A Single Arm Phase 2 Multicenter Study Determining the Response to Cabazitaxel in Metastatic Prostate Cancer (mCRPC) Patients With AR-V7 Positive Circulating Tumor Cells (CTCs)
Trial Snapshot
- Phase
- Phase 2
- Sponsor
- Erasmus Medical Center
- Enrollment
- 140
- Locations
- 9
- Primary Endpoint
- PSA response
Study Overview
Brief Summary
After failure on docetaxel, which has been the standard first line therapy for patients with metastatic castration-resistant prostate cancer (mCRPC), several treatment options are currently available.
In retrospective studies, resistance has been described to two of the treatment options, enzalutamide and abiraterone, when a splice variant of the Androgen Receptor (AR-V7) is present on circulating tumor cells (CTCs). The investigators hypothesize that patients with AR-V7 positive CTCs do have a meaningful response to cabazitaxel.
Detailed Description
After failure on docetaxel, which has been the standard first line therapy for patients with metastatic castration-resistant prostate cancer (mCRPC), several treatment options are currently available.
Two of the treatment options are directed against the androgen receptor (AR), enzalutamide and abiraterone. A third option is cabazitaxel, a next generation taxane. No head-to-head comparisons have been done for these three therapies in second-line mCRPC and as of yet, the optimal choice is unknown.
Resistance to the AR-targeted therapies is at least in part a consequence of signaling through constitutively active AR splice variants (AR-Vs). Because AR splice variants only occur after conversion to a castration-resistant tumor, and can be acquired during systemic therapy for mCRPC, analysis of the castration-naïve primary tumor is not informative in the setting of second-line treatment of mCRPC.
Circulating tumor cells (CTCs) can be analyzed repetitively and in real-time. Recently, AR-V7 messenger ribonucleid acid (mRNA) expression in CTCs was shown to be associated with lack of response to AR-targeted therapy (reference 1). AR-V7 mRNA expression does not seem to hinder response to cabazitaxel in our retrospective pilot study (reference 2) nor in two recently published retrospective studies (reference 3 and reference 4).
Therefore we hypothesize that the mRNA expression of AR-V7 in CTCs assessed before start of second-line treatment for mCRPC does not affect prostate-specific antigen (PSA) response to cabazitaxel in patients who have progressed to docetaxel.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Diagnostic
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.
- •Continued androgen deprivation therapy either by luteinizing hormone-releasing hormone (LHRH) agonists/antagonists or orchiectomy.
- •Serum testosterone <50 ng/mL (1.7 nmol/L) within 21 days before prescreening.
- •Age ≥18 years
- •Received prior docetaxel, and experienced disease progression during or after treatment with docetaxel.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (appendix A)
- •Written informed consent according to ICH-GCP (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical Practice) before study treatment and any study specific procedures
Exclusion Criteria
- •Geographical, psychological or other non-medical conditions interfering with follow-up
- •Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus or active systemic or local bacterial, viral, fungal - or yeast infection)
- •Symptomatic central nervous system (CNS) metastases or history of psychiatric disorder that would prohibit the understanding and giving of informed consent.
- •Chemotherapy or immunotherapy (other than LHRH analogues) within the last 4 weeks before study inclusion.
- •Prior treatment with cabazitaxel
- •Treatment with both abiraterone and enzalutamide in the post-docetaxel setting
- •Radiotherapy to 40% or more of the bone marrow
- •Known hypersensitivity to corticosteroids
- •History of severe hypersensitivity reaction (≥grade 3) to docetaxel
- •History of severe hypersensitivity reaction (≥grade 3) to polysorbate 80 containing drugs
- •Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments)
- •Concomitant vaccination with yellow fever vaccine
- •Abnormal liver functions
- •Abnormal hematological blood counts
Arms & Interventions
Treatment
Treatment intervention with Cabazitaxel with premedication as necessary (antihistamine, corticosteroid, H2 antagonist, antiemetic prophylaxis)
Intervention: Cabazitaxel (Drug)
Treatment
Treatment intervention with Cabazitaxel with premedication as necessary (antihistamine, corticosteroid, H2 antagonist, antiemetic prophylaxis)
Intervention: Antihistamine (Other)
Treatment
Treatment intervention with Cabazitaxel with premedication as necessary (antihistamine, corticosteroid, H2 antagonist, antiemetic prophylaxis)
Intervention: Corticosteroid (Other)
Treatment
Treatment intervention with Cabazitaxel with premedication as necessary (antihistamine, corticosteroid, H2 antagonist, antiemetic prophylaxis)
Intervention: H2 antagonist (Other)
Treatment
Treatment intervention with Cabazitaxel with premedication as necessary (antihistamine, corticosteroid, H2 antagonist, antiemetic prophylaxis)
Intervention: Antiemetic (Other)
Outcomes
Primary Outcomes
PSA response
Time Frame: 12 weeks after start of treatment
The primary endpoint is PSA response, defined as a ≥50% PSA decline from baseline during therapy.
Secondary Outcomes
- CTC response(9-12 weeks after start of treatment)
- Cumulative dose Cabazitaxel(Until last day of administration of study medication (Cabazitaxel), Cabazitaxel treatment will consist of a maximum 10 cycles Cabazitaxel (given once every 3 weeks if there are no delays))
- Splice variants(Splice variant will be compared before and after cabazitaxel treatment in AR-V7 positive patients, as well as before start of enzalutamide or abiraterone and after disease progression to this treatment.)
- Total systemic exposure(After infusion of first cycle of study treatment (Cabazitaxel))
- PSA decrease(PSA will be assessed at baseline, every 3 weeks during study treatment (before every cycle), and in case of study treatment discontinuation without progression every 3 months until progression, death, whichever comes first)
- Progression free survival(Until end of study, which is anticipated to be 4 years after inclusion of first patient. If progression is not observed during the study, data on PFS will be censored)
- Value ctDNA quantification(Until end of study, which is anticipated to be 4 years after inclusion of first patient)
- Adverse Events(Until 30 days after end of treatment, Cabazitaxel treatment will consist of a maximum 10 cycles Cabazitaxel (given once every 3 weeks if there are no delays))
- PSA change(12 weeks after start of treatment)
- Overall survival(Until end of study, which is anticipated to be 4 years after inclusion of first patient. If death is not observed during the study, data on OS will be censored at the date patient is known to be alive or at the cut-off date, whichever comes first)
Investigators
M.P.J.K. Lolkema
Dr.
Erasmus Medical Center