Sequencing of Radium-223 and Docetaxel in Symptomatic Bone-only Metastatic Castration-resistant Prostate Cancer (RAPSON)

Randomized, Multicentre Phase II Trial of the Sequencing of Radium-223 and Docetaxel Plus Prednisone in Symptomatic Bone-only Metastatic Castration-resistant Prostate Cancer (mCRPC)

Randomized, multicentre phase II trial of the sequencing of Radium-223 and Docetaxel plus prednisone in symptomatic bone-only metastatic castration-resistant prostate cancer (mCRPC)

Open-label, randomized phase II trial in patients with symptomatic bone-only metastatic castration-resistant prostate cancer. Eligible patients are randomly assigned into two arms:

• Arm A: radium-223 initially followed by docetaxel plus prednisone at the time of progression (the second step is optional according to clinical evolution of disease)
• Arm B: docetaxel plus prednisone initially followed by radium-223 at the time of progression (the second step is optional according to clinical evolution of disease).

Study Overview

• Status: Recruiting
• Conditions: Metastatic Castration-resistant Prostate Cancer
• Intervention / Treatment: Drug: Radium-223; Drug: Docetaxel

Detailed Description

Randomized, multicentre phase II trial of the sequencing of Radium-223 and Docetaxel plus prednisone in symptomatic bone-only metastatic castration-resistant prostate cancer (mCRPC) Primary objective: To determine the effects of sequential treatment between radium-223 and docetaxel on the percentage of symptomatic bone-only CRPC patients experiencing improvement or worsening in health-related quality of life (HRQoL) Secondary objective: To compare survival in patients treated with sequential therapy between radium-223 and docetaxel and to identify predictive factors of Radium-223 for clinical outcome (progression free survival and overall survival) in this patient population.

Study Treatment:

Radium-223: administered at the dose of 55 kBq per kg body weight, given at 4 week intervals for 6 injections, by slow intravenous injection.

Docetaxel: administered at the dose of 75 mg/m2 by intravenous infusion over a period of 1 hour every 3 weeks for 10 cycles. It is associated with prednisone 5 mg orally twice daily administered continuously.

Statistical methodology A responder analysis investigating treatment effects on percentage of patients experiencing meaningful HRQoL improvement/worsening on treatment will be conducted. When defining meaningful improvement/worsening, the upper limit of the minimally important difference (MID) range will be used. The MIDs for FACT-P total score and subscales that will be used in this study will be 10 and 3, respectively.

Patients experiencing a QoL increase >=MID from baseline at week 12 will be considered responders while patients experiencing a decrease in HRQoL score >=MID at this time point will be considered to have experienced worsening HRQoL.

According to primary endpoint, considering a type I error 0.10, type II error 0.20, proportion of responder patients in the standard arm 0.10 and in the experimental arm of 0.40, a total of 70 patients (35 for each arm) will be enrolled in the study. Chi-square tests will be used to test for an association between treatment and meaningful improvement (i.e. responder) or worsening in HRQoL.

According to secondary endpoints, PFS, TPFS and OS will be estimated by the Kaplan-Meier method. The treatment groups will be compared with a two-sided log rank test. All analyses will be done in the intention-to-treat population. For translational studies, we will conduct a prognostic and predictive factor analysis for time-to-event clinical outcomes using a univariate Cox model; significant factors subsequently will be included in a multivariable Cox regression model (cutoff p<0•05).

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Oriana Nanni; Phone Number: +390543739266; Email: oriana.nanni@irst.emr.it

Study Locations

• Italy
  • Aviano, Italy
    • Recruiting
    • UO Oncologia medica, IRCCS Centro di Riferimento Oncologico di Aviano
    • Principal Investigator: Lucia Fratino, MD
    • Sub-Investigator: Eugenio Borsatti, MD
  • Bolzano, Italy
    • Recruiting
    • IO Oncologia Medica, Ospedale Regionale Bolzano - Az. Sanitaria Alto Adige
    • Principal Investigator: Susanne Baier, MD
    • Sub-Investigator: Mohsen Farsad, MD
  • Genova, Italy
    • Not yet recruiting
    • IRCCS Ospedale Policlinico San Martino
    • Contact: Giuseppe Fornarini
  • Milano, Italy
    • Not yet recruiting
    • Istituto Europeo Di Oncologia
    • Contact: Franco Nole
  • Napoli, Italy
    • Terminated
    • INT di Napoli Fondazione "G. Pascale"
  • Parma, Italy
    • Recruiting
    • UO Oncologia Medica, Azienda Ospedaliera-Universitaria di Parma
    • Principal Investigator: Donatello Gasparro, MD
    • Sub-Investigator: Livia Ruffini, MD
  • Pisa, Italy
    • Recruiting
    • UO Oncologia Medica, AOU PISANA - Ospedale Santa Chiara
    • Principal Investigator: Luca Galli, MD
    • Sub-Investigator: Giuseppe Boni, MD
  • Reggio Emilia, Italy
    • Terminated
    • Azienda Ospedaliera Arcispedale S. Maria Nuova/IRCCA di Reggio Emilia
  • FC
    • Meldola, FC, Italy, 47014
      • Recruiting
      • UO Oncologia Medica, IRST IRCCS
      • Principal Investigator: Ugo De Giorgi, MD
      • Contact: Ugo de Giorgi, MD; Phone Number: 0543739100; Email: ugo.degiorgi@irst.emr.it
  • LE
    • Lecce, LE, Italy, 73100
      • Recruiting
      • U.O. Oncologia PO Vito Fazzi
      • Contact: Vincenzo Emanuele Chiuri
  • Milano
    • Rozzano, Milano, Italy, 20089
      • Recruiting
      • Irccs Istituto Clinico Humanitas
      • Contact: Paolo Andrea Zucali
  • PZ
    • Rionero in Vulture, PZ, Italy
      • Terminated
      • UO Oncologia Medica, C.R.O.B. - I.R.C.C.S
  • TN
    • Trento, TN, Italy, 38122
      • Recruiting
      • Ospedale S. Chiara - UO Oncologia Medica
      • Contact: Orazio Caffo
  • TO
    • Orbassano, TO, Italy, 10043
      • Recruiting
      • Oncologia Medica San Luigi Gonzaga
      • Contact: Consuelo Buttigliero
  • VR
    • Negrar, VR, Italy
      • Recruiting
      • Ospedale Sacro Cuore "Don Calabria"
      • Sub-Investigator: Matteo Salgarello, MD
      • Principal Investigator: Stefania Gori, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed adenocarcinoma of prostate
2. Two or more bone metastases confirmed by bone scintigraphy within 4 weeks prior to study entry
3. Symptomatic disease defined as regular use of opioid or non-opioid analgesic medication or treatment with external beam radiation therapy within the previous 12 weeks for cancer-related bone pain
4. Known castration-resistant disease, defined according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria as: castrate serum testosterone level: ≤50 ng/dL (≤1.7 nmol/L)
5. Subjects who have failed initial hormonal therapy, either by orchiectomy or by using a gonadotropin-releasing hormone (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

6. Progressive disease based on prostate-specific antigen (PSA) and/or radiographic PCWG3 criteria:

   • 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
   • or radiographic disease progression based on documented bone lesions by the appearance of two or more new lesions by bone scintigraphy
7. Patients who failed treatment with any Androgen deprivation therapy (ADT) abiraterone and/or enzalutamide for CRPC that must be terminated at least 4 weeks before study entry.
8. Male, aged ≥18 years.
9. Life expectancy of greater than 6 months.
10. Eastern Cooperative Oncology Group (ECOG) performance status≤2 .

