CABAzitaxel With or Without Prednisone in Patients With Metastatic CAstration REsistant Prostate Cancer Progressed During or After a Previous Docetaxel-based Chemotherapy

Prostate Cancer Clinical Trial

Official title: CABAzitaxel With or Without Prednisone in Patients With Metastatic CAstration REsistant Prostate Cancer (mCRPC) Progressed During or After a Previous Docetaxel-based Chemotherapy:a Multi-center,Prospective,Two-arm, Open Label, Non Inferiority Phase II Study

Status Enrolling by invitation

Clinical Trial Summary

Patients with metastatic castration resistant prostate cancer (mCRPC) progressed during or after a previous docetaxel-based chemotherapy, for whom cabazitaxel has been scheduled as per clinical practice and label indication.

In the "TROPIC" Trial, cabazitaxel, administered concomitantly with prednisone 10 mg daily, showed a significant advantage vs. mitoxantrone in both Overall Survival (OS) and Progression Free Survival (PFS) / radiographic PFS in patients failing docetaxel-based chemotherapy. Similar to docetaxel, cabazitaxel has been approved in combination with daily prednisone, but the benefits of adding daily corticosteroids to taxane chemotherapy remain to be proven. In fact, corticosteroids have a variety of biological effects, and a number of studies in large cohorts of patients show that they may have both favourable effects, mediated by adrenal androgen and cytokine suppression, and detrimental effects related to their adverse events associated with their long-term use as well to the potential promiscuous activation of the AR. In fact, prednisone and dexamethasone can activate some AR variants that make tumors sensitive to glucocorticoids even at low concentrations. It has been showed that point mutations of the AR, which appear to cluster in the ligand-binding domain, are rare in therapy naive patients but occur in 15- 45% of patients with castration-resistant disease and can increase AR affinity for a wide range of steroids. On the other hand, insofar as safety is concerned, omitting daily corticosteroids does not seem to increase toxicity (e.g. hypersensitivity reactions). In fact, in the CHARTEED trial, docetaxel was safely administered without daily corticosteroids. Safety data about the use of cabazitaxel without daily prednisone/prednisone alone are missing.

The CABACARE study is designed to assess the effects in terms of efficacy, safety as well as quality of life of omitting daily corticosteroids in patients treated with cabazitaxel. Furthermore, the CABACARE study evaluates the mutational status of the RB gene as well as presence of AR-V7 variant. The AR-V7 status assessed in circulating tumor cells has a strong predictive value for abiraterone/enzalutamide effectiveness, but its role in patients receiving cabazitaxel requires to be defined.

Clinical Trial Description

Patients will be randomly assigned (1:1) to receive either:

Arm A Cabazitaxel 25 mg/m² intravenously (Day 1) every 3 weeks, plus prednisone 10 mg orally given daily. Premedication must be administered according to Cabazitaxel Package Insert.

Arm B Cabazitaxel 25 mg/m² intravenously (Day 1) every 3 weeks, without daily prednisone. Premedication must be administered according to Cabazitaxel Package Insert.

Each patient will be treated until radiological disease progression, unacceptable toxicity, or patient refusal. Patients will be followed through subsequent therapy lines of treatments until death or the study cut-off, whichever comes first.

Every effort will be made to administer the full dose regimen to maximize dose-intensity.

Dose reduction and/or treatment delay and/or treatment discontinuation are planned in case of severe toxicity. If toxicity occurs, dose of Cabazitaxel can be reduced to 20 mg/mq in both arms. If a second dose reduction is required the patient should be withdrawn from study.

Prednisone doses should not be delayed or modified or stopped (unless there is a contraindication to continue, the decision will be let to the investigator's discretion).

In case a dose reduction is required, cabazitaxel dose cannot be re-escalated. Prophylactic use of G-CSF is allowed, as per EORTC / ASCO guidelines and according to physician judgment. Patients experiencing neutropenia G 3-4 have to receive G-CSF in prophylaxis in subsequent cycles.

Primary Objective(s)

To evaluate whether cabazitaxel alone is non inferior in terms of radiographic PFS with respect to cabazitaxel plus daily prednisone in patients with castration resistant prostate cancer

Secondary Objective(s)

Safety in the two treatment arms; Health-Related Quality of Life (HRQL) and pain; Objective Response Rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST 1.1); Biochemical response (assessed considering PSA decrease ≥50% and waterfall plot results); Time to PSA Progression (TTPP); Radiographic Time to Progression (rTTP); Overall Survival (OS); Association of Overall

l Survival (OS), Progression Free Survival (PFS) and Objective Response Rate (ORR) with AR-V7 and RB status in circulating tumor cells assessed at flow-cytometry; Time to Skeletal-Related Event (SRE);

Primary end Point

Radiographic Progression-Free Survival (rPFS).

Secondary end points

Safety in the two treatment arms; Health-Related Quality of Life HRQL and pain; Objective Response Rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST 1.1); Biochemical response (PSA decrease ≥50%, waterfall plot); Time to PSA Progression (TTPP); Radiographic Time To Progression (rTTP); Overall Survival (OS); Association of Overall Survival (OS), Progression Free Survival (PFS) and Objective Response Rate (ORR) with AR-V7 and RB status in circulating tumor cells by the use of a DNA test; Time to Skeletal-Related Event (SRE). ;

Related Conditions & MeSH terms

• Castration-resistant Prostate Cancer
• Prostate Cancer
• Prostatic Neoplasms

• NCT number: NCT03356912
• Study type: Interventional
• Source: Consorzio Oncotech
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: November 22, 2017
• Completion date: May 4, 2021