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

Phase I/II Study With Temsirolimus Versus no add-on in Patients With Castration Resistant Prostate Cancer (CRPC) Receiving First-line Docetaxel Chemotherapy

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.

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).