Orteronel Maintenance Therapy in Patients With Metastatic Castration Resistant Prostate Cancer and Non-progressive Disease After First-line Docetaxel Therapy
The main objective of this multicenter, randomized, double-blind, placebo-controlled phase III trial is to assess the impact of maintenance orteronel on disease progression and hence on quality of life in patients with metastatic castration-resistant prostate cancer who have achieved at lease disease stabilization after first line chemotherapy with docetaxel.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Orteronel Maintenance Therapy in Patients With Metastatic Castration Resistant Prostate Cancer and Non-progressive Disease After First-line Docetaxel Therapy: a Multicenter Randomized Double-blind Placebo-controlled Phase III Trial.|
- Event free survival (EFS) [ Time Frame: At baseline; every 4 weeks until disease progression (estimated up to 1 year) ] [ Designated as safety issue: No ]
- Adverse events (AEs) [ Time Frame: Throughout treatment phase (estimated up to 1 year) until 30 days after last drug administration or prior to start of subsequent anticancer treatment (whichever occurs first) ] [ Designated as safety issue: Yes ]
- Prostate-specific antigen (PSA) response (30%, 50%, 90% and best) [ Time Frame: PSA level at baseline and every 4 weeks until disease progression (estimated up to 1 year) ] [ Designated as safety issue: No ]
- Time to PSA progression [ Time Frame: PSA level at baseline and every 4 weeks until disease progression (estimated up to 1 year) ] [ Designated as safety issue: No ]
- Radiographic progression-free survival (rPFS) [ Time Frame: Every 12 weeks until disease progression (estimated up to 1 year) ] [ Designated as safety issue: No ]
- QL and pain response [ Time Frame: First 6 months of trial treatment ] [ Designated as safety issue: No ]
- Overall survival (OS) [ Time Frame: time from trial randomization to the date of death from any cause (estimated up to 4 years) ] [ Designated as safety issue: No ]
|Study Start Date:||September 2012|
|Estimated Study Completion Date:||December 2020|
|Estimated Primary Completion Date:||August 2016 (Final data collection date for primary outcome measure)|
Experimental: Orteronel and best supportive care
Arm A: 300mg Orteronel twice daily and best supportive care until occurrence of an event.
Other Name: TAK-700
Placebo Comparator: Placebo and best supportive care
Arm B: Placebo twice daily and best supportive care until occurrence of an event.
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One in six men will be diagnosed with cancer of the prostate during his lifetime. Accordingly, prostate cancer is the most common cancer amongst men in the western world. In Switzerland approximately 5'400 men are diagnosed with the disease and 1'300 die of prostate cancer every year. Prostate cancer represents 30% of all cancer diagnoses in men. Despite earlier detection and new treatments the life time risk to die of prostate cancer has remained stable at 3% since 1980.
Metastatic prostate cancer is hormone-sensitive and therefore androgen deprivation therapy (ADT) is the treatment of choice. Yet, virtually all patients with metastatic prostate cancer progress on androgen deprivation therapy (so called castration-resistant prostate cancer: CRPC). Further hormonal manipulations are often administered (e.g. maximal androgen blockade with addition of a non-steroidal antiandrogen such as bicalutamide), however these interventions have only modest impact. Metastatic CRPC (mCRPC) that progresses despite these therapies is nowadays treated with docetaxel-based chemotherapy. In a phase III trial, treatment of mCRPC patients with docetaxel in combination with low dose prednisone resulted in a significant survival advantage in comparison to the previous standard of care of mitoxantrone plus prednisone. Moreover docetaxel treatment improved response rate, progression free survival and symptom control.
The current standard of care in patients with disease stabilization after first line chemotherapy with docetaxel is a wait-and-watch strategy, where patients are regularly examined in the hospital every 3-4 weeks. A second line chemotherapy in patients with mCRPC was not standardized until recently. However, two trials presented in 2010 have changed the landscape: the novel taxane cabazitaxel was tested in a phase III trial against mitoxantrone as a second line chemotherapy in patients progressing under or after docetaxel. There was a significant improvement in overall survival, progression free survival and response rate. Most of the included patients had experienced disease progression during or within three months of docetaxel first line treatment. Cabazitaxel was associated with increased toxicity including 5% toxic deaths. Another randomized phase III trial using abiraterone in patients with progression after docetaxel showed a significant improvement in overall survival and pain palliation. Abiraterone belongs to a group of agents that very effectively inhibits the androgen synthesis via blockade of the key enzyme cytochrome P-450c17 (CYP17).
The new drug orteronel (TAK-700) belongs to the same group of active substances as abiraterone. Orteronel is currently the subject of a large international Phase III study in patients with metastatic carcinoma of the prostate and progression of disease following docetaxel. Initial results have shown that orteronel effectively inhibits testosterone synthesis and, in contrast to abiraterone, has fewer side effects.
CYP17 inhibitors are active and well tolerated agents for treatment of patients with castration-resistant prostate cancer. However, despite its activity patients become resistant to this new form of antihormonal treatment and hence develop further progression after a median of approximately 6 months. In that case, the options are very limited as outlined above.
In all reported post-docetaxel trials and in the large phase III trials, patients start on the CYP17 inhibitor treatment at the time of disease progression. Trials examining other advanced malignant diseases such as lung cancer have shown that initiating an effective treatment earlier in the disease course at the end of a first-line chemotherapy (so called switch maintenance therapy) is beneficial in terms of progression free survival (PFS) but also overall survival (OS). This may also hold true for early administration of antihormonal agents in patients with mCRPC.
Therefore, the aim of this trial is to test the hypothesis that starting orteronel after disease stabilization with docetaxel prolongs event-free survival (EFS), consequently maintains a good quality of life (QL) and eventually also improves OS.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01707966
|Aarau, Switzerland, CH-5001|
|Basel, Switzerland, 4031|
|Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli|
|Bellinzona, Switzerland, 6500|
|Bern, Switzerland, CH-3010|
|Chur, Switzerland, 7000|
|Freiburg, Switzerland, 1708|
|Hôpitaux Universitaires de Genève HUG|
|Geneva 14, Switzerland, 1211|
|Centre Hospitalier Universitaire Vaudois CHUV|
|Lausanne, Switzerland, CH-1011|
|Luzern, Switzerland, 6000|
|Muensterlingen, Switzerland, 8596|
|Männedorf, Switzerland, 8708|
|Kantonsspital St. Gallen|
|St. Gallen, Switzerland, 9007|
|SpitalSTS AG Simmental-Thun-Saanenland|
|Thun, Switzerland, 3600|
|Winterthur, Switzerland, 8401|
|Zurich, Switzerland, 8091|
|Study Chair:||Richard Cathomas, MD||Kantonsspital Graubünden|
|Study Chair:||Silke Gillessen, Prof||Cantonal Hospital of St. Gallen|