cesar study in prostate cancer with temsirolimus added to standard docetaxel therapy (ceptas)

Conditions: Prostatic Neoplasms

Summary: in this phase i study safety of the combination of docetaxel and temsirolimus needs to be shown before the study can be expanded into a phase ii study to examine the activity of a safe combination of temsirolimus and docetaxel in a comparison with docetaxel alone.

the purpose of this phase i study is to evaluate feasibility of dose levels dl1, dl2 and dl3 (which are combinations of temsirolimus and docetaxel) and defining a recommended dose (rd) for the phase ii part using these dose levels in a dose escalating scheme. secondary objectives are the collection of safety data on the dose levels used in this part.

Eligibility criteria:
inclusion criteria phase i part: * adult males ≥18 years of age. * patients with crpc defined as confirmed rise of psa levels after orchiectomy or lhrh agonist based therapy. * progressive disease, defined as psa progression by confirmed rising psa levels. * psa at time of study entry ≥2ng/ml within 1 week prior to treatment (according to scher 2008). * bone metastasis and/or lymph node and/or visceral organ metastases allowed. measurable and non measurable disease allowed. * performance status (ps) 0-1 ecog. * signed written informed consent. * white blood cell count (wbc) ≥4x10\^9/l with neutrophils ≥1.5x10\^9/l, platelet count ≥100x10\^9/l, hemoglobin ≥9g/dl. * total bilirubin \<=2 x upper limit of normal. * ast and alt \<=2.5 x upper limit of normal, or \<=5 x upper limit of normal in case of liver metastases. * serum creatinine \ 60 ml/min. * androgen ablation will have to be continued. antiandrogens such as bicalutamide will have to be discontinued at least 4 weeks prior to the start of study treatment. exclusion criteria phase i part: * clinically symptomatic brain or meningeal metastasis. * receiving known strong cyp3a4 isoenzyme inhibitors and/or inducers. * any investigational drug within the 30 days before inclusion. * not recovered from prior biopsy, surgery, traumatic injury, and/or radiation therapy, as judged by the investigator. * nonhealing wound or ulcer. * grade ≥ 3 hemorrhage within the past month. * any condition / concomitant disease not allowing chemotherapy with docetaxel, prednisone and temsirolimus in the discretion of the treating physician, like: renal insufficiency requiring dialyses; congestive heart failure or uncontrolled angina pectoris; prior myocardial infarction within 6 months of start of chemotherapy; uncontrolled severe hypertension (failure of diastolic blood pressure to fall below 90 mm hg despite the use of ≥ 3 anti-hypertensive drugs) or arrhythmias; instable diabetes mellitus, ulceration from diabetes mellitus or other conditions not allowing high dose corticosteroids; effusions in pericardium, pleura or abdomen symptomatic and in need of being punctured. * known hypersensitivity to any of the components in the temsirolimus infusion or other medical reasons for not being able to receive adequate premedication (antihistamine agents). * legal incapacity or limited legal capacity * medical or psychological conditions that would not permit the patient to * complete the study or sign informed consent. inclusion criteria phase ii part, chemotherapy period: * adult males ≥ 18 years of age. * patients with crpc defined as confirmed rise of psa levels after orchiectomy or lhrh agonist based therapy * progressive disease, defined as psa progression by confirmed rising psa levels * psa at time of study entry ≥ 2ng/ml within 1 week prior to treatment (according to scher 2008). * bone metastasis and/or lymph node and/or visceral organ metastases allowed. measurable and non measurable disease allowed. * performance status (ps) 0-1 ecog. * signed written informed consent. * white blood cell count (wbc) ≥4x10\^9/l with neutrophils ≥1.5x10\^9/l, platelet count ≥100x10\^9/l, hemoglobin ≥9g/dl. * total bilirubin \<= 2 x upper limit of normal. * ast and alt \<=2.5 x upper limit of normal, or \<=5 x upper limit of normal in case of liver metastases. * serum creatinine \ 60 ml/min. * androgen ablation will have to be continued. antiandrogens such as bicalutamide will have to be discontinued at least 4 weeks prior to the start of study treatment. exclusion criteria phase ii part, chemotherapy period: * prior chemotherapy. * clinically symptomatic brain or meningeal metastasis. * receiving known strong cyp3a4 isoenzyme inhibitors and/or inducers. * any investigational drug within the 30 days before inclusion. * not recovered from prior biopsy, surgery, traumatic injury, and/or radiation therapy, as judged by the investigator. * nonhealing wound or ulcer. * grade ≥ 3 hemorrhage within the past month. * any condition / concomitant disease not allowing chemotherapy with docetaxel, prednisone and temsirolimus in the discretion of the treating physician, like: renal insufficiency requiring dialyses; congestive heart failure or uncontrolled angina pectoris; prior myocardial infarction within 6 months of start of chemotherapy; uncontrolled severe hypertension (failure of diastolic blood pressure to fall below 90 mm hg despite the use of ≥ 3 anti-hypertensive drugs) or arrhythmias; instable diabetes mellitus, ulceration from diabetes mellitus or other conditions not allowing high dose corticosteroids; effusions in pericardium, pleura or abdomen symptomatic and in need of being punctured. * known hypersensitivity to any of the components in the temsirolimus infusion or other medical reasons for not being able to receive adequate premedication (antihistamine agents). * legal incapacity or limited legal capacity. * medical or psychological conditions that would not permit the patient to complete the study or sign informed consent. inclusion criteria phase ii part, maintenance period: * completed 8 cycles (up to 26 weeks) treatment in arm a * white blood cell count (wbc) ≥4x10\^9/l with neutrophils ≥1.5x10\^9/l, platelet count ≥100x10\^9/l, hemoglobin ≥9g/dl. * total bilirubin \<=2 x upper limit of normal. * ast and alt \<=2.5 x upper limit of normal, or \<=5 x upper limit of normal in case of liver metastases. * serum creatinine \ 60 ml/min. * general condition sufficient to allow therapy with temsirolimus. * signed informed consent. exclusion criteria phase ii part, maintenance period: * disease progression in the first 8 cycles (up to 26 weeks).

Keywords: castration prostate cancer castration resistant prostate cancer psa docetaxel temsirolimus disease progression free survival dpfs dose escalation