Clinical Trials /

Cabazitaxel in mCRPC Patients With AR-V7 Positive Circulating Tumor Cells (CTCs)

NCT03050866

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. 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.

Related Conditions:
  • Prostate Adenocarcinoma
  • Prostate Small Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabazitaxel in mCRPC Patients With AR-V7 Positive Circulating Tumor Cells (CTCs)
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: NL58639.056.16
  • NCT ID: NCT03050866

Conditions

  • Circulating Tumor Cell
  • Metastatic Prostate Cancer

Interventions

DrugSynonymsArms
CabazitaxelJevtanaTreatment

Purpose

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.

      Patients who are eligible to undergo second or third line treatment will be asked to undergo
      prescreening consisting of a CTC count and, in case ≥3 CTCs are detected, AR V7
      determination. Patients with ≥3 CTCs with AR-V7 expression will be asked to sign a second
      informed consent to enter the treatment study. In this study they will receive Cabazitaxel 25
      mg/m² every 3 weeks plus prednisone 10 mg daily, and undergo repeated blood sampling for
      biomarker sample collection.

      During the prescreening in all patients, 2 x 10 mL blood will be drawn for enumeration and
      isolation of CTCs. All patients with ≥3 CTCs with AR-V7 expression will be asked to sign
      consent for the treatment study.

      All patients included in the treatment study will be administrated cabazitaxel intravenously
      at a dose of 25 mg/m², during a one-hour infusion every 3 weeks, as well as continuous
      treatment with prednisone 5 mg orally twice daily, or 10 mg once daily. In the treatment
      study patients, an additional 2 x 10 mL blood will be drawn after the third cycle of
      treatment for CTC enumeration and isolation. An additional 10 mL blood will be drawn for
      storage of plasma at baseline and before start of every cycle (i.e., every 3 weeks) for
      analysis of cell-free DNA (cfDNA). Moreover, 4 x 5 mL blood (baseline; end of infusion, 2 and
      6 hours after end of the first cabazitaxel infusion) will be drawn for pharmacokinetic
      studies, in order to explore a cabazitaxel exposure effect relation.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentOtherTreatment intervention with Cabazitaxel with premedication as necessary (antihistamine, corticosteroid, H2 antagonist, antiemetic prophylaxis)
  • Cabazitaxel

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:PSA response
Time Frame:12 weeks after start of treatment
Safety Issue:
Description:The primary endpoint is PSA response, defined as a ≥50% PSA decline from baseline during therapy.

Secondary Outcome Measures

Measure:CTC response
Time Frame:9-12 weeks after start of treatment
Safety Issue:
Description:CTC response defined as a decrease from ≥5 CTCs per 7.5 mL blood at baseline to <5 CTCs per 7.5 mL blood
Measure:PSA change
Time Frame:12 weeks after start of treatment
Safety Issue:
Description:PSA change from baseline at 12 weeks defined as the percent change in PSA from baseline at 12 weeks, according to PCWG2 criteria
Measure:PSA decrease
Time Frame: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
Safety Issue:
Description:Maximum PSA decrease defined according to PCWG2 criteria
Measure:Progression free survival
Time Frame:Until end of study, which is anticipated to be 3 years after inclusion of first patient. If progression is not observed during the study, data on PFS will be censored
Safety Issue:
Description:Progression-free survival (PFS) defined as time from prescreening to the date of the first documentation of disease progression (PCWG2)
Measure:Overall survival
Time Frame:Until end of study, which is anticipated to be 3 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
Safety Issue:
Description:Overall survival (OS) calculated from the date of prescreening to death due to any cause
Measure:Adverse Events
Time Frame: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)
Safety Issue:
Description:Grade 3-4 adverse events (AEs) and serious adverse events (SAEs) during cabazitaxel according to CTCAE v4.03 in second and third-line treatment
Measure:Cumulative dose Cabazitaxel
Time Frame: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)
Safety Issue:
Description:Cumulative administered dose of cabazitaxel in second and third-line treatment
Measure:Splice variants
Time Frame: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.
Safety Issue:
Description:AR-V7 mRNA expression as well as mRNA expression of other splice variants in CTCs indicated as absent (─) or present (+)
Measure:Total systemic exposure
Time Frame:After infusion of first cycle of study treatment (Cabazitaxel)
Safety Issue:
Description:Cabazitaxel concentration in the blood and total systemic exposure to cabazitaxel, measured by the calculated area under the curve (AUC)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Erasmus Medical Center

Trial Keywords

  • Androgen Receptor
  • AR-V7
  • Predictive Factor

Last Updated

March 13, 2017