Phase III Comparative Study of Docetaxel Versus Docetaxel Plus Radium-223 Dichloride in Metastatic Castration-Resistant Prostate Cancer

Trial ID: 2024-513867-19-00
Protocol: c16-174
Sponsor: Memorial Sloan Kettering Cancer Center

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Diseases & Conditions

Hormone-refractory prostate cancer

Objectives

The primary objective of the DORA Trial is to **compare overall survival** in subjects with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel versus those treated with a combination of docetaxel and Radium-223. This comparison is clinically significant as it aims to determine the efficacy of adding Radium-223 to the standard docetaxel treatment regimen, potentially improving survival outcomes for patients with mCRPC.

Secondary objectives include: - Comparing radiographic progression-free survival (PFS) as defined by the Prostate Cancer Working Group 3 (PCWG3) criteria. - Evaluating symptomatic skeletal event (SSE) free survival. - Assessing time to total alkaline phosphatase (ALP) progression. - Analyzing on-treatment alterations in quality of life (QOL) using FACT-P, BPI, and BFI measures between the two treatment groups. - Determining the incidence of febrile neutropenia in subjects treated with docetaxel plus Radium-223. - Investigating treatment discontinuation rates in subjects on their fourth line of therapy.

Participants

The clinical trial involves a total of **453 male participants** diagnosed with **metastatic Castration-Resistant Prostate Cancer (mCRPC)**. The study population consists of males aged 18 years and above, with a requirement for histological or cytological proof of prostate cancer. Participants were selected based on documented progressive mCRPC, evidenced by criteria such as PSA progression, soft-tissue progression, or progression of bone disease. All participants are required to have an ECOG performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial excludes female subjects and does not involve a vulnerable population. Participants must have normal organ function and acceptable laboratory values prior to randomization. Lifestyle considerations include the use of medically acceptable birth control methods or sexual abstinence during the study and for six months after the last dose of the study drug. The trial aims to compare overall survival between subjects treated with docetaxel alone and those treated with docetaxel plus Radium-223.

Plans and Procedures

The clinical trial is designed to evaluate the **overall survival** of subjects with **metastatic castration-resistant prostate cancer (mCRPC)** treated with docetaxel alone versus docetaxel in combination with **radium Ra 223 dichloride**. This is a Phase III, randomized, double-blind, controlled trial. The trial is expected to run from October 2019 to October 2026, with the primary objective of comparing overall survival between the two treatment groups. Participants will be randomly assigned to receive either docetaxel alone or in combination with radium Ra 223 dichloride, administered via **intravenous administration**.

The study involves several key visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as documented progressive mCRPC and normal organ function. Participants must provide informed consent and meet all inclusion criteria, including a histological or cytological proof of prostate cancer and an ECOG performance status of 0 or 1. Follow-up visits will occur regularly to monitor treatment effects, adverse events, and compliance with the protocol. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment.

Participant involvement is expected to last for the duration of the treatment period, which is a maximum of 31 weeks, plus additional follow-up visits. Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, withdrawal of consent, or non-compliance with the study protocol. The primary endpoint of the trial is the comparison of overall survival between the treatment groups, evaluated using a stratified logrank test. Secondary endpoints include time to event analyses, such as time to first skeletal-related event and time to alkaline phosphatase progression, as well as quality of life assessments and treatment discontinuation rates.

Treatment

The clinical trial involves the administration of **Xofigo**, a **solution for injection** containing **radium Ra 223 dichloride** as the active substance. This experimental medication is provided in a concentration of 1100 kBq/mL and is administered via **intravenous administration**. The dosing regimen specifies a maximum daily dose of 55 kBq/kg, with a total maximum dose of 330 kBq/kg over a treatment period not exceeding 31 days. The pharmaceutical form is a solution for injection, and the medication is chemically synthesized. The administration of Xofigo is conducted under controlled conditions to ensure participant safety and adherence to the dosing schedule.

In addition to the experimental treatment, the study includes a comparator treatment with **docetaxel**, a standard-of-care therapy for **metastatic castration-resistant prostate cancer (mCRPC)**. Docetaxel is administered according to established clinical guidelines, serving as a reference to evaluate the efficacy of the combination therapy with radium-223. The trial aims to compare overall survival between subjects receiving docetaxel alone and those receiving the combination of docetaxel and radium-223. Participant compliance with the treatment regimen is monitored through regular assessments and documentation of dosing adherence.

Efficacy

Efficacy in the clinical trial titled "DORA Trial: Phase III Trial of Docetaxel vs. Docetaxel and Radium-223 for Metastatic Castration-Resistant Prostate Cancer (mCRPC)" will be assessed through several primary and secondary endpoints. The primary endpoint is the comparison of overall survival (OS) between the treatment groups, which will be evaluated at each interim analysis and the final analysis using the stratified logrank test. Stratification factors include prior docetaxel for castration-sensitive disease and the presence or absence of visceral disease.

Secondary endpoints include time to event endpoints such as SSE-free survival and radiographic progression-free survival (PFS), which will also be analyzed using a stratified logrank test. Kaplan-Meier estimates will be computed for these endpoints. The cumulative incidence function will be used to compute probabilities for the time to first skeletal-related event and the time to alkaline phosphatase (ALP) progression. Total ALP response will be compared between treatment groups using a CMH test, adjusting for randomization strata. Descriptive statistics will summarize the time to maximum percentage post-therapy decrease in prostate-specific antigen (PSA) and the maximum percentage decrease in PSA.

