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Safety, Tolerability, and PK of GT0918 (Proxalutamide) in Subjects With Metastatic Castrate Prostate Cancer

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ClinicalTrials.gov Identifier: NCT02826772
Recruitment Status : Completed
First Posted : July 11, 2016
Last Update Posted : March 17, 2020
Sponsor:
Information provided by (Responsible Party):
Suzhou Kintor Pharmaceutical Inc,

Tracking Information
First Submitted Date  ICMJE June 23, 2016
First Posted Date  ICMJE July 11, 2016
Last Update Posted Date March 17, 2020
Actual Study Start Date  ICMJE February 10, 2016
Actual Primary Completion Date May 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 28, 2017)
  • dose-limiting toxicities (DLTs) [ Time Frame: 1 month ]
    abnormal laboratory value
  • maximum tolerated dose (MTD),biological dose or minimal effective dose, (MED), and recommended Phase 2 dose(s) (RP2D). [ Time Frame: 1 month ]
    50 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg of GT0918
Original Primary Outcome Measures  ICMJE
 (submitted: July 5, 2016)
  • dose-limiting toxicities (DLTs) [ Time Frame: 1 month ]
    abnormal laboratory value
  • maximum tolerated dose (MTD) [ Time Frame: 1 month ]
    50 mg, 100 mg, 200 mg, 400 mg, or 600 mg of GT0918
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2017)
  • maximum concentration (Cmax) [ Time Frame: 6 months ]
    Pharmacokinetics
  • time that maximum concentration is observed (tmax) [ Time Frame: 6 months ]
    Pharmacokinetics
  • area under the concentration time-curve from time zero to infinity (AUC0∞) [ Time Frame: 6 months ]
    Pharmacokinetics
  • area under the plasma concentration-time curve from time zero hours to time (t hrs), (AUC0-t) [ Time Frame: 6 months ]
    Pharmacokinetics
  • area under the plasma concentration-time curve from time zero hours to 24 hours (AUC0-24) [ Time Frame: 6 months ]
    Pharmacokinetics
  • terminal elimination rate constant (λz) [ Time Frame: 6 months ]
    Pharmacokinetics
  • terminal elimination half life (t½) [ Time Frame: 6 months ]
    Pharmacokinetics
  • volume of distribution (Vz) [ Time Frame: 6 months ]
    Pharmacokinetics
  • volume of plasma cleared of the drug per unit time (C) [ Time Frame: 6 months ]
    Pharmacokinetics
  • circulating tumor deoxyribonucleic acid (ctDNA) [ Time Frame: 6 months ]
    antitumor activities
  • circulating messenger ribonucleic acid (mRNA) [ Time Frame: 6 months ]
    antitumor activities
  • circulating tumor cells (CTC) [ Time Frame: 6 months ]
    antitumor activities
  • prostate-specific antigen (PSA) [ Time Frame: 6 months ]
    biomarker
Original Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2016)
  • maximum concentration (Cmax) [ Time Frame: 6 months ]
    Pharmacokinetics
  • time that maximum concentration is observed (tmax) [ Time Frame: 6 months ]
    Pharmacokinetics
  • area under the concentration time-curve from time zero to infinity (AUC0∞) [ Time Frame: 6 months ]
    Pharmacokinetics
  • area under the plasma concentration-time curve from time zero hours to time (t hrs), (AUC0-t) [ Time Frame: 6 months ]
    Pharmacokinetics
  • area under the plasma concentration-time curve from time zero hours to 24 hours (AUC0-24) [ Time Frame: 6 months ]
    Pharmacokinetics
  • terminal elimination rate constant (λz) [ Time Frame: 6 months ]
    Pharmacokinetics
  • terminal elimination half life (t½) [ Time Frame: 6 months ]
    Pharmacokinetics
  • volume of distribution (Vz) [ Time Frame: 6 months ]
    Pharmacokinetics
  • volume of plasma cleared of the drug per unit time (C) [ Time Frame: 6 months ]
    Pharmacokinetics
  • luteinizing hormone (LH) [ Time Frame: 6 months ]
    Pharmacodynamics
  • follicle stimulation hormone (FSH) [ Time Frame: 6 months ]
    Pharmacodynamics
  • adrenocorticotrophic hormone (ACTH) [ Time Frame: 6 months ]
    Pharmacodynamics
  • cortisol [ Time Frame: 6 months ]
    Pharmacodynamics
  • deoxycorticosterone [ Time Frame: 6 months ]
    Pharmacodynamics
  • corticosterone [ Time Frame: 6 months ]
    Pharmacodynamics
  • dehydroepiandrosterone (DHEA) [ Time Frame: 6 months ]
    Pharmacodynamics
  • testosterone [ Time Frame: 6 months ]
    Pharmacodynamics
  • dihydrotestosterone (DHT) [ Time Frame: 6 months ]
    Pharmacodynamics
  • circulating tumor cells (CTC) [ Time Frame: 6 months ]
    antitumor activities
  • circulating tumor deoxyribonucleic acid (ctDNA) [ Time Frame: 6 months ]
    antitumor activities
  • circulating messenger ribonucleic acid (mRNA) [ Time Frame: 6 months ]
    antitumor activities
  • prostate-specific antigen (PSA) [ Time Frame: 6 months ]
    biomarker
  • prostatic acid phosphatase (PAP) [ Time Frame: 6 months ]
    biomarker
  • bone alkaline phosphatase (BAP) [ Time Frame: 6 months ]
    biomarker
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability, and PK of GT0918 (Proxalutamide) in Subjects With Metastatic Castrate Prostate Cancer
Official Title  ICMJE A Phase 1/2, Multi-Center, Open-Label, Two-Stage Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of GT0918 in Subjects With Metastatic Castrate Resistant Prostate Cancer (mCRPC)
Brief Summary

