Non-randomized Phase 2 Open-label Multicenter Study Determining the Response to Cabazitaxel in Metastatic Prostate Cancer (mCRPC) Patients With AR-V7 Positive Circulating Tumor Cells (CTCs): CARVE
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Prostate specific antigen (PSA) response rate
研究概览
简要总结
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.
详细描述
Rationale: 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 mRNA expression in CTCs was shown to be associated with lack of response to AR-targeted therapy. AR-V7 mRNA expression does not seem to hinder response to cabazitaxel in the investigator's retrospective pilot study nor in a recently published small retrospective study.
Therefore the investigators hypothesize that the mRNA expression of AR-V7 in CTCs assessed before start of second-line treatment for mCRPC does not affect PSA response rate to cabazitaxel in patients who have progressed to docetaxel.
Objective: The primary objective of this study is to explore the PSA response rate to cabazitaxel in mCRPC patients who have progressed to docetaxel and have detectable AR-V7 expression in CTCs. Exploratory objectives include documenting the PSA response to cabazitaxel after enzalutamide or abiraterone treatment in initially AR-V7 negative patients, describing the toxicity of cabazitaxel in second and third-line treatment as well as exploring if response measured by CTC counts and PSA is related to systemic cabazitaxel exposure.
Study design: This is a multicenter, non-randomized phase 2 study. Patients will be allocated to one of the following treatment groups according to the results of CTC enumeration and characterization in the screening phase:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.
- •Continued androgen deprivation therapy either by LHRH agonists/antagonists or orchiectomy.
- •Serum testosterone <50 ng/mL (1.7 nmol/L) within 21 days before treatment group allocation.
- •Age ≥18 years
- •Disease progression during or after treatment with docetaxel. Disease progression for study entry is defined as one or more of the following criteria:
- •PSA progression defined by at least 2 consecutive PSA rises over a reference value, with an interval of ≥ 1 week between each determination. PSA at screening visit should be ≥ 2.0 μg/l.
- •Bone disease progression defined by the appearance of new lesions on a bone scan, confirmed on a second bone scan ≥ 6 weeks later.
- •Soft tissue disease progression defined by modified RECIST criteria 1.1 (baseline LN size must be ≥ 2.0 cm to be considered target or evaluable lesion) (15)
- •ECOG performance status 0-2 (appendix A)
- •Written informed consent according to ICH-GCP before study treatment and any study specific procedures
排除标准
- •Impossibility or unwillingness to take oral drugs
- •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 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
- •Successive 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) (see Appendix C)
- •Concomitant vaccination with yellow fever vaccine
- •Abnormal liver functions consisting of any of the following (within 21 days before treatment group allocation):
- •Total bilirubin > 1.5 x ULN (except for patients with documented Gilbert's disease)
- •If total bilirubin > 1 x ULN or AST > 1.5 x ULN inclusion is permitted but cabazitaxel dose should be reduced 20mg/m2
- •Abnormal hematological blood counts consisting of any of the following (within 21 days before treatment group allocation):
- •Absolute neutrophil count < 1.5 x 109/L
- •Platelets < 100 x 109/L
- •Hemoglobin < 6.2 mmol/L
研究组 & 干预措施
B
patients with AR-V7 positive CTCs are treated with cabazitaxel 25mg/m2 q3w
干预措施: cabazitaxel (Drug)
结局指标
主要结局
Prostate specific antigen (PSA) response rate
时间窗: 12 weeks after start of treatment
PSA response rate is defined as a reduction of at least 50% from baseline during therapy, confirmed after ≥4 weeks by an additional PSA evaluation.
次要结局
- Circulating tumor cell (CTC) response rate(9 weeks after start of treatment)
- Prostate specific antigen (PSA) change from baseline(12 weeks after start of treatment)
- Maximum Prostate specific antigen (PSA) decrease(through study completion, an average of two years)
- Progression-free survival(from date of treatment allocation until the date of first documented progression (see description) or date of death from any cause, whichever came first, assessed through study completion, up to 100 months)
- Overall survival(time from treatment group allocation to death due to any cause, assessed through study completion, up to 100 months)
- grade 3-4 adverse events and serious adverse events (SAEs)(through study treatment until 30 days after end of treatment)
- Cabazitaxel concentration in the blood (measured in ng/mL)(during the first cycle of cabazitaxel, until 6 hours after end of cabazitaxel infusion)
- Total systemic exposure to cabazitaxel (measured in mg/m2)(through study treatment, an average of 10 cycles, i.e., 30 weeks of treatment)
- AR-V7 mRNA expression as well as mRNA expression of other splice variants in CTCs indicated as absent (-) or present (+) on a per-patient basis(at screening visit)
研究者
M.P.J.K. Lolkema
oncologist
Erasmus Medical Center