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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Docetaxel|DL 1: Docetaxel 60mg/m^2, Temsirolimus 15mg. DL 2: Docetaxel 60mg/m^2, Temsirolimus 25mg. DL 3: Docetaxel 75mg/m^2, Temsirolimus 25mg. One cycle is defined as a 3 week period (21 days) where docetaxel is given on day 1, and temsirolimus on days 1, 8 and 15.|
|Drug: Temsirolimus|DL 1: Docetaxel 60mg/m^2, Temsirolimus 15mg. DL 2: Docetaxel 60mg/m^2, Temsirolimus 25mg. DL 3: Docetaxel 75mg/m^2, Temsirolimus 25mg. One cycle is defined as a 3 week period (21 days) where docetaxel is given on day 1, and temsirolimus on days 1, 8 and 15.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| recommended dose | Phase I Part: Primary endpoint is the Recommended Dose (RD) for the Phase II Part chosen between the three DLs based on the dose escalation scheme. | 10 months | 
| disease progression-free survival | Phase II Part: Primary endpoint is to evaluate the activity of the addition of Temsirolimus to standard treatment on the disease progression-free survival (DPFS Chemotherapy) in patients with castration resistant prostate cancer receiving first-line Docetaxel chemotherapy. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety as defined as occurence of treatment related adverse events | Phase I Part: Secondary endpoint is the collection of safety data on the dose levels used in this part. | 10 months | 
| overall response | Phase II Part: Responses of measurable disease (RECIST 1.1 criteria) including the overall response rate (RR, CFR+PR) and the disease control rate (PR+CR+SD). In addition to the overall response rate RR, the trial will also evaluate the number of responders based on PSA evaluation only (RR-PSA) and the number of responders based on RECIST evaluation only (RR-RECIST) among those who are evaluable by that criterion, respectively. RR is only evaluated for the chemotherapy part of the Phase II part of the trial. | 24 months | 
| 1-year Disease-Progression Free Survival Rate | Phase II Part: 1-year Disease-Progression Free Survival Rate (DPFS-1yR); defined as the quotient defined exactly in the same way as DPFS-6mR with the landmark time point equal to 1 year, +/- 4 weeks for assessment one year after randomization. | 24 months | 
| DPFS time | Phase II Part: DPFS time measured as failure time between 1st randomization and disease progression or death whatever occurred first. Patients lost-to follow-up, dropping out (e.g. when withdrawing consent) or patients surviving progression free at the end-of-study time point are treated as censored cases. | 24 months | 
| TTP-PSA | Phase II Part: Time to PSA progression (TTP-PSA) measured from randomization until PSA progression as defined in Scher et al. Decline from baseline: record time from start of therapy to first PSA increase that is ≥ 25% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value 3 or more weeks later (ie, a confirmed rising trend)† | 24 months | 
| toxicity based on treatment-related toxicities using CTCAE v4.0 | Phase II Part: Evaluation of toxicity using CTCAE v4.0 | 24 months | 
| PSA | Phase II Part: Proportion of patients with drop of PSA of > 30% in the evaluation period compared to baseline compared to baseline. | 24 months | 
| quality of life | Phase II Part: Quality of life using the EORTC questionnaire | 24 months | 
| overall survival | Phase II Part: overall survival (OS) measured from randomization until death or lost to follow up (censored survival time) | 24 months | 
| Frequency of medication for pain | Phase II Part: Frequency of medication for pain | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DPFS, castration, prostate cancer, castration resistant prostate cancer, PSA, Docetaxel, Temsirolimus, disease progression free survival, dose escalation