Sequential Administration of Radium-223 and Docetaxel with Prednisone in Symptomatic Bone-Only Metastatic Castration-Resistant Prostate Cancer
- Trial ID
- 2024-511660-89-00
- Protocol
- IRST185.04
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized, multicentre phase II trial is to determine the effects of sequential treatment between **radium-223** and **docetaxel** on the percentage of patients with symptomatic bone-only metastatic castration-resistant prostate cancer (mCRPC) experiencing improvement or worsening in health-related quality of life (HRQoL). This is clinically relevant as it aims to assess the impact of treatment sequencing on patient well-being, which is a critical aspect of managing mCRPC.
Secondary objectives include:
- Comparing survival in patients treated with sequential therapy between **radium-223** and **docetaxel**.
- Identifying predictive factors of **radium-223** for clinical outcomes.
These secondary objectives are important for understanding the potential benefits of treatment sequencing and identifying factors that may influence patient response, thereby aiding in personalized treatment strategies for mCRPC.
Participants
The clinical trial focuses on **metastatic castration-resistant prostate cancer (mCRPC)**, specifically targeting patients with symptomatic bone-only mCRPC. The study population comprises exclusively male participants aged 18 years and older. The sponsor has not provided the total number of participants. Participants were selected based on specific criteria, including a confirmed diagnosis of adenocarcinoma of the prostate, a life expectancy greater than six months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. All participants are required to have normal organ and marrow function, and they must have two or more bone metastases confirmed by bone scintigraphy. Lifestyle considerations include the use of opioid or non-opioid analgesic medication or recent treatment with external beam radiation therapy for cancer-related bone pain. The trial excludes individuals with evidence of prior malignancies within the last five years, except for successfully treated basal cell or squamous cell carcinoma of the skin. Participants must have a known castration-resistant disease and have failed initial hormonal therapy. The trial does not include female subjects or vulnerable populations.
Plans and Procedures
The clinical trial is a **randomized**, multicenter, phase II study designed to evaluate the sequencing of **Radium-223** and **Docetaxel** plus **prednisone** in patients with symptomatic bone-only metastatic castration-resistant prostate cancer (mCRPC). The primary objective is to assess the effects of sequential treatment on the percentage of patients experiencing improvement or worsening in health-related quality of life (HRQoL). The trial is expected to run from August 2017 to November 2025, with participants involved for a maximum treatment period of 7 weeks, depending on the specific treatment arm and regimen.
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, life expectancy greater than 6 months, and normal organ and marrow function. Following randomization, participants will attend regular follow-up visits at each cycle of therapy to monitor HRQoL, progression-free survival, and overall survival. The end-of-study visit will occur at the conclusion of the treatment sequence, with additional follow-up assessments to evaluate long-term outcomes.
The trial employs a **double-blind** design to ensure unbiased results, with participants and investigators unaware of the treatment allocation. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study will also collect data on safety and potential predictive markers of clinical outcomes, including circulating tumor DNA and serum biomarkers. The trial's endpoints include HRQoL clinical benefit, progression-free survival, total progression-free survival, and overall survival, with assessments conducted at baseline, during treatment cycles, and at the end of treatment.
Treatment
The clinical trial involves the administration of **Docetaxel Accord**, a concentrate for solution for infusion, containing the active substance **docetaxel**. This pharmaceutical form is a solution for infusion, administered via injection. The dosage is calculated based on body surface area, with a maximum daily dose of 75 mg/m² and a total maximum dose of 150 mg. The treatment period is limited to 7 days. Docetaxel is classified as an antineoplastic agent and is not a paediatric formulation.
**Xofigo**, containing **radium Ra 223 dichloride**, is provided as a solution for injection. This radiopharmaceutical is administered intravenously, with a dosage of 55 kBq/kg per day and a total maximum dose of 6600 kBq. The treatment duration is up to 6 days. Xofigo is used in the context of this trial for its therapeutic properties in bone metastases.
**DELTACORTENE** tablets, containing **prednisone**, are administered orally. The maximum daily dose is 10 mg, with a total maximum dose of 2100 mg over a 7-day treatment period. Prednisone is utilized for its anti-inflammatory properties in this study.
**SOLDESAM** oral drops, containing **dexamethasone sodium phosphate**, are administered orally. The maximum daily dose is 24 mg, with a total maximum dose of 240 mg over a 7-day period. This formulation is used for its anti-inflammatory effects.
**Decadron** solution for injection, containing **dexamethasone phosphate**, is administered intravenously. The maximum daily dose is 24 mg, with a total maximum dose of 240 mg over a 7-day treatment period. Dexamethasone is included in the trial for its anti-inflammatory properties.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the effects of sequential treatment with these medications on health-related quality of life in patients with symptomatic bone-only metastatic castration-resistant prostate cancer.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the **Health-Related Quality of Life (HRQoL)** clinical benefit, which will be evaluated using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) and the Brief Pain Inventory-Short Form (BPI) questionnaire for bone pain intensity. These assessments will be conducted at baseline, during every cycle of therapy, at the end-of-treatment (EOT) visit, and during follow-up for both Step 1 and Step 2, across both arms of the trial.
Secondary endpoints include progression-free survival (PFS), total progression-free survival (TPFS), overall survival (OS), and safety. PFS is defined as the duration from randomization to the time of progression or death, whichever occurs first. TPFS is the total PFS at the end of the therapeutic sequence, while OS is the time from randomization to the date of death from any cause or the last date the patient was known to be alive. Safety assessments will be conducted throughout the trial.
