Prostatic Neoplasms
Conditions
Keywords
castration, prostate cancer, castration resistant prostate cancer, PSA, Docetaxel, Temsirolimus, disease progression free survival, DPFS, dose escalation
Brief 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.
Detailed description
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.
Interventions
DRUGDocetaxel
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.
DRUGTemsirolimus
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.
Sponsors
Central European Society for Anticancer Drug Research
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| recommended dose | 10 months | 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. |
| disease progression-free survival | 24 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 1-year Disease-Progression Free Survival Rate | 24 months | 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. |
| DPFS time | 24 months | 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. |
| TTP-PSA | 24 months | 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)† |
| toxicity based on treatment-related toxicities using CTCAE v4.0 | 24 months | Phase II Part: Evaluation of toxicity using CTCAE v4.0 |
| safety as defined as occurence of treatment related adverse events | 10 months | Phase I Part: Secondary endpoint is the collection of safety data on the dose levels used in this part. |
| quality of life | 24 months | Phase II Part: Quality of life using the EORTC questionnaire |
| overall survival | 24 months | Phase II Part: overall survival (OS) measured from randomization until death or lost to follow up (censored survival time) |
| Frequency of medication for pain | 24 months | Phase II Part: Frequency of medication for pain |
| PSA | 24 months | Phase II Part: Proportion of patients with drop of PSA of \> 30% in the evaluation period compared to baseline compared to baseline. |
| overall response | 24 months | 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. |
Countries
Germany
Outcome results
None listed