This was a Phase 1, multicenter, open-label, clinical trial in adult subjects with metastatic castrate resistant prostate cancer who progressed after both hormonal therapy (abiraterone or enzalutamide) and chemotherapy (docetaxel), or cannot tolerate either or both therapies.

The study involved a Phase 1 dose escalation of oral GT0918 to evaluate its safety, tolerability, pharmacokinetics and pharmacodynamics.

Detailed Description

GT0918 treatment was initiated with the first dose of 50 mg/day in a cohort of 3 patients, and 6- patients per cohort for the subsequent escalated dose levels at 100 mg, 200 mg, 300 mg, 400 mg, 500 mg and 600 mg/day. Patients received orally administered GT0918 once daily at the indicated doses for 28 consecutive days (4 weeks), followed by a 7-day off-treatment period for PK analysis. This concluded the Cycle 1 treatment. Patients who could not complete the first cycle of 28 days for DLT evaluation were to be considered as early termination and replaced. Upon completion of the Cycle 1 treatment, if no DLT occurred in the cohort of 3 patients, or no more than 1 patient had DLT in cohorts with at least 6 patients, dose escalation was allowed for the subsequent higher dose.

Patients were to receive up to 6 cycles of GT0918 treatments at their assigned dose levels if they were evaluated by the investigator to have no unacceptable toxicity and show evidence of clinical benefit (stable disease or a response) per RECIST v1.1 criteria and PSA assessments. No off-treatment periods were scheduled for the additional cycles from Cycle 2 beyond. Patients had to be evaluated bi-monthly for their eligibility to continue the treatment of additional cycles. Patient evaluations included CT and/or MRI scans performed every 2 cycles (8 weeks), as well as physical examinations, ECOG performance status, PSA measurements, which were performed every 4 weeks. Cycles beyond the 6th cycle were optional for eligible subjects that did not exhibit progressive disease (PD). Eligible patients could be treated for a total of 6 months at their assigned dose level at the investigator's discretion.

