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Treatment intervention with Cabazitaxel with premedication as necessary (antihistamine, corticosteroid, H2 antagonist, antiemetic prophylaxis)

Cabazitaxel

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

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As intravenous premedication (dexamethasone 8 mg or equivalent)

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As intravenous premedication (ranitidine or equivalent)

H2 antagonist

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

Antiemetic

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.

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.

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

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)

Information can be shared by importing it into another databases

The primary endpoint is PSA response, defined as a ≥50% PSA decline from baseline during therapy.

CTC response defined as a decrease from ≥5 CTCs per 7.5 mL blood at baseline to \<5 CTCs per 7.5 mL blood

PSA change from baseline at 12 weeks defined as the percent change in PSA from baseline at 12 weeks, according to PCWG2 criteria

Maximum PSA decrease defined according to PCWG2 criteria

Progression-free survival (PFS) defined as time from prescreening to the date of the first documentation of disease progression (PCWG2)

Overall survival (OS) calculated from the date of prescreening to death due to any cause

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

Cumulative administered dose of cabazitaxel in second and third-line treatment

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

Cabazitaxel concentration in the blood and total systemic exposure to cabazitaxel, measured by the calculated area under the curve (AUC)

To explore the value of ctDNA quantification during cabazitaxel treatment to predict tumor progression

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Cabazitaxel in mCRPC Patients With AR-V7 Positive Circulating Tumor Cells (CTCs)	NCT03050866	Circulating Tum... Metastatic Pros...	Cabazitaxel Antihistamine Corticosteroid H2 antagonist Antiemetic	18 Years -	Erasmus Medical Center
Cabazitaxel in mCRPC Patients With AR-V7 Positive Circulating Tumor Cells (CTCs)	NCT03050866	Circulating Tum... Metastatic Pros...	Cabazitaxel Antihistamine Corticosteroid H2 antagonist Antiemetic	18 Years -	Erasmus Medical Center

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