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Title A Phase 1/2, open-label, uncontrolled, multiple dose escalation, cohort expansion and extension study to evaluate the safety, tolerability, and pharmacokinetics of ASN001 in subjects with metastatic progressive castrate resistant prostate cancer.

IRB ASNA1815

CC 15-979

Hospital Main Campus

Phase Phase 1, Phase 2

Disease Prostate

Drug ASN001

Description

Primary Objectives

Part A: To evaluate the safety and tolerability of ASN001 including DLTs and to determine the MTD
• Part B: To evaluate the safety, tolerability, and antitumor activity of ASN001 by analysis of prostate-specific antigen (PSA)

Secondary Objectives

• Part A: To evaluate the PK profile of ASN001 after single and multiple doses
• Part B: To evaluate the PK profile of ASN001 after single and multiple doses and the antitumor activity of ASN001 by analysis of soft tissue and bone lesions, Eastern Cooperative Oncology Group (ECOG) performance status, and by time on treatment with ASN001
• Part C: To evaluate the long-term safety and tolerability of ASN001

Exploratory/Pharmacodynamic Objectives

• Parts A and B:
  • To evaluate the effects of ASN001 on the concentration of serum bone-specific alkaline phosphatase (BAP)
  • To evaluate the effects of ASN001 on serum concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), cortisol, deoxycorticosterone, corticosterone, dehydroepiandrosterone (DHEA), testosterone, and dihydrotestosterone (DHT)

Inclusion Criteria

1. Written informed consent obtained prior to any study-related procedure being performed
2. Male subjects at least 18 years of age or older at the time of consent
3. Histologically confirmed adenocarcinoma of the prostate
4. Ongoing and continuing androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, or bilateral orchiectomy and serum testosterone level < 50 ng/dL (< 0.5 ng/mL, < 1.7 nmol/L) at screening
5. Metastatic disease documented by computed tomography (CT)/magnetic resonance imaging (MRI) or bone scan.
6. Progressive disease despite ongoing androgen deprivation therapy. Progressive disease is defined by 1 or more of the following criteria:
   • Subjects with a PSA value ≥ 2 ng/mL that has a confirmed increase over the previous nadir in at least 2 measurements at least 1 week apart. If the confirmatory PSA value is less than the initial increased value, additional testing is required to confirm disease progression.
   • Subjects with measurable disease, progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Subjects with evaluable non-measurable disease are eligible to enroll in Part A only.
   • Subjects with metastatic bone disease, progression defined by 2 or more new lesions in a radionuclide bone scan
7. Subjects with prior cytotoxic chemotherapy are eligible to participate if they have been progression free for at least 12 months since the initiation cytotoxic chemotherapy.
8. ECOG performance status of 0 or 1 at screening
9. Screening blood counts of the following:
   • Absolute neutrophil count ≥ 1500/μL
   • Platelets ≥ 100,000/μL
   • Hemoglobin ≥ 9 g/dL
   • INR ≤ ULN
10. Screening chemistry values of the following:
    • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x upper limit of the normal reference range (ULN)
    • Total bilirubin ≤ ULN. ULN. Subjects with known Gilbert's syndrome may be eligible with Sponsor approval;
    • Creatinine ≤ 1.5 x ULN
    • Albumin > 2.8 g/dL
11. At screening, life expectancy of at least 3 months
12. Subject is willing and able to comply with all protocol required visits and assessments

Exclusion Criteria

1. Patients with rapidly progressive disease who are candidates for other approved therapies such as docetaxel, abiraterone, and enzalutamide
2. Prior therapy with abiraterone, orteronel, ketoconazole, or any other CYP17 lyase inhibitor.
3. Prior therapy with enzalutamide or other androgen receptor antagonist.
4. Prior treatment with experimental immunotherapy.
5. The subject requires treatment with potassium supplementation, aldosterone antagonists, or any other prohibited medication (Section 10.2.1 Prohibited Medications)
6. Radiotherapy or any other investigational/experimental therapy within 4 weeks of the start of study medication
7. Ongoing acute treatment-related toxicity associated with a previous therapy greater than grade 1 except for alopecia and/or grade 2 neuropathy
8. Therapy with estrogen within 30 days prior to the start of study medication
9. Use of systemic glucocorticoid (e.g.: prednisone, dexamethasone) within 14 days prior to the start of study medication
10. Prior use of any herbal products known to decrease PSA levels
11. Known metastases to the brain
12. History of other malignancy within the previous 5 years, except adequately excised basal cell or squamous cell carcinoma of the skin
13. Major surgery within 30 days prior to the start of study medication
14. Blood transfusion (including blood products) within 1 week of screening
15. Serious concurrent medical condition including, but not limited to:
    • History of congestive heart failure New York Heart Association (NYHA) class III or IV
    • Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg) at screening. Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive therapy;
    • Clinically significant heart disease including but not limited to: myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or known cardiac ejection fraction measurement of < 50 %;
    • History or family history of long QT syndrome
    • 12-Lead ECG abnormalities considered by the investigator to be clinically significant or QTcF ≥ 450 milliseconds at screening. Abnormal values may be confirmed from one additional assessment. For subjects with QTcF ≥ 450 , the mean of the two QTcF assessments will be used to determine eligibility.
    • Psychiatric illness.
    • History of impaired adrenal gland function (e.g.: Addison's disease, Cushing's syndrome;
    • Serious persistent infection within 14 days prior to the start of study medication;
    • Known gastrointestinal disease or condition which may affects the absorption of ASN001;
    • Active or symptomatic viral hepatitis, chronic liver disease, or liver cirrhosis;
    • Condition or situation which may put the patient at significant risk, may confound the study results, or may interfere significantly with the subject's participation in the study.
16. Receipt of any investigational treatment within 4 weeks prior to the start of study medication
17. Previous history of difficulty swallowing large capsules
18. Known hypersensitivity to ASN001 or its excipients
19. Subject has received prior ASN001.
20. Any condition that, in the opinion of the investigator, would impair the subject's ability to comply with study procedures
21. The subject has been involved in the planning and/or conduct of the study (applies to both sponsor staff and staff at the study sites)