Patients would have an End-of-Study (EOS) visit if treatment were discontinued due to intolerable toxicities, disease progression, withdrawal of consent. Safety follow-up for possible delayed drug-related AE or side effects can be performed by phone call or office visit if needed.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Castrate Resistant Prostate Cancer (mCRPC)
Intervention  ICMJE Drug: GT0918
anti-tumor activity
Other Names:
  • androgen receptor antagonist
  • proxalutamide
Study Arms  ICMJE Experimental: Phase 1 GT0918 level 1
generic name: not applicable dosage form: tablet dosage: oral dosage to be determined dosage frequency: daily dosage duration: 6 months
Intervention: Drug: GT0918
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 13, 2020)
40
Original Estimated Enrollment  ICMJE
 (submitted: July 5, 2016)
90
Actual Study Completion Date  ICMJE February 15, 2020
Actual Primary Completion Date May 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Written informed consent obtained prior to any study-related procedure being performed.
  2. Subjects at least 18 years of age or older at the time of consent.
  3. Histologically confirmed metastatic castrate resistant cancer (mCRPC) who progressed after both hormonal therapy (abiraterone or enzalutamide) and chemotherapy (docetaxel, for example); or cannot tolerate either or both of these classes of therapies.
  4. Ongoing androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) "super-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 or chemotherapy. Progressive disease is defined by 1 or more of the following criteria:

    • Subjects with a rising PSA value > 2 ng/mL in at least 2 measurements, at least 1 week apart. If the confirmatory PSA value is less than the screening PSA value, then an additional test for the rising PSA is required to document progression.
    • Subjects with measurable disease, progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
    • Subjects with metastatic bone disease, progression defined by 2 or more new lesions in a radionuclide bone scan.
  7. ECOG performance status of 0-2 (dose escalation phase); ECOG performance status of 0-1 (expansion phase).
  8. Screening blood counts of the following:

    • Absolute neutrophil count ≥ 1500/μL
    • Platelets ≥ 100,000/μL
    • Hemoglobin > 9 g/dL
  9. Screening chemistry values of the following:

    • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 × upper limit of the normal reference range (ULN)
    • Total bilirubin ≤ 2 × ULN
    • Creatinine ≤ 1.5 × ULN
    • Albumin > 2.8 g/dL.
  10. At screening, life expectancy of at least 3 months.
  11. Subjects whose partners are women of childbearing potential (WOCBP) must use an adequate method of birth control while on study drug and at least for 3 weeks after discontinuation of study drug.
  12. Subject is willing and able to comply with all protocol required visits and assessments.

Exclusion Criteria:

  1. Subjects with life expectancy less than 3 months.
  2. Discontinuation of bicalutamide or nilutamide less than 6 weeks, and other antiandrogens less than 4 weeks, abiraterone less than 3 weeks, prior to the start of study medication.
  3. Prior chemotherapy, radiation, sipuleucel-T or other experimental immunotherapy less than 4 weeks prior to the start of study medication.
  4. Prior chemotherapies more than 2 lines (Phase II part only) .
  5. Ongoing acute treatment-related toxicity associated with a previous therapy greater than grade 1 except for grade 2 alopecia or neuropathy.
  6. History of impaired adrenal gland function (eg, Addison's disease, Cushing's syndrome).
  7. Known gastrointestinal disease or condition that affects the absorption of GT0918.
  8. History of congestive heart failure New York Heart Association (NYHA) class III or IV or uncontrolled hypertension at screening.
  9. History or family history of long QT syndrome.
  10. History of other malignancy within the previous 3 years, except basal cell or squamous cell carcinoma, or non-muscle invasive bladder cancer.
  11. Use of systemic glucocorticoid (eg, prednisone, dexamethasone) within 14 days prior to the start of study medication.
  12. Co-administration of CYP3A4 ligands that serve as substrates or induce or inhibit the enzyme.
  13. Prior use of any herbal products known to decrease PSA levels (eg, PC-SPES or saw palmetto) within 30 days prior to the start of study medication.
  14. Major surgery within 30 days prior to the start of study medication.
  15. Blood transfusion (including blood products) within 1 week of screening.
  16. Serious persistent infection within 14 days prior to the start of study medication.
  17. Serious concurrent medical condition including CNS disorders.
  18. Previous history of difficulty swallowing capsules.
  19. Known hypersensitivity to GT0918 or its excipients.
  20. Any condition that, in the opinion of the investigator, would impair the subject's ability to comply with study procedures.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02826772
Other Study ID Numbers  ICMJE GT0918-US-1001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Suzhou Kintor Pharmaceutical Inc,
Study Sponsor  ICMJE Suzhou Kintor Pharmaceutical Inc,
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Phoebe Zhang, PhD Suzhou Kintor Pharmaceuticals, Inc.
PRS Account Suzhou Kintor Pharmaceutical Inc,
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP