A Study to Determine the Maximum Tolerated Dose of ASG-5ME in Subjects With Castration-Resistant Prostate Cancer

• Safety assessed by recording of adverse events, laboratory assessments and vital signs [ Time Frame: For 12 weeks during treatment period and up to 4 weeks follow up ] [ Designated as safety issue: No ]
• Pharmacokinetics assessment of ASG-5ME blood levels through analysis of blood samples [ Time Frame: Up to day 15 for cycle 1 and cycle 4 and pre-dose for cycles 2 and 3; every 3 weeks during the second 12 weeks of treatment; and if subject continues on study drug, every 12 weeks thereafter ] [ Designated as safety issue: No ]

• Incidence of anti-ASG-5ME antibody formation [ Time Frame: Baseline; up to day 64 during the first 12 weeks; and if subject continues on study drug, every 3 weeks during the second 12 weeks of treatment and every 12 weeks thereafter ] [ Designated as safety issue: No ]
• Incidence of tumor response (complete or partial response) [ Time Frame: Baseline and every 12 weeks while on study drug ] [ Designated as safety issue: No ]
• Changes in prostate-specific antigen (PSA) levels [ Time Frame: Baseline; up to day 64 during the first 12 weeks; and if the subject continues on study drug, every 3 weeks thereafter ] [ Designated as safety issue: No ]
• Changes in bone scans [ Time Frame: Baseline and every 12 weeks while on study drug ] [ Designated as safety issue: No ]
• Changes in circulating tumor cells [ Time Frame: Baseline; up to day 64 during the first 12 weeks; and if the subject continues on study drug, every 3 weeks during the second 12 weeks of treatment and every 12 weeks thereafter ] [ Designated as safety issue: No ]
• Changes in cytokeratin-18 levels [ Time Frame: Up to day 79 and 4 weeks after the last dose of study drug ] [ Designated as safety issue: No ]

• Pharmacokinetics assessment of ASG-5ME blood levels through analysis of blood samples [ Time Frame: Every 3 weeks for 12 weeks during drug treatment and up to 4 weeks follow up ] [ Designated as safety issue: No ]
• Incidence of anti-ASG-5ME antibody formation [ Time Frame: Every 3 weeks for 12 weeks during drug treatment and up to 4 weeks follow up ] [ Designated as safety issue: No ]
• Incidence of tumor response (complete or partial response) [ Time Frame: Every 3 weeks for 12 weeks during drug treatment and up to 4 weeks follow up ] [ Designated as safety issue: No ]
• Changes in prostate-specific antigen (PSA) levels [ Time Frame: Every 3 weeks for 12 weeks during drug treatment and up to 4 weeks follow up ] [ Designated as safety issue: No ]
• Changes in bone scans [ Time Frame: Every 3 weeks for 12 weeks during drug treatment and up to 4 weeks follow up ] [ Designated as safety issue: No ]
• Changes in circulating tumor cells [ Time Frame: Every 3 weeks for 12 weeks during drug treatment and up to 4 weeks follow up ] [ Designated as safety issue: No ]

The purpose of this dose escalation study is to determine the Maximum Tolerated Dose (MTD) and the recommended Phase 2 dose of ASG-5ME in subjects with castration-resistant prostate cancer (CRPC).

The study has two components. The first aims to establish a safe dose of ASG-5ME. Once identified, the safety and preliminary estimate of antitumor activity of ASG-5ME will be tested in additional subjects with castration-resistant prostate cancer (CRPC) who are either chemotherapy naïve or chemotherapy exposed in expanded cohorts.

• Experimental: Dose level 1
  Intervention: Drug: ASG-5ME
• Experimental: Dose level 2
  Intervention: Drug: ASG-5ME
• Experimental: Dose level 3
  Intervention: Drug: ASG-5ME
• Experimental: Dose level 4
  Intervention: Drug: ASG-5ME
• Experimental: Dose level 5
  Intervention: Drug: ASG-5ME
• Experimental: Dose level 5A
  Intervention: Drug: ASG-5ME
• Experimental: Dose level 6
  Intervention: Drug: ASG-5ME
• Experimental: Dose level 7
  Intervention: Drug: ASG-5ME
• Experimental: Dose level 8
  Intervention: Drug: ASG-5ME
• Experimental: Dose level 9
  Intervention: Drug: ASG-5ME
• Experimental: Chemotherapy-naïve subjects
  Intervention: Drug: ASG-5ME
• Experimental: Chemotherapy exposed subjects
  Intervention: Drug: ASG-5ME

Inclusion Criteria:

• Subject has histologically-confirmed castration-resistant prostate cancer and meets at least 1 of the following criteria:

  • subject's disease has progressed on or after available standard therapy -OR-
  • there is no effective standard therapy available for treating the subject's disease -OR-
  • subject or his disease is not suitable for standard therapy -OR-
  • subject chooses to defer or decline standard therapy (subject is adequately informed of the availability of clinically meaningful therapy and chooses instead to partake in this research using a product with no documented clinical activity)
• Testosterone ≤ 50 ng/dL
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of > 6 months as evaluated and documented by the investigator

• Hematologic function, as follows (no red blood cell (RBC) or platelet transfusions are allowed within 4 weeks of the first dose of ASG-5ME):

  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Platelet count ≥ 100 x 109/L
  • Hemoglobin ≥ 9 g/dL
• Renal function, as follows: creatinine ≤ 1.5 x upper limit of normal (ULN), or creatinine clearance of > 60 mL/min if serum creatinine is > 2.0 mg/dL
• Total bilirubin < 1. 5 x ULN
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT)≤ 1.5 x ULN
• International Normalized Ratio (INR) < 1.3 (or < 3.0 if on therapeutic anticoagulation)
• Serum calcium ≤ ULN
• Subjects must be taking and agree to remain on a stable dose of luteinizing hormone-releasing hormone (LHRH) agonist therapy or gonadotropin-releasing hormone (GnRH) antagonist for the duration of the trial if not surgically castrated
• Additional Inclusion criteria for Chemotherapy Naïve Cohort: No prior systemic cytotoxic chemotherapies

• Additional Inclusion criteria for Chemotherapy Exposed Cohort:

  • Documented disease progression during or after docetaxel treatment or intolerability to docetaxel treatment
  • No additional prior chemotherapy for CRPC is allowed

Exclusion Criteria:

• History of central nervous system metastasis, including incompletely treated epidural disease

• History of other primary malignancy (including premalignant myeloid malignancy e.g. myelodysplastic syndrome), unless:

  • Curatively resected non-melanomatous skin cancer
  • Other malignancy curatively treated with no known active disease present and no treatment administered for the last 3 years
• Active angina or Class III or IV Congestive Heart Failure (CHF) (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 12 months of study enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, congestive heart failure, uncontrolled hypertension, or arrhythmias not controlled by outsubject medication
• The following treatments are not allowed within 4 weeks of enrollment: cytotoxic chemotherapy, radiation therapy or the dietary supplement PC-SPES
• Use of prednisone (or equivalent corticosteroids) > 20 mg/day are not allowed. Doses < 20 mg/day are allowed only if they have been at the same dose for > 4 weeks
• Use of anti-androgen therapy (ie, flutamide, bicalutamide and nilutamide) within 6 weeks of study enrollment; non-responders to second-line anti-androgen therapy do not require the 6 week withdrawal period
• Monoclonal antibody therapy within 3 months of enrollment with the exception of denosumab (prior or concurrent use of denosumab is allowed)
• Peripheral neuropathy of ≥ grade 2 as defined by the CTCAE criteria version 4.0
• Major surgery (that requires general anesthesia) within 4 weeks of study enrollment
• Active infection requiring treatment with systemic (intravenous or oral) anti-infectives (antibiotic, antifungal, or antiviral agent) within 72 hours of screening
• Use of any investigational drug (including marketed drugs not approved for this indication) within 30 days prior to enrollment
• History of thromboembolic events and bleeding disorders ≤ 3 months (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE))
• Known positive test for human immunodeficiency virus (HIV), hepatitis C, or hepatitis B surface antigen