Phase III Randomized Study of Cabazitaxel and Pelvic Radiotherapy in High-Risk Localized Prostate Cancer with Androgen Deprivation Therapy

Trial ID: 2024-517622-25-00
Sponsor: Unicancer

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Diseases & Conditions

Prostate cancer

Objectives

The primary objective of this study is to evaluate the effect of neoadjuvant **cabazitaxel** and pelvic radiotherapy in combination with androgen deprivation therapy (ADT) and radiotherapy on clinical progression-free survival in patients with high-risk localized prostate cancer. This is clinically relevant as it aims to improve outcomes in patients with at least two high-risk features of relapse, potentially offering a more effective treatment strategy for this patient population.

Secondary objectives include assessing:

Prostate-specific antigen response at 3 months
Biochemical progression-free survival
Metastases-free survival
Local relapse-free survival
Overall survival
Prostate cancer-specific survival
Acute toxicity
Impact of treatment on serum testosterone
Long-term toxicity, including toxicity related to radiotherapy
Predictive biomarkers of treatment efficacy
Quality of life

Participants

The clinical trial involves **male** participants aged between 18 and 75 years, diagnosed with localized **prostate cancer** exhibiting high-risk features of relapse. The sponsor has not provided the total number of participants. The study population was selected based on specific inclusion criteria, including histologically confirmed adenocarcinoma of the prostate, adequate platelet count, hemoglobin levels, hepatic and renal function, and an ECOG performance status of 0-1. Participants must have no clinically or radiologically suspected metastases and meet at least two high-risk criteria, such as a Gleason score of 8 or higher, T3 or T4 disease, or a prostate-specific antigen level of 20 ng/mL or greater. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use effective contraception if potentially reproductive. The trial excludes individuals with prior prostate cancer treatment, except for lymph node dissection or androgen deprivation therapy initiated up to six weeks before randomization. Participants are expected to have a life expectancy of more than 10 years and must be willing to comply with the study's scheduled visits and procedures.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **cabazitaxel** in combination with pelvic radiotherapy and androgen deprivation therapy (ADT) in patients with high-risk localized prostate cancer. This is a Phase III, randomized, double-blind, controlled trial utilizing a 2 by 2 factorial design. The primary objective is to assess the impact on clinical progression-free survival. The trial is expected to run from December 16, 2013, to July 16, 2041, with participant involvement lasting up to 3 years, depending on individual treatment response and progression.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed adenocarcinoma of the prostate, specific blood count and organ function parameters, and absence of metastases. Following randomization, participants will receive the investigational product, **JEVTANA 60 mg concentrate and solvent for solution for infusion**, administered intravenously. Follow-up visits will occur at regular intervals to monitor treatment response, assess prostate-specific antigen levels, and evaluate any acute or long-term toxicities using NCI-CTC v4.0 criteria. The end-of-study visit will conclude the participant's involvement, with assessments of overall survival and quality of life using the QLQ-C30 and PR25 questionnaires.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they are unable to comply with the study protocol. The trial will also assess secondary endpoints, including biochemical progression-free survival, metastases-free survival, and local relapse-free survival. The study aims to provide comprehensive data on the efficacy and safety of the treatment regimen, contributing to the understanding of therapeutic strategies for high-risk localized prostate cancer.

Treatment

The clinical trial involves the administration of **JEVTANA**, a pharmaceutical product containing the active substance **cabazitaxel**. JEVTANA is provided as a **concentrate and solvent for solution for infusion**. The pharmaceutical form is a **solution for infusion**, and it is administered via **intravenous use**. The dosage is calculated based on body surface area, with a maximum daily dose of 25 mg/m² and a total maximum dose of 95 mg/m². The treatment period is limited to a maximum of 3 cycles. JEVTANA is classified as an **antineoplastic agent** and is manufactured by Sanofi Winthrop Industrie. The active substance, cabazitaxel, is of chemical origin.