11. Patients must have normal organ and marrow function as defined below:

    • leukocytes >3,000 x 10 9/L
    • absolute neutrophil count >1,500 x 10 9/L
    • platelets >100,000 x 10 9/L
    • total bilirubin within normal institutional limits
    • aspartate aminotransferase (AST/SGOT)/alanine aminotransferase (ALT/SGPT) <2.5 X institutional upper limit of normal
    • creatinine within normal institutional limits
12. 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", (2014_09_15 section 4.1) . 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 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.
13. No evidence (within 5 years) of prior malignancies (except successfully treated basal cell or squamous cell carcinoma of the skin).
14. Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

1. Patients who have had previous chemotherapy.
2. Patients who have had radiotherapy within 4 weeks prior to entering the study.
3. Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
4. Concurrent use of other anticancer agents or treatments, with the following exceptions: luteinizing hormone-releasing hormone (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.
5. 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.
6. Patients who received systemic radiotherapy (e.g. samarium, strontium etc.) for the treatment of bone metastases.
7. Patients who received blood transfusion or erythropoietin within the last 4 weeks prior to start of study treatment.
8. Patients who received prior treatment with Radium-223.
9. Patients with malignant lymphadenopathy exceeding 3 cm in short-axis diameter, or symptomatic nodal disease, i.e. scrotal, penile or leg edema.
10. 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).
11. 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.
12. Patients with imminent or established spinal cord compression based on clinical findings and/or magnetic resonance imaging.
13. Positive test for HIV

14. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm A; radium-223 initially followed by docetaxel plus prednisone at the time of progression (PD)	Drug: Radium-223; Radium-223: administered at the dose of 55 kBq per kg body weight, given at 4 week intervals for 6 injections, by slow intravenous injection; Drug: Docetaxel; Docetaxel: administered at the dose of 75 mg/m2 by intravenous infusion over a period of 1 hour every 3 weeks for 10 cycles. It is associated with prednisone 5 mg orally twice daily administered continuously.
Experimental: Treatment Arm B; docetaxel plus prednisone initially followed by radium-223 at the time of progression (PD)	Drug: Radium-223; Radium-223: administered at the dose of 55 kBq per kg body weight, given at 4 week intervals for 6 injections, by slow intravenous injection; Drug: Docetaxel; Docetaxel: administered at the dose of 75 mg/m2 by intravenous infusion over a period of 1 hour every 3 weeks for 10 cycles. It is associated with prednisone 5 mg orally twice daily administered continuously.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
health-related quality of life (HRQoL) clinical benefit	HRQoL clinical benefit, according to the Functional Assessment of Cancer Therapy-Prostate (FACT-P)	up to 36 months
health-related quality of life (HRQoL ) clinical benefit	HRQoL clinical benefit, according to Brief Pain Inventory-Short Form questionnaire (BPI) for bone pain intensity.	up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS defined as the duration of time from randomization to time of progression or death, whichever occurred earlier	up to 36 months
Total progression-free survival (TPFS)	TPFS defined as total PFS at the end of the therapeutic sequence	up to 36 months
Overall survival (OS)	OS defined as the time from randomization to the date of death due to any cause or the last date the patient was known to be alive	up to 36 months
toxic effects categorization for safety monitoring	evaluation of toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03	up to 36 months
Identification of markers predictive to clinical outcome	Identification of markers predictive to clinical outcome including: translational studies of circulating tumor DNA and/or circulating tumor cells and/or circulating RNA; serum chromogranin A and neuron specific enolase levels; positron emission tomography (PET) with choline and/or new tracer	up to 36 months

Collaborators and Investigators

• Sponsor: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
• Collaborators: Bayer
• Investigators: Study Director: Vincenza Conteduca, MD, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Via Maroncelli 40, 47014 Meldola, ITALY

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2017
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: July 24, 2017
• First Submitted That Met QC Criteria: July 25, 2017
• First Posted (Actual): July 26, 2017

Study Record Updates

• Last Update Posted (Actual): May 30, 2023
• Last Update Submitted That Met QC Criteria: May 26, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Docetaxel; prostate cancer; metastatic prostate cancer; castration-resistant prostate cancer; radium-223; bone only metastatic prostate cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Docetaxel
• Other Study ID Numbers: IRST185.04; 2016-004452-29 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No