Phase 1b Study of ARN 509 Plus Everolimus in Men With Progressive Metastatic Castration-Resistant Prostate Cancer After Treatment With Abiraterone Acetate
Phase 1b Study of ARN 509 Plus Everolimus in Men With Progressive Metastatic Castration-Resistant Prostate Cancer After Treatment With Abiraterone Acetate
The purpose of this study is to test the safety of the combination of apalutamide plus everolimus at different dose levels.
Inclusion Criteria:
Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features with progressive metastatic disease based on any of the following:
Castration-resistant prostate cancer: patients must have surgical or ongoing chemical (androgen deprivation therapy) castration, with baseline testosterone level ≤ 50 ng/dL determined within 4 weeks of starting study drug.
Dose-Escalation: Prior treatment with abiraterone acetate. At least 4 weeks must have elapsed from the last dose of abiraterone acetate.
Expansion Cohort only (if conducted in the study): Men with mCRPC and disease progression as defined by PCWG2 within 3 months (primary resistance); or after at least 6 months of treatment (acquired resistance) of starting treatment with abiraterone acetate. At least 4 weeks must have elapsed from the last dose of abiraterone .acetate
Physiologic doses of corticosteroids are allowed (i.e. no more than 10 mg prednisone daily).
Patients currently receiving bone loss prevention treatment (e.g. bisphosphonates, denosumab, etc.) must be on a stable dose for at least 4 weeks prior to starting study treatment.
Patients who received a first generation anti-androgen (e.g., bicalutamide, flutamide, nilutamide) as part of their first-line hormonal therapy must have shown progression of disease off the anti-androgen prior to enrollment.
At least 4 weeks must have elapsed from the use of androgen receptor antagonists (e.g., bicalutamide, flutamide, nilutamide); 5-α reductase inhibitors (e.g., dutasteride, finasteride, aminoglutethimide); estrogens; ketoconazole and other anti-cancer pharmacologic therapy prior to enrollment.
At least 6 weeks must have elapsed from the use of bicalutamide if used as part of an initial combined androgen blockage therapy for more than 6 months or if used as second line hormonal therapy and associated with a PSA response of at least 3 months duration.
At least 12 weeks must have elapsed from the use of Strontium-89, Radium-223 or any investigational or approved immunotherapy (e.g., Provenge) prior to starting study drug.
At least 4 weeks must have elapsed from the use of any other investigational agent prior to starting study drug.
At least 4 weeks must have elapsed from major surgery prior to starting study drug.
Patients with treated, non-progressive epidural disease are eligible.
At least 18 years of age, with a life expectancy of at least 3 months.
ECOG performance status 0 or 1 (2 is allowed only if due to bone pain).
Toxicities related to prior therapy must either have returned to ≤ Grade 1, baseline, or deemed irreversible.
Physical and laboratory test findings:
Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment.
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Exclusion Criteria:
Prior treatment with apalutamide, or PI3K/mTOR pathway inhibitors.
History of, or current metastases in the brain, meninges, or untreated spinal cord compression.
Patients previously treated with chemotherapy for mCRPC. At least 12 months must have elapsed from chemotherapy given in the adjuvant or neoadjuvant setting.
History of any other malignancy within the previous 5 years except for the following: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, stage I or II cancer currently in complete remission, or any other cancer that has been in complete remission for at least 5 years.
History of seizure or condition that may predispose to seizure (e.g., prior stroke within 1 year of starting study drug, brain arteriovenous malformation)
Concurrent therapy with medications known to have seizure potential
Known intolerance or hypersensitivity to Vitamin E, everolimus or to rapamycin derivatives.
Use of herbal products that may decrease PSA levels (e.g., saw palmetto).
Known human immunodeficiency virus (HIV) infection.
Patients who have received live attenuated vaccines within 1 week of start of Everolimus and during the study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.
Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study.
Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing.
Male patients whose sexual partner(s) are women of child-bearing potential (WOCBP) who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment. Highly effective contraception methods include combination of any two of the following (a+b or a+c or b+c):
Patients with a known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Everolimus.
Patients with uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary.
Patients who have any severe and/or uncontrolled medical conditions such as:
i. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to start of Everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease ii. Symptomatic congestive heart failure of New York heart Association Class III or IV iii. active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA), iv. known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air), v. active, bleeding diathesis;