In addition to the experimental treatment with JEVTANA, the study includes standard-of-care therapy, which involves **androgen deprivation therapy (ADT)** combined with pelvic radiotherapy. This combination is used as a comparator treatment to assess the effect of neoadjuvant cabazitaxel and pelvic radiotherapy on clinical progression-free survival in patients with high-risk localized prostate cancer. The trial employs a 2 by 2 factorial design to evaluate the efficacy of these treatments. Participant compliance with the dosing schedule and treatment regimen is monitored throughout the study to ensure adherence to the protocol.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the calculation of prostate cancer-specific survival, measured from the date of randomization to the date of death due to prostate cancer. Secondary endpoints include several measures: the **prostate-specific antigen (PSA)** response at 3 months, defined as a serum PSA value of ≤ 0.2 ng/mL; biochemical progression-free survival, which is the time from randomization to PSA relapse or death; metastases-free survival, defined as the time from randomization to the appearance of metastases on imaging or death; and local relapse-free survival, which is the time from randomization to the first local relapse or death. Overall survival will also be calculated from the date of randomization to the date of death from any cause or the last follow-up date.

Additional assessments include the evaluation of acute toxicity during the treatment period according to NCI-CTC v4.0 criteria, and the impact of treatment on serum testosterone levels at baseline, 6 months, and then yearly. Long-term toxicity, including potency, cardiac issues, hot flashes, and late toxicity related to radiotherapy or chemotherapy, will be evaluated at 1 year, 2 years, and 5 years, with radiotherapy-related toxicity assessed using NCI-CTC v4.0 criteria. Predictive biomarkers of treatment efficacy will be assessed on archival biopsy specimens. Quality of life will be evaluated using the QLQ-C30 and PR25 questionnaires at baseline, 6 months, and then yearly up to 10 years after randomization.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Any T histologically confirmed adenocarcinoma of the prostate
No clinically or radiologically suspected metastases, including no enlarged pelvic lymph nodes (> 1 cm in small diameter)
Gleason score ≥ 6
Meets at least 2 of the following criteria for high-risk: - Gleason score ≥ 8 - T3 or T4 disease (T3 defined by MRI is acceptable) - Prostate-specific antigen equal or greater than 20 ng/mL
No prior treatment for prostate cancer except lymph node dissection (patients with pN- and pN+ disease can be accrued) or ADT (started up to 6 weeks before randomization).
18 years ≤ Age≤ 75 years
ECOG 0-1 performance status
Expected life expectancy of more than 10 years
Absolute neutrophil count ≥ 1.5 x 10^9/L
Platelets ≥ 100 x 10^9/L
Hb≥ 9.0 g/dL
Hepatic function: serum bilirubin ≤ 1 ULN (except in case of Gilbert's syndrome) ; AST and ALT ≤ 2.5 x ULN
Renal function (creatinine clearance using the CKD-EPI formula (Chronic Kidney Disease Epidemiology group, see Appendix 4) ≥ 60 mL/min).
Potentially reproductive patients must agree to use an effective contraceptive method while on treatment and for 6 months after the final dose of investigational product.
Patient must be affiliated to a Social Security System or should fulfill the country legislation for clinical trials.
Patient who have received the information sheet and signed the informed consent form.
Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures

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Exclusion Criteria

Patient with other known concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as: a- infection, b- cardiac disease such as uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within one year, LVEF > grade 2, c- uncontrolled diabetes mellitus, d- current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, stable chronic liver disease per investigator assessment), e- renal disease, f- active GI tract ulceration, malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with active, uncontrolled ulcerative colitis are also excluded, g- known severely impaired lung function (spirometry and DLCO 70% or less of normal and O2 saturation of 88% or less at rest on room air).
Other prior malignancy within the last 5 years, except basal cell skin cancer
Physical or psychological condition that would preclude study compliance
Hypersensitivity to cabazitaxel (hypersensitivity reaction ≥grade 3), to other taxanes, or to any excipients of the formulation including polysorbate 80
Patient with significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
Patient who received any other investigational drugs within the 30 days prior to the start of cabazitaxel.
Previous pelvic irradiation that make prostatic irradiation impossible
Severe GI disorders precluding pelvic irradiation
Patient already included in another therapeutic trial involving an experimental drug
Individual deprived of liberty or placed under the authority of a tutor.
Concomitant prohibited treatment. 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.