Docetaxel with or without Radium Ra 223 Dichloride in Treating Patients with Metastatic Castration-Resistant Prostate Cancer

This phase III trial studies docetaxel and radium Ra 223 dichloride to see how well it works compared with docetaxel alone in treating patients with prostate cancer that has spread to other places in the body, despite the surgical removal of the testes or medical intervention to block androgen production. Drugs used in chemotherapy, such as docetaxel and radium Ra 223 dichloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not known whether docetaxel with or without radium Ra 223 dichloride works better at treating metastatic castration-resistant prostate cancer.

Inclusion Criteria

• Willing and able to provide written informed consent (ICF) and Health Insurance Portability and Accountability Act (HIPAA) authorization for the release of personal health information. A signed informed consent must be obtained before screening procedures are performed * NOTE: HIPAA authorization may be either included in the informed consent or obtained separately
• Histological or cytological proof of prostate cancer
• Documented progressive metastatic castrate resistant prostate cancer (mCRPC) based on at least one of the following criteria: * PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 1.0 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 1.0 ng/mL * 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 * Progression of bone disease (evaluable disease) or two or more new bone lesions by bone scan
• Two or more bone lesions
• Eastern Cooperative Oncology Group (ECOG) 0- 1
• Albumin > 30 g/L (within 14 days of randomization)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 14 days of randomization)
• Hemoglobin >= 10 g/dL (within 14 days of randomization)
• Platelet count >= 100 x 10^9/L (within 14 days of randomization)
• Creatinine =< 1.5 x the institutional upper limit of normal (ULN) (within 14 days of randomization)
• Bilirubin =< ULN (unless documented Gilbert's disease) (within 14 days of randomization)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 1.5 x ULN (within 14 days of randomization)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 1.5 x ULN (within 14 days of randomization)
• White blood cell (WBC) count >= 3 x 10^9/L (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 30 days after the last dose of study drug. Sperm donation is prohibited during the study and for 30 days 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 National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 or less
• Willing and able to comply with the protocol, including follow-up visits and examinations

Exclusion Criteria

• Received any other investigational therapeutic agents or other anticancer therapies within 4 weeks prior to randomization
• Received external beam radiotherapy within the 4 weeks prior to randomization
• Has an immediate need for external beam radiotherapy
• Has received any systemic bone-seeking radiopharmaceutical in the past
• Has received any prostate cancer directed chemotherapy in the castration resistant 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. Treatment with docetaxel or abiraterone for non-castrate metastatic disease is permissible and does not count towards the lines of therapy for mCRPC. A ‘line’ is a regimen. Combinations of hormones and other types of therapies count as single lines
• Has known grade >= 3 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 computed tomography (CT) scan or magnetic resonance imaging (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 “currently active” second malignancy other than non-melanoma skin cancers or non-invasive bladder cancers or other in-situ or non-invasive malignancies. Subjects are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for >= 3 years
• 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-alpha-reductase inhibitors, herbal medications, natural hormonally active foods (e.g., phytoestrogens) or other food supplements known to alter PSA in humans
• 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 * New York Heart Association (NYHA) III or IV heart failure * Crohn’s disease or those with ulcerative colitis who have not undergone a colectomy * Known active infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C

PRIMARY OBJECTIVE:

I. Compare overall survival for subjects treated with docetaxel versus subjects treated with docetaxel plus radium-223.

SECONDARY OBJECTIVES:

I. To compare radiographic progression free survival as defined in Prostate Cancer Working Group 3 (PCWG3) criteria.

II. To compare symptomatic skeletal event free survival.

III. To compare time to total alkaline phosphatase (ALP) progression.

IV. To compare on-treatment alterations in quality of life (QOL) as assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P), Brief Pain Inventory (BPI), and Brief Fatigue Inventory (BFI) measures between subjects who receive docetaxel with those who receive docetaxel and radium-223.

V. To determine if there is excessive febrile neutropenia in subjects treated with docetaxel plus radium-223.

VI. To determine if there is excessive treatment discontinuation in subjects who are on their fourth line of therapy.

CORRELATIVE/EXPLORATORY/TERTIARY OBJECTIVES:

I. To evaluate on treatment alterations in prostate specific antigen (PSA).

II. To evaluate time to first symptomatic skeletal event (SSE).

III. To evaluate on-treatment alterations in urine C-telopeptide (UCTx1), N-terminal propeptide of procollagen type 1 (P1NP), and pyridinoline cross-linked carboxyterminal telopeptide (ICTP).

IV. To evaluate total ALP response.

V. To evaluate on-treatment alterations in circulating tumor cells (CTC) enumeration, and AR-V7 characterization.

VI. To evaluate on-treatment alterations in circulating tumor deoxyribonucleic acid (ctDNA).

VII. To evaluate on-treatment changes in automated Bone Scan Index (aBSI).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive docetaxel intravenously (IV) on day 1 and prednisone orally (PO) twice daily (BID). Treatment repeats every 3 weeks for up to 10 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive docetaxel IV on day 1 and prednisone PO BID. Treatment repeats every 3 weeks for up to 10 courses in the absence of disease progression or unacceptable toxicity. Patients also receive radium Ra 223 dichloride via injection on day 1. Treatment with radium Ra 223 dichloride repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, then every 6 months thereafter.

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Michael J. Morris