CESAR Study in Prostate Cancer With Temsirolimus Added to Standard Docetaxel Therapy (CEPTAS)

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 \<=1.5 x upper limit of normal or creatinine clearance \> 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 \<=1.5 x upper limit of normal or creatinine clearance \>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 \<=1.5 x upper limit of normal or creatinine clearance \>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).