Clinical Trials /

Evaluation of Safety and Efficacy of KPG-121 Plus Enzalutamide, Abiraterone or Apalutamide in CRPC Patients

NCT03569280

Description:

This is a Phase 1, open-label, multicenter study of KPG-121 administered orally once daily (QD) in 28-day treatment cycles (21 days on and 7 days off) to adult subjects. The primary objective is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and assess dose-limiting toxicity (DLT) of KPG-121 in combination with Enzalutamide or Abiraterone or Apalutamide when administered orally to adult subjects with non-metastatic or metastatic castration-resistant prostate cancer (CRPC).

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety, Tolerability, PK and Antitumor Activity of KPG-121 Plus Enzalutamide in mCRPC Patients
  • Official Title: Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Evidence of Antitumor Activity of KPG-121 in Combination With Enzalutamide in Adults With Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Clinical Trial IDs

  • ORG STUDY ID: KPG-121-101
  • NCT ID: NCT03569280

Conditions

  • Metastatic Castration-Resistant Prostate Cancer

Purpose

This is a Phase 1, open-label, multicenter study of KPG-121 administered orally once daily (QD) in 28-day treatment cycles (21 days on and 7 days off) to adult subjects with mCRPC receiving stable doses of enzalutamide. The primary objective is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and assess dose-limiting toxicity (DLT) of KPG-121 in combination with enzalutamide when administered orally to adult subjects with metastatic castration-resistant prostate cancer (mCRPC).

Detailed Description

      This Phase 1 study will comprise two parts: Part 1 will be a 3+3 dose escalation design to
      characterize the MTD and a RP2D, Part 2 will be an expansion cohort at RP2D. In Part 1,
      multiple escalating dose levels of KPG-121 (six cohorts: 1.5, 2.5, 5.0, 10, 20, and 30
      mg/day) in combination with enzalutamide will be evaluated to determine the MTD and RP2D of
      KPG-121. The MTD is the dose level prior to that which causes ≥33% of subjects to experience
      a DLT. Even though an MTD may have been reached, a RP2D may still be selected which will take
      into account the MTD as well as the available information on lower grade AEs that occur in
      later cycles including safety, efficacy, and PSA data. There will be 6 mid-cycle Safety
      Review Meetings that will be held when the first enrolled subject in each cohort reaches Day
      14. All safety data collected through that timepoint for that cohort will be reviewed. An
      End-of-Treatment (EOT) or Early Termination (ET) visit will be conducted within 14 days of
      the last dose of KPG-121, and a Safety Follow-up/End-of-Study (EOS) visit will be conducted
      approximately 28 days after the last dose of KPG-121. All subjects will be followed for AEs,
      serious adverse events, and concomitant medications (including any new cancer treatments) for
      28 days following the last dose of KPG-121. The Part 2, expansion cohort 7, will follow the
      same Schedule of Procedures as Part 1 once the RP2D has been decided. For the expansion
      cohort of part 2, 6-12 subjects will be given the RP2D once daily for 21 consecutive days
      along with oral 4 x 40 mg enzalutamide capsules followed by 7 days without KPG-121 for each
      28-day cycle.
    

Trial Arms

NameTypeDescriptionInterventions
KPG-121 dose escalation + EnzalutamideExperimentalAntitumor Activity of KPG-121 capsules 1.5, 2.5, 5.0, 10, 20, and 30 mg/day daily for 21 days

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Have provided written informed consent prior to any study-related procedure being
                 performed;
    
              2. Male of at least 18 years of age or older at the time of consent;
    
              3. Histologically confirmed mCRPC who failed to achieve and/or maintain >90% reduction in
                 PSA after >3 months of enzalutamide (pre-enzalutamide PSA values must be available);
    
              4. Radiographically stable or better disease while on enzalutamide (no new evidence of
                 metastatic disease or disease progression) and ongoing treatment on enzalutamide for
                 >3 months;
    
              5. Subjects who have received a single prior regimen of either abiraterone or apalutamide
                 (but not both) are eligible if their duration of response (defined as radiographically
                 non-progressive disease) on these therapies was at least 6 months;
    
              6. Serum testosterone level < 50 ng/dL (< 0.5 ng/mL, < 1.7 nmol/L). Patients may have
                 ongoing androgen deprivation therapy (ADT) with a luteinizing hormone-releasing
                 hormone (LHRH) "super-agonist" or antagonist, and/or be surgically or medically
                 castrated;
    
              7. ECOG performance status of 0-2;
    
              8. If subject's partner is a woman of childbearing potential (WOCBP), then an adequate
                 method of birth control should be used while on the study drug and enzalutamide, and
                 for 3 months post last dose of study drug and enzalutamide; and
    
              9. Willing and able to comply with all protocol required visits and assessments.
    
            Exclusion Criteria:
    
              1. Life expectancy less than 3 months;
    
              2. Discontinuation of bicalutamide or nilutamide less than 6 weeks, and other
                 antiandrogens less than 4 weeks, prior to the start of study medication;
    
              3. Prior chemotherapy, radiation (limited radiotherapy to control bone pain is
                 permitted), sipuleucel-T or other experimental immunotherapy less than 4 weeks prior
                 to the start of study medication (prior abiraterone acetate and apalutamide use is
                 permitted);
    
              4. Have an indication for the use of cytotoxic chemotherapy, including marked visceral
                 disease or substantial pain;
    
              5. Screening blood counts with:
    
                   1. absolute neutrophil count <1500/μL
    
                   2. platelets <100,000/μL
    
                   3. hemoglobin < 9 g/dL;
    
              6. Screening chemistry test results with:
    
                   1. alanine aminotransferase (ALT) and aspartate transaminase (AST) >2.5 × ULN
    
                   2. total bilirubin >2 × ULN
    
                   3. creatinine clearance of <70 mL/min as determined by Cockcroft and Gault formula
                      for entry into the dose escalation part of the study. In the cohort expansion
                      part of the study, subjects with creatinine clearance of <50 mL/min will be
                      excluded (if kidneys are not working properly, there is a risk that KPG-121 may
                      stay in the blood circulation longer than expected and may increase side-effects)
    
                   4. albumin <2.8 g/dL;
    
              7. Uncontrolled hypothyroidism, or thyroid stimulating hormone (TSH) >2.0 x ULN at
                 screening. Subjects who are clinically euthyroid and on stable thyroid replacement
                 therapy for 2 months prior to screening are allowed;
    
              8. Ongoing acute treatment-related toxicity associated with a previous therapy greater
                 than grade 1 except for grade 2 alopecia or neuropathy;
    
              9. History of impaired adrenal gland function (e.g., Addison's disease, Cushing's
                 syndrome);
    
             10. History of congestive heart failure New York Heart Association (NYHA) class III or IV,
                 uncontrolled hypertension or evidence of coronary artery disease (including a
                 myocardial infarction) within the previous 6 months at screening;
    
             11. History or family history of long QT syndrome or a screening ECG showing a QTc
                 interval of more than 450 msec;
    
             12. History of other malignancy within the previous 3 years, except basal cell or squamous
                 cell carcinoma, or non-muscle invasive bladder cancer;
    
             13. Anticoagulants used by subjects with a history of thromboembolic conditions. Note:
                 Subjects receiving anticoagulants for atrial fibrillation are eligible for the study;
    
             14. Use of systemic glucocorticoid (e.g., prednisone, dexamethasone) within 14 days prior
                 to the start of study medication;
    
             15. Prior use of any herbal products known to decrease PSA levels (e.g., PC-SPES or saw
                 palmetto) within 30 days prior to the start of study medication;
    
             16. Major surgery within 30 days prior to the start of study medication;
    
             17. Blood transfusion (including blood products) within 1 week of screening;
    
             18. Serious persistent infection within 14 days prior to the start of study medication;
    
             19. Serious concurrent medical condition including central nervous system (CNS) disorders;
    
             20. Previous history of difficulty swallowing capsules;
    
             21. Any condition that, in the opinion of the investigator, would impair the subject's
                 ability to comply with study procedures;
    
             22. History of or active thromboembolism within last 6 months;
    
             23. Allergy to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs);
    
             24. History of Stevens-Johnson syndrome; or
    
             25. Baseline left ventricular ejection fraction (LVEF) <45% at Screening; or
    
             26. Prior treatment with any inhibitors of PD-1 or PD-L1 within 3 months.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Male
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Maximum Tolerated Dose (MTD)
    Time Frame:Day 21
    Safety Issue:
    Description:MTD is one dose level below the dose level that results in ≥33% of subjects with a DLT

    Secondary Outcome Measures

    Measure:Incidence of Adverse Events [Safety and Tolerability]
    Time Frame:up to 56 days
    Safety Issue:
    Description:Treatment-Emergent Adverse events
    Measure:Pharmacokinetic (PK) profile of KPG-121
    Time Frame:Days 1 and 21
    Safety Issue:
    Description:Plasma concentrations of KPG-121

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Kangpu Biopharmaceuticals, Ltd.

    Trial Keywords

    • KPG-121
    • enzalutamide
    • prostate
    • cancer
    • metastatic

    Last Updated

    November 6, 2019