 5 hours after start of temsirolimus infusion), cycle 2 day 3, cycle 2 day 5, and cycle 2 day 8
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Through cycle 2 day 8
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To determine any anti-tumor activity and response to the combination of temsirolimus and pegylated liposomal doxorubicin in treatment of patients with resistant solid malignancies.
Periodo de tiempo: End of study treatment
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End of study treatment
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Colaboradores e Investigadores
Patrocinador
Publicaciones y enlaces útiles
Publicaciones Generales
- Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000 Feb 2;92(3):205-16. doi: 10.1093/jnci/92.3.205.
- Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000 Jun;18(12):2354-62. doi: 10.1200/JCO.2000.18.12.2354. Erratum In: J Clin Oncol. 2004 Jan 1;22(1):209.
- Elit L. CCI-779 Wyeth. Curr Opin Investig Drugs. 2002 Aug;3(8):1249-53.
- Teachey DT, Obzut DA, Cooperman J, Fang J, Carroll M, Choi JK, Houghton PJ, Brown VI, Grupp SA. The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood. 2006 Feb 1;107(3):1149-55. doi: 10.1182/blood-2005-05-1935. Epub 2005 Sep 29.
- Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol. 2004 Jun 15;22(12):2336-47. doi: 10.1200/JCO.2004.08.116. Epub 2004 May 10.
- Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004 Mar 1;22(5):909-18. doi: 10.1200/JCO.2004.08.185.
- Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, Ansell SM, Luyun R, Flynn PJ, Morton RF, Dakhil SR, Gross H, Kaufmann SH. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005 Aug 10;23(23):5347-56. doi: 10.1200/JCO.2005.13.466. Epub 2005 Jun 27.
- Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, De Angelis L, Raizer J, Hess K, Aldape K, Lamborn KR, Kuhn J, Dancey J, Prados MD; North American Brain Tumor Consortium and the National Cancer Institute. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs. 2005 Aug;23(4):357-61. doi: 10.1007/s10637-005-1444-0.
- Margolin K, Longmate J, Baratta T, Synold T, Christensen S, Weber J, Gajewski T, Quirt I, Doroshow JH. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer. 2005 Sep 1;104(5):1045-8. doi: 10.1002/cncr.21265.
- Chan S, Scheulen ME, Johnston S, Mross K, Cardoso F, Dittrich C, Eiermann W, Hess D, Morant R, Semiglazov V, Borner M, Salzberg M, Ostapenko V, Illiger HJ, Behringer D, Bardy-Bouxin N, Boni J, Kong S, Cincotta M, Moore L. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol. 2005 Aug 10;23(23):5314-22. doi: 10.1200/JCO.2005.66.130. Epub 2005 Jun 13.
- Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12. doi: 10.1056/NEJMoa040720.
- Punt CJ, Boni J, Bruntsch U, Peters M, Thielert C. Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncol. 2003 Jun;14(6):931-7. doi: 10.1093/annonc/mdg248.
- Schuette W, Nagel S, Blankenburg T, Lautenschlaeger C, Hans K, Schmidt EW, Dittrich I, Schweisfurth H, von Weikersthal LF, Raghavachar A, Reissig A, Serke M. Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel. J Clin Oncol. 2005 Nov 20;23(33):8389-95. doi: 10.1200/JCO.2005.02.3739.
- Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, Mills GB, Meric-Bernstam F. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res. 2004 Oct 15;10(20):7031-42. doi: 10.1158/1078-0432.CCR-04-0361.
- Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. doi: 10.1200/JCO.2005.02.027.
- Smolewski P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway. Anticancer Drugs. 2006 Jun;17(5):487-94. doi: 10.1097/00001813-200606000-00001.
- Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006 Feb 10;124(3):471-84. doi: 10.1016/j.cell.2006.01.016.
- Adjei AA, Hidalgo M. Intracellular signal transduction pathway proteins as targets for cancer therapy. J Clin Oncol. 2005 Aug 10;23(23):5386-403. doi: 10.1200/JCO.2005.23.648. Epub 2005 Jun 27.
- Thomas GV. mTOR and cancer: reason for dancing at the crossroads? Curr Opin Genet Dev. 2006 Feb;16(1):78-84. doi: 10.1016/j.gde.2005.12.003. Epub 2005 Dec 15.
- Huang S, Houghton PJ. Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol. 2003 Aug;3(4):371-7. doi: 10.1016/s1471-4892(03)00071-7.
- Sawyers CL. Will mTOR inhibitors make it as cancer drugs? Cancer Cell. 2003 Nov;4(5):343-8. doi: 10.1016/s1535-6108(03)00275-7. No abstract available.
- Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. 2006 Jun 1;66(11):5549-54. doi: 10.1158/0008-5472.CAN-05-2825.
- Chan S. Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer. 2004 Oct 18;91(8):1420-4. doi: 10.1038/sj.bjc.6602162.
- Hidalgo M, Rowinsky E, Erlichmann C, et al. A Phase I and Pharmacological Study of CCI-779, a Rapamycin Ester Cell Cycle Inhibitor. Annals of Oncology 11(Suppl4): 133, 2000.
- Oza A, Elit L, Biagi J, Gotlieb W, Tonkin K, Tsao MN, et al. A Phase II Study of Temsirolimus (CCI-779) in Patients with Metastatic and/or Recurrent Endometrial Cancer. Clinical Cancer Research 11: 9099s, 2005
- Pandya KJ, Levy DE, Hidalgo M, et al. A Randomized, Phase II ECOG Trial of Two Dose Levels of Temsirolimus (CCI-779) in Patients with Extensive Stage Small Cell Lung Cancer in Remission After Induction Chemotherapy. A Preliminary Report. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings; 23: 7005, 2005.
- Hudes G, Carducci M, Tomczak P, et al. A Phase 3, Randomized, 3-arm Study of Temsirolimus (TEMSR) or Interferon-alpha (IFN) or the Combination of TEMSR + IFN in the Treatment of First-Line, Poor-Risk Patients with Advanced Renal Cell Carcinoma (adv RCC). Journal of Clinical Oncology, ASCO Annual Meeting Proceedings; 24: LBA4, 2006.
- Ramaswamy B, Puhalla S. Docetaxel: a tubulin-stabilizing agent approved for the management of several solid tumors. Drugs Today (Barc). 2006 Apr;42(4):265-79. doi: 10.1358/dot.2006.42.4.968648.
- Charles KA, Rivory LP, Stockler MR, Beale P, Beith J, Boyer M, Clarke SJ. Predicting the toxicity of weekly docetaxel in advanced cancer. Clin Pharmacokinet. 2006;45(6):611-22. doi: 10.2165/00003088-200645060-00004.
- Chen YM, Shih JF, Perng RP, Tsai CM, Whang-Peng J. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest. 2006 Apr;129(4):1031-8. doi: 10.1378/chest.129.4.1031.
- Ford HE, Yap YS, Miles DW, Makris A, Hall M, Miller L, Harries M, Smith IE, Johnston SR. A phase II study of weekly docetaxel in patients with anthracycline pretreated metastatic breast cancer. Cancer Chemother Pharmacol. 2006 Dec;58(6):809-15. doi: 10.1007/s00280-006-0222-9. Epub 2006 Mar 10.
- Yazbeck VY, Georgakis GV, Li Y, and Younes A. The mTOR Inhibitor CCI-779 (Temsirolimus) Downregulates p21 and Induces Cell Cycle Arrest and Autophagy in Mantle Cell Lymphoma (MCL). Journal of Clinical Oncology, ASCO Annual Meeting Proceedings; 24:7573, 2006.
- Duran I, Siu LL, Oza AM, Chung TB, Sturgeon J, Townsley CA, Pond GR, Seymour L, Niroumand M. Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer. 2006 Aug;42(12):1875-80. doi: 10.1016/j.ejca.2006.03.015. Epub 2006 Jun 27.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Actual)
Finalización del estudio (Actual)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimar)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Términos MeSH relevantes adicionales
- Neoplasias
- Efectos fisiológicos de las drogas
- Mecanismos moleculares de acción farmacológica
- Agentes antiinfecciosos
- Agentes antineoplásicos
- Agentes inmunosupresores
- Factores inmunológicos
- Moduladores de tubulina
- Agentes antimitóticos
- Moduladores de mitosis
- Agentes antibacterianos
- Antibióticos, Antineoplásicos
- Agentes antifúngicos
- Docetaxel
- Sirolimus
Otros números de identificación del estudio
- 07-0444
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