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

Study Overview

• Status: Completed
• Conditions: Prostatic Neoplasms
• Intervention / Treatment: Drug: Docetaxel; Drug: Temsirolimus

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.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Essen, Germany
    • CESAR Study Center
  • Freiburg, Germany
    • CESAR Study Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Central European Society for Anticancer Drug Research
• Investigators: Study Chair: Rudolf Morant, MD, Tumor-und Brustzentrum ZeTuP, St. Gallen, Switzerland

Publications and helpful links

Helpful Links

• web page of CESAR (Central European Society for Anticancer Drug Research-EEIG)

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: August 17, 2010
• First Submitted That Met QC Criteria: September 19, 2010
• First Posted (Estimate): September 21, 2010

Study Record Updates

• Last Update Posted (Estimate): January 27, 2016
• Last Update Submitted That Met QC Criteria: January 26, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Docetaxel; prostate cancer; PSA; Temsirolimus; dose escalation; castration resistant prostate cancer; castration; disease progression free survival; DPFS
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Docetaxel; Sirolimus
• Other Study ID Numbers: C-II-007; 2010-018370-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED