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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03050866
Recruitment Status : Recruiting
First Posted : February 13, 2017
Last Update Posted : July 5, 2019
Information provided by (Responsible Party):
M.P.J.K. Lolkema, Erasmus Medical Center

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.

Condition or disease Intervention/treatment Phase
Circulating Tumor Cell Metastatic Prostate Cancer Drug: Cabazitaxel Other: Antihistamine Other: Corticosteroid Other: H2 antagonist Other: Antiemetic Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
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)
Actual Study Start Date : February 21, 2017
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer
Drug Information available for: Cabazitaxel

Arm Intervention/treatment
Treatment intervention with Cabazitaxel with premedication as necessary (antihistamine, corticosteroid, H2 antagonist, antiemetic prophylaxis)
Drug: Cabazitaxel
25mg/m2 q3w
Other Name: Jevtana

Other: Antihistamine
As intravenous premedication (dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or equivalent)

Other: Corticosteroid
As intravenous premedication (dexamethasone 8 mg or equivalent)

Other: H2 antagonist
As intravenous premedication (ranitidine or equivalent)
Other Name: histamine H2 receptors blockers

Other: Antiemetic
Antiemetic prophylaxis is recommended and can be given orally or intravenously if necessary

Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. CTC response [ Time Frame: 9-12 weeks after start of treatment ]
    CTC response defined as a decrease from ≥5 CTCs per 7.5 mL blood at baseline to <5 CTCs per 7.5 mL blood

  2. PSA change [ Time Frame: 12 weeks after start of treatment ]
    PSA change from baseline at 12 weeks defined as the percent change in PSA from baseline at 12 weeks, according to PCWG2 criteria

  3. 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 ]
    Maximum PSA decrease defined according to PCWG2 criteria

  4. Progression free survival [ Time Frame: 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 ]
    Progression-free survival (PFS) defined as time from prescreening to the date of the first documentation of disease progression (PCWG2)

  5. Overall survival [ Time Frame: 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 ]
    Overall survival (OS) calculated from the date of prescreening to death due to any cause

  6. 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) ]
    Grade 3-4 adverse events (AEs) and serious adverse events (SAEs) during cabazitaxel according to CTCAE v4.03 in second and third-line treatment

  7. 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) ]
    Cumulative administered dose of cabazitaxel in second and third-line treatment

  8. 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. ]
    AR-V7 mRNA expression as well as mRNA expression of other splice variants in CTCs indicated as absent (-) or present (+)

  9. Total systemic exposure [ Time Frame: After infusion of first cycle of study treatment (Cabazitaxel) ]
    Cabazitaxel concentration in the blood and total systemic exposure to cabazitaxel, measured by the calculated area under the curve (AUC)

  10. Value ctDNA quantification [ Time Frame: Until end of study, which is anticipated to be 4 years after inclusion of first patient ]
    To explore the value of ctDNA quantification during cabazitaxel treatment to predict tumor progression

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03050866

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Contact: Ilse Oosterom 0107032570
Contact: Soumia Aammari 0107042129

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Reinier de Graaf Groep Recruiting
Delft, Netherlands
Contact: A.C.M. Van de Luijtgaarden, MD         
Principal Investigator: A.C.M. Van de Luijtgaarden, MD         
Medisch Centrum Haaglanden Recruiting
Den Haag, Netherlands
Contact: H. Helgason, MD         
Principal Investigator: H Helgason, MD         
Groene Hart Ziekenhuis Recruiting
Gouda, Netherlands
Contact: W. Van der Deure, MD         
Principal Investigator: W Van der Deure, MD         
Canisius Wilhelmina Ziekenhuis Recruiting
Nijmegen, Netherlands
Contact: R. Somford, MD         
Principal Investigator: R. Somford, MD         
Erasmus MC Recruiting
Rotterdam, Netherlands
Contact: Bodine Belderbos   
Franciscus Gasthuis en Vlietland Recruiting
Rotterdam, Netherlands
Contact: Paul Hamberg         
Maasstad Ziekenhuis Recruiting
Rotterdam, Netherlands
Contact: B. Haberkorn, MD         
Principal Investigator: B. Haberkorn, MD         
Tweesteden Ziekenhuid Recruiting
Tilburg, Netherlands
Contact: A. Coumou, MD         
Principal Investigator: A Coumou, MD         
Admiraal de Ruyter Ziekenhuis Recruiting
Vlissingen, Netherlands
Contact: H.K. Van Halteren, MD         
Principal Investigator: H.K. Van Halteren, MD         
Sponsors and Collaborators
Erasmus Medical Center
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Responsible Party: M.P.J.K. Lolkema, Dr., Erasmus Medical Center Identifier: NCT03050866    
Other Study ID Numbers: NL58639.056.16
First Posted: February 13, 2017    Key Record Dates
Last Update Posted: July 5, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Information can be shared by importing it into another databases

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by M.P.J.K. Lolkema, Erasmus Medical Center:
Androgen Receptor
Predictive Factor
Additional relevant MeSH terms:
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Prostatic Neoplasms
Neoplastic Cells, Circulating
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Prostatic Diseases
Neoplasm Metastasis
Neoplastic Processes
Pathologic Processes
Histamine Antagonists
Histamine H1 Antagonists
Histamine Agonists
Histamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents