Rapid Cycle Combination Therapy in Treating Patients with Metastatic Castrate-Resistant Prostate Cancer

This phase II trial studies how well rapid cycle combination therapy works in treating patients with prostate cancer that has not responded to surgery or hormone therapy and has spread to other places in the body. Androgen can cause the growth of tumor cells. Antihormone therapy, such as abiraterone acetate and enzalutamide, may lessen the amount of androgen made by the body. Drugs used in the chemotherapy, such as radium Ra 223 dichloride, cabazitaxel, and carboplatin, 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. Switching between different combinations of androgen deprivation therapy and chemotherapy after a short time may prevent drug resistance and help achieve better long-term control of prostate cancer.

Inclusion Criteria

• Histologically or cytologically confirmed adenocarcinoma of the prostate
• Metastatic castrate resistant prostate cancer, defined by progressive disease based on either rising PSA, new bone metastases, or progression of measurable disease on imaging, according to Prostate Cancer Working Group 2 (PCWG2) guidelines, despite androgen deprivation therapy
• Ongoing androgen deprivation therapy with a GnRH analogue, GnRH antagonist, or bilateral orchiectomy
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Serum testosterone level < 50 ng/dL
• Absolute neutrophil count > 1,500/uL
• Platelet count > 100,000/uL
• Hemoglobin > 9 g/dL
• Creatinine < 2 mg/dL
• Total bilirubin < 1.5 times the upper limit of normal
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 1.5 times the upper limit of normal

Exclusion Criteria

• History of uncontrolled seizure disorder
• Clinically significant cardiovascular disease including: * Myocardial infarction or uncontrolled angina within 6 months * Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past * Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at the screening visit
• Have used or plan to use from 30 days prior to enrollment through the end of the study medication known to lower the seizure threshold or prolong the QT interval
• Major surgery within 4 weeks of enrollment
• Radiation therapy within 4 weeks of enrollment
• Prior use of abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, carboplatin, or radium-223 for the treatment of castration-resistant disease * Prior docetaxel use in the hormone-sensitive disease setting is allowed, but must be completed >= 4 weeks prior to enrollment * Prior sipuleucel-T use is allowed, but must be completed >= 4 weeks prior to enrollment * Concurrent use of zolendronic acid or denosumab is allowed on study

PRIMARY OBJECTIVE:

I. To evaluate time to disease progression, as determined by either prostate specific antigen (PSA) or radiographic progression, after completion of all modules of the rapidly-cycling, non-cross reactive regimen in patients with metastatic castration-resistant prostate cancer (mCRPC).

SECONDARY OBJECTIVES:

I. To evaluate overall survival.

II. To assess PSA response rate with each treatment module.

III. To assess changes to alkaline phosphatase levels.

IV. To assess safety of the rapidly-cycling, non-cross reactive regimen.

EXPLORATORY OBJECTIVES:

I. To evaluate the correlation of a peripheral whole-blood ribonucleic acid (RNA) signature with clinical outcome measures during and after treatment.

II. To evaluate changes to AR-V7 expression in circulating tumor cells (CTCs) with different treatment modalities and clinical outcomes.

OUTLINE:

MODULE I: Patients receive abiraterone acetate orally (PO) once daily (QD). Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.

MODULE II: Patients receive cabazitaxel IV on day 1 and carboplatin IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

MODULE III: Patients receive enzalutamide PO QD. Patients with known bone metastases also receive radium Ra 223 dichloride IV on day 1. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 weeks for 1 year.

Lead Organization
Icahn School of Medicine at Mount Sinai

Principal Investigator
Bobby Liaw