Title A Study of HSP90 Inhibitor AT13387 Alone or in Combination with Abiraterone Acetate in the Treatment of Castration-Resistant Prostate Cancer (CRPC) no Longer Responding to Abiraterone
IRB ASTX 1812
Hospital Main Campus
- Part A: To assess the safety and tolerability (incidence and severity of adverse events [AEs]) of the combination of AT13387 and abiraterone acetate and to select the most promising treatment regimen for the combination in subjects with castration-resistant prostate cancer (CRPC) who are no longer responding to treatment with abiraterone acetate alone, based on the overall assessment of safety and antitumor activity.
- Part B: To assess and compare the antitumor activity (response rate per the Prostate Cancer Working Group 2 [PCWG2] recommendations) between single-agent AT13387 and the combination of AT13387 plus abiraterone acetate in subjects who are no longer responding to treatment with abiraterone acetate alone.
- Part A: 1) To assess pharmacokinetic interactions between AT13387 and abiraterone; 2) To assess progression-free survival (PFS) per PCWG2 recommendations and overall survival (OS); and 3) To assess the androgen receptor (AR) depletion in circulating tumor cells (CTCs) and/or tumor tissue.
- Part B: 1) To assess and compare the safety of AT13387 alone and in combination with abiraterone acetate in CRPC; 2) To assess and compare pharmacodynamic markers of AR depletion and other client protein depletion in CTCs and/or tumor tissue in the 2 arms; and 3) To assess and compare PFS and OS in the 2 arms.
- Have a histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology;
- Have received prior castration by orchiectomy and/or luteinizing hormone-releasing hormone agonist with or without antiandrogen and documented serum testosterone < 50 ng/dL;
- Males > 18 years of age;
- Have Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2;
- Have not had androgen receptor (AR) antagonist treatment in the 6 weeks prior to the first dose of study drug;
- Have been receiving abiraterone acetate therapy with a steroid for ≥ 1 month. Only subjects tolerating abiraterone acetate 1000 mg at screening will be eligible to participate in the study;
- Have documented disease progression on abiraterone acetate defined by 1 or more of the following criteria: Prostate-specific antigen (PSA) progression according to PCWG2 criteria with 3 consecutive rising PSA measurements, all collected at least 1 week apart;, Radiographic progression in soft tissue or bone by modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for subjects with measurable disease; or Bone disease progression defined by 2 or more new lesions on 2 consecutive bone scans in the absence of falling PSA;
- Have any detectable CTS (CTC count ≥ 1) (for Part A only);
- Have adequate bone marrow function, defined as absolute neutrophil count > 1.5 K/mL and platelet count > 100 K/mL;
- Have adequate hepatic function, defined as bilirubin ≤ 1.5 x the upper limit of normal (ULN), alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN (ALT and AST ≤ 5 x ULN, if liver metastases are present);
- Have adequate renal function, defined as creatinine ≤ 1.25 x ULN or creatinine clearance > 50 mL/min;
- Must be willing to provide pre-existing diagnostic or resected tumor samples, such as formalin-fixed, paraffin-embedded sections or slides, if this material exists. If pre-existing samples are not available, a sample must be obtained during screening if safe and feasible. A pre-dose biopsy is not required if an archival sample is available. A post treatment biopsy is however, still required, if safe and feasible.
- Subjects and their female partners with reproductive potential must agree to use effective contraceptive measures during the study and for 3 months following the last dose of study drug. Effective contraception includes methods such as oral contraceptives, double-barrier method (condom plus spermicide or diaphragm) or abstaining from sexual intercourse; and
- Must be willing and able to provide written informed consent and comply with the protocol and study procedures.
- Prior anti-cancer treatment with any Heat Shock Protein 90 (HSP90) inhibitor or histone deacetylase (HDAC) inhibitor compound;
- Have received chemotherapy within 4 weeks prior to receiving study drug;
- Prior prostate surgery or radiotherapy within 4 weeks from the first dose of study drug and single fraction radiotherapy within 2 weeks prior to the first dose of study drug;
- Hypersensitivity to AT13387 or other components of the drug product;
- Treatment with any investigational drug within 4 weeks prior to the first dose of study drug;
- Poor medical risk because of other systemic diseases or active uncontrolled infections;
- Presence of a life-threatening illness, medical condition, organ system dysfunction, or other factors which, in the Investigators opinion, could compromise the subjects safety, interfere with the metabolism of AT13387, or compromise the integrity of the study outcomes;
- Abnormal left ventricular ejection fraction < 50% on echocardiogram or multigated acquisition scan; history of ischemic cardiac event, including myocardial infarction within 3 months of study entry, congestive cardiac failure of ≥ Grade 3 severity according to New York Heart Association functional classification; history of long QTc syndrome or ventricular arrhythmias; or screening QTcF > 450 msec after correction of any electrolyte imbalance and confirmation of QTc by triplicate measurement;
- Prior malignancy except for adequately treated basal cell or squamous cell carcinoma of the skin, or superficial bladder cancer, or other cancer from which the subject has been disease-free for at least 3 years;
- Known symptomatic brain or central nervous system involvement such as a result of cord compression;
- Contraindication to the use of corticosteroids or history of pituitary or adrenal dysfunction;
- Prior dose reduction of abiraterone acetate as a result of increased transaminases; or
- Known history of human immunodeficiency virus (HIV) or seropositive test for hepatitis C virus or hepatitis B virus.