Longitudinal kernel smoothing methods will estimate trajectories of PSA, bone markers, bone scan index (BSI), circulating tumor cells (CTC), and circulating tumor DNA (ctDNA) over time, with joint modeling used to evaluate these trajectories concerning OS. Patient-reported outcomes (PROs) will include scores from quality of life (QOL) questionnaires: FACT-P, BPI, and BFI. These will be administered at baseline, week 19, safety follow-up, and follow-up visits every three months for one year from the last dose of either study drug. The area under the curve (AUC) for these scores will be derived and compared between treatments. Additionally, the number and percentage of febrile neutropenia in subjects treated with docetaxel plus Radium-223 and the percentage of treatment discontinuation in subjects on their fourth line of therapy will be calculated by treatment arm and total.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Willing and able to provide, or have a legally authorized representative provide, written informed consent (ICF) and HIPAA authorization for the release of personal health information. A signed ICF must be obtained before screening procedures are performed. NOTE: HIPAA authorization may be either included in the ICF or obtained separately
Males 18 years of age and abov
Histological or cytological proof of prostate cancer
Documented progressive mCRPC based on at least one of the following criteria: a) PSA progression defined as a minimum of 2 rising PSA levels with a minimum of a 1 week interval between each determination. A minimum PSA of 1.0 ng/mL is required for study entry. b) Soft-tissue progression defined as an increase ≥ 20% in the sum of the longest diameter (LD) of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions. c) Progression of bone disease (evaluable disease) by two or more new bone lesions by bone scan
Two or more bone lesions defined by nuclear bone scan
ECOG of 0 or 1 (Appendix A: Performance Status Criteria)
Normal organ function with acceptable initial laboratory values within 14 days of randomization
Subjects must agree to use a medically acceptable method of birth control (e.g., spermicide in conjunction with a barrier such as a condom) or sexual abstinence for the duration of the study, including 6 months after the last dose of study drug. Sperm donation is prohibited during the study and for 6 months after the last dose of study drug. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent
Serum testosterone < 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy
All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less
Willing and able to comply with the protocol, including follow-up visits and examinations

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Exclusion Criteria

Received any other investigational therapeutic agents or other anticancer therapies within 2 weeks or 5 half-lives, whichever is shorter, prior to randomization. Note: If this requirement to have a washout of 2 weeks or 5 half-lives prior to randomization causes potential treatment delay due to Radium-223 importation timelines, the PCCTC must be contacted to request approval to randomize the subject prior to the completion of the washout. Requests for early randomization must be accompanied by written assurance by the site that the washout will be completed prior to treatment start.
Received external beam radiotherapy (EBRT) within the 2 weeks prior to randomization. Note: If prolonging randomization to complete EBRT washout causes potential treatment delay due to Radium-223 importation timelines, the PCCTC must be contacted to request approval to randomize the subject prior to the completion of the washout. Requests for early randomization must be accompanied by written assurance by the site that the washout will be completed prior to treatment start
Has an immediate need for EBRT.
Has received any other systemic investigational or anti-cancer radiopharmaceutical in the past
Has received any prostate cancer directed chemotherapy in the castration resistant setting
Has received > 6 prior doses of docetaxel in the castration sensitive setting. Subjects who have received up to 6 prior doses of docetaxel in the castration sensitive setting are permitted if they have not experienced disease progression within 36 weeks of last treatment with docetaxel
Has received four or more systemic anticancer regimens for mCRPC
Has known Grade ≥3 non-hematological docetaxel-related toxicities or docetaxel toxicity related dose interruption or discontinuation
Has received blood transfusions or growth factors within the last 4 weeks prior to randomization.
Symptomatic nodal disease (i.e., scrotal, penile, or leg edema)
Has visceral metastases with > 3 lung and/or liver metastases or individual lesion >2 cm, as assessed by CT scan or MRI of the chest/abdomen/pelvis within the last 8 weeks prior to randomization
Symptomatic loco-regional disease that causes ongoing Grade 3 or Grade 4 urinary or rectal symptoms
Subjects with a second malignancy with a risk of recurrence >30% within the next 3 years. Non-melanoma skin cancers, non-invasive bladder cancers, and other in-situ or non-invasive malignancies are permitted while on study
Has imminent or established cord compression based on clinical findings and/or MRI
Known bone marrow dysplasia
Has received any of the following in the 4 weeks prior to randomization: 5-alphareductase inhibitors, natural hormonally active foods (e.g., phytoestrogens) or other food supplements known to alter PSA in humans
Is receiving ongoing treatment with herbal medications that are known in humans to alter PSA or the natural history of prostate cancer. Subjects must discontinue any such herbal medications prior to the first dose of study drug
Any other serious illness or medical condition that would, in the opinion of the Investigator, make this protocol unreasonably hazardous, including but not limited to: • Uncontrolled infection • NYHA III or IV heart failure • Crohn’s disease or those with ulcerative colitis who have not undergone a colectomy • Known active infection with HIV, Hepatitis B or Hepatitis C