Additionally, the trial will identify markers predictive of clinical outcomes through translational studies involving circulating tumor DNA, circulating tumor cells, circulating RNA, and germ line DNA. Blood samples will be collected at various timepoints, including at C1D1 for both steps and arms, before cycle 4 for Step 1 ARM A and Step 2 ARM B, before cycle 5 for Step 1 ARM B and Step 2 ARM A, at the EOT visit, and at 3 months of follow-up for both steps and arms. Serum chromogranin A and neuron-specific enolase levels will also be measured at these timepoints. Optional PET scans with choline or new tracers will be conducted at baseline, 4 weeks after C1D1, and at the EOT for Step 1.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must have histologically or cytologically confirmed adenocarcinoma of prostate
- Two or more bone metastases confirmed by bone scintigraphy within 8 weeks prior to randomization
- Symptomatic disease defined as regular use of opioid or nonopioid analgesic medication or treatment with external beam radiation therapy within the previous 12 weeks for cancer-related bone pain
- Known castration-resistant disease, defined according to PCWG3 criteria (59) as: castrate serum testosterone level: ≤50 ng/dL (≤1.7 nmol/L)
- Subjects who have failed initial hormonal therapy, either by orchiectomy or by using a GnRH agonist in combination with an anti-androgen, must first progress through antiandrogen withdrawal prior to being eligible. The minimum timeframe to document failure of anti-androgen withdrawal will be four weeks
- Progressive disease based on PSA and/or radiographic PCWG3 criteria: a. Serum PSA progression defined as two consecutive increases in PSA over a previous reference value within 6 months of first study treatment, each measurement at least one week apart. Serum PSA at screening ≥ 1ng/mL is the minimal starting value; b. or radiographic disease progression based on documented bone lesions by the appearance of two or more new lesions by bone scintigraph
- Patients who failed treatment with any ADT, abiraterone and/or enzalutamide for CRPC that must be terminated at least 4 weeks before C1D1
- Patients who received prior docetaxel for hormone-naïve prostate cancer should only be allowed if more than 2 years have been between the last administration of docetaxel and C1D1
- Male, aged ≥18 years
- Life expectancy of greater than 6 months
- ECOG performance status≤2
- Patients must have normal organ and marrow function as defined below: leukocytes >3,000/uL, absolute neutrophil count >1,500/uL, platelets >100,000/uL, total bilirubin within normal institutional limits, AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal, creatinine within normal institutional limits. In the presence of borderline values, the participating Centers will be able to discuss individual cases with the Coordinating Center.
- Male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 6 months after the last dose of radium-223 or docetaxel, according to guideline “Recommendation related to contraception and pregnancy testing in clinical trials”, (2020_09) (See Appendix F). Two acceptable methods of birth control thus include condom (barrier method of contraception) and one of the following is required (established use of oral, or injected or implanted hormonal method of contraception by the female partner; placement of an intrauterine device (IUD) or intrauterine IRST185.04 - RAPSON Pag. 25 of 83 Eme5.0_24.01.24 system (IUS) by the female partner; additional barrier method like occlusive cap with spermicidal foam/gel/film/cream/suppository in the female partner; tubal ligation in the female partner; vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy), for more than 6 months.
- No evidence (within 5 years) of prior malignancies (except successfully treated basal cell or squamous cell carcinoma of the skin)
- Participant is willing and able to give informed consent for participation in the study
Exclusion Criteria
- Patients who have had radiotherapy within 4 weeks prior to C1D1
- Patients with known visceral metastases
- Participation in another clinical trial with any investigational agents within 30 days prior to C1D1
- Concurrent use of other anticancer agents or treatments, with the following exceptions: LHRH agonists or antagonists, denosumab or bisphosphonate (eg, zoledronic acid). Ongoing treatment should be kept at a stable schedule; however, if medically required, a change of dose, compound, or both is allowed
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- Patients who received systemic radiotherapy (e.g. samarium, strontium etc.) for the treatment of bone metastases
- Patients who received blood transfusion or erythropoietin within the last 4 weeks prior to start of study treatment
- Patients who received prior treatment with Radium-223
- Patients with malignant lymphadenopathy exceeding 3 cm in short-axis diameter, or symptomatic nodal disease, i.e. scrotal, penile or leg edema
- Other primary tumor (other than CRPC) including hematological malignancy present within the last 5 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)
- Maintenance treatment with corticosteroids corresponding to a prednisolone or prednisone dose above 10 mg/day. The dose must have been stable for at least 5 days
- Patients with imminent or established spinal cord compression based on clinical findings and/or magnetic resonance imaging
- Positive test for HIV in case of known positivity to human immunodeficiency virus (HIV)
- Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 Aug 2017 | 70 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Xofigo 1100 kBq/mL solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS INJECTION | 55 | 6 | PRD970869 |
DELTACORTENE 5 mg compresse | Test | COMPRESSE | ORAL | 10 | 7 | PRD349595 |
Decadron “4 mg/1 ml Soluzione iniettabile” | Test | SOLUZIONE INIETTABILE | INTRAVENOUS USE | 24 | 7 | PRD7535050 |
Docetaxel Accord 20 mg/1 ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INJECTION | 75 | 7 | PRD3445550 |
SOLDESAM 0,2% gocce orali, soluzione | Test | GOCCE ORALI, SOLUZIONE | ORAL USE | 24 | 7 | PRD362173 |