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Enzalutamide and Relacorilant in Treating Patients with Metastatic Castration Resistant Prostate Cancer

Trial Status: Active

This phase I trial studies the best dose and side effects of enzalutamide and relacorilant in treating patients with castration resistant prostate cancer that has spread to other places in the body (metastatic). Androgens and glucocorticoids can cause the growth of prostate cancer cells. Enzalutamide blocks the use of androgens by the tumor cells. Relacorilant blocks the use of glucocorticoids by the tumor cells. It is not yet known whether enzalutamide and relacorilant may work better in treating patients with castration resistant prostate cancer.

Inclusion Criteria

  • Histologically or cytologically confirmed prostate cancer with documented metastatic disease
  • Evidence of castrate testosterone level < 50 ng/dl (or surgical castration)
  • Evidence of disease progression: * 2 or more new lesions on bone scan or * Progressive disease on computed tomography (CT)/magnetic resonance imaging (MRI) according to RECIST 1.1 criteria or * Rising PSA: PSA evidence for progressive prostate cancer consists of a minimum PSA level of at least 2 ng/ml, which has subsequently risen on at least 2 successive occasions, at least 2 weeks apart
  • Prior treatment with at least one line of potent androgen receptor signaling inhibitor (e.g. abiraterone, enzalutamide, apalutamide) in either castration-sensitive or castration-resistant setting
  • Any prior therapy for castrate disease is acceptable except prior GR antagonist treatment (e.g. mifepristone or relacorilant)
  • Any other radiotherapy or radionuclide require 28-day washout prior to first dose of study drug
  • Denosumab or zoledronic acid are allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Total bilirubin =< 1.5 x the upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Albumin >= 3.0 g/dL
  • Platelet count (plt) >= 80,000 /uL
  • Hemoglobin (Hgb) >= 9 g/dL
  • Absolute neutrophil count (ANC) >= 1500
  • Glomerular filtration rate (GFR) >= 30 mL/min
  • Ability to understand and the willingness to sign a written informed consent document
  • Patients with active diabetes mellitus on glucose lowering medications are eligible provided they agree to and are able to self-monitor daily blood glucose levels due to potential risk of lowering glucose levels on relacorilant
  • Male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration. Two acceptable methods of birth control thus include the following: * 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: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female partner; ** Tubal ligation in the female partner; ** Vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy), for more than 6 months

Exclusion Criteria

  • Therapy with other hormonal therapy, including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart), or any herbal product known to decrease PSA levels (e.g., saw palmetto and PC-SPES), or any systemic corticosteroid within 2 weeks prior to first dose of study drug * Patients who have been on systemic corticosteroids with prednisone equivalent of 10 mg or greater for greater than 3 months immediately prior to participation in this study must have documented ability to tolerate cessation of corticosteroids prior to enrollment
  • Inability to swallow capsules or known gastrointestinal malabsorption
  • Evidence of visceral disease on imaging in a patient who is an appropriate candidate for and has not received cytotoxic chemotherapy (docetaxel or cabazitaxel)
  • History of other malignancies, with the exception of: adequately treated non-melanoma skin cancer, adequately treated superficial bladder cancer, stage 1 or 2 malignancies who are without evidence of disease, or other cancers curatively treated with no evidence of disease for >= 5 years from enrollment
  • Blood pressure that is not controlled despite > 2 oral agents (systolic blood pressure [SBP] >160 and diastolic blood pressure [DBP] > 90 documented during the screening period with no subsequent blood pressure readings > 160/100)
  • History of seizure disorder or active use of anticonvulsants. Medications used to treat neuropathic pain such as gabapentin or pregabalin are allowed
  • Documented history of or current brain metastases due to seizure risk
  • Serious intercurrent infections or non-malignant medical illnesses that are uncontrolled
  • Active psychiatric illness/social situations that would limit compliance with protocol requirements
  • New York Heart Association (NYHA) class II, NYHA class III, or IV congestive heart failure (any symptomatic heart failure)
  • Concurrent therapy with strong inhibitors of CYP3A4 or CYP2C8 due to concerning possible drug-drug interactions
  • Concurrent therapy with strong inducers of CYP3A4 due to concerning possible drug-drug interactions
  • Presence of concurrent medical conditions requiring systemic glucocorticoids for immunosuppression (e.g. Autoimmune diseases, organ transplantation) that is active and has required glucocorticoids in the last 6 months

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: ACTIVE
Contact: Russell Zelig Szmulewitz
Phone: 773-702-7609

PRIMARY OBJECTIVE:

I. To assess the safety of relacorilant in combination with enzalutamide for the treatment of metastatic castration resistant prostate cancer (mCRPC) and to establish safe and pharmacologically active doses of relacorilant and enzalutamide to use in combination.

SECONDARY OBJECTIVES:

I. To determine if relacorilant has preliminary anticancer activity in CRPC through measurement of prostate specific antigen (PSA) response, tumor response per Response Evaluation Criteria in Solid Tumors (RECIST).

II. To determine the effect of enzalutamide on relacorilant clearance and steady state exposure.

III. Assess steady state enzalutamide pharmacokinetics (PK) when given with relacorilant.

IV. To determine the radiographic progression free survival (PFS) of relacorilant in combination with enzalutamide according to standard working group criteria.

V. Evaluate the effect of relacorilant on glucocorticoid receptor (GR) target gene expression within metastatic tumor tissues (screening, day 29).

EXPLORATORY OBJECTIVES:

I. To evaluate the effect of relacorilant on endocrine biomarkers such as serum cortisol and adrenocorticotropic hormone (ACTH).

II. Quantify GR and AR-V7 expression within circulating tumor cells (CTC) using imagestreamx, Epic Sciences platform (day 1, end of study).

III. Explore the concurrent expression of AR-V7 and GR within CTC using ImageStream X (day 1, day 29, end of study).

IV. Explore any association between CTC GR expression and response to treatment or duration on treatment.

V. Explore the evolution of androgen receptor (AR) or GR ligand binding domain mutations based on circulating tumor deoxyribonucleic acid (DNA) (day 1, day 29, end of study).

VI. Evaluate the messenger ribonucleic acid (mRNA) expression from isolated CTC's and circulating blood cells for GR target genes during treatment.

OUTLINE: This is a dose-escalation study.

Patients receive enzalutamide orally (PO) once daily (QD) and relacorilant PO QD on days 1-28. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
University of Chicago Comprehensive Cancer Center

Principal Investigator
Russell Zelig Szmulewitz

  • Primary ID IRB18-0152
  • Secondary IDs NCI-2018-02863
  • Clinicaltrials.gov ID NCT03674814