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Study of the Efficacy, Safety, and Pharmacokinetics of SM88 in Patients With Prostate Cancer

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ClinicalTrials.gov Identifier: NCT02796898
Recruitment Status : Recruiting
First Posted : June 13, 2016
Last Update Posted : October 29, 2018
Sponsor:
Information provided by (Responsible Party):
Tyme, Inc

Tracking Information
First Submitted Date  ICMJE May 30, 2016
First Posted Date  ICMJE June 13, 2016
Last Update Posted Date October 29, 2018
Study Start Date  ICMJE June 2016
Estimated Primary Completion Date December 31, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 26, 2016)
The dose limiting toxicity (DLT), and maximum tolerated dose (MTD) or minimum effective optimum dose of SM88, when 2 dose levels of SM88 are evaluated. [ Time Frame: Six months ]
During 4 days of single dose PK evaluations [Phase 1b only], and six 4-week treatment cycles, we will determine if patients in consecutive cohorts experience any dose limiting toxicity to determine MTD, or a complete response with no DLTs observed to determine the optimum dose.
Original Primary Outcome Measures  ICMJE
 (submitted: June 7, 2016)
  • Identify the optimum dose of SM88. [ Time Frame: Six months ]
    During 4 days of single dose PK evaluations [Phase 1b only], and six 4-week treatment cycles, we will determine if patients in consecutive cohorts experience a complete response with no DLTs observed. The higher of those 2 dose levels will be determined to be the optimum dose will be further developed.
  • Identify the dose limiting toxicity of SM88 [ Time Frame: Six months ]
    4 days of single dose PK evaluations [Phase 1b only], and six 4-week treatment cycles will be used to determine dose limiting toxicity when any of the following occur:
    • Any Grade 4 neutropenia or febrile neutropenia
    • Any Grade 3 neutropenia with fever
    • Any Grade 4 thrombocytopenia
    • Any Grade 3 thrombocytopenia with bleeding
    • Any recurrent >Grade 3 anemia not associated with bleeding
    Non-hematological DLTs will include: • Any >Grade 3 toxicity except for:
    • Any >Grade 3 nausea and vomiting of <72 hours duration with maximal supportive care
    • Any >Grade 3 diarrhea of < 72 hours duration with maximal supportive care
    • Any >Grade 3 electrolyte or mineral abnormality which does not resolve within 24 hour to < Grade 1 with repletion
    • Any treatment related toxicity of >Grade 2 that does not resolve to <Grade 1 within 7 days while study therapy is held
  • Identify the maximum tolerated dose of SM88 [ Time Frame: Six months ]
    4 days of single dose PK evaluations [Phase 1b only], and six 4-week treatment cycles will be used to determine the MTD defined as: If 2 or more subjects in a cohort experience a DLT, then the previous dose will be defined as the MTD and will be selected for further evaluation.
  • Identify the minimum effective dose of SM88 [ Time Frame: Six months ]
    4 days of single dose PK evaluations [Phase 1b only], and six 4-week treatment cycles will be used to identify the minimum effective dose. Minimum effective dose is defined as: If 2 patients in 2 consecutive cohorts experience a complete response with no DLTs, then the higher of those 2 dose levels will be determined to be the minimum effective dose, and selected for further evaluation.
Change History Complete list of historical versions of study NCT02796898 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 16, 2017)
  • Single dose pharmacokinetics (PK) of tyrosine based isomer alone and as a component of SM88 in patients with prostate cancer. [ Time Frame: Six months ]
    After a single dose of tyrosine based isomer alone on PK Day 1, and a single dose of SM88 on PK Day 3, the plasma concentrations of tyrosine isomers in patients with prostate cancer will be assayed.
  • Multi-dose PK of the individual isomers of tyrosine. [ Time Frame: Six months ]
    The plasma concentrations of tyrosine isomers associated with morning and evening doses of tyrosine isomers on PK Day 1, and also associated with morning and evening doses of SM88, in patients with prostate cancer will be assayed.
  • Multi-dose steady state PK of all 4 components of SM88 in patients with prostate cancer. [ Time Frame: Six months ]
    After approximately 2 weeks of daily dosing of SM88, the plasma concentrations of tyrosine isomers as well as the other 3 drugs of SM88 in patients with prostate cancer will be assayed.
  • Safety and tolerability of SM88 in patients with prostate cancer. [ Time Frame: Six months ]
    Changes from baseline in blood work results and incidence of adverse events associated with treatment of SM88 in patients with prostate cancer.
  • Anti-cancer activities of SM88 in patients with prostate cancer. [ Time Frame: Six Months ]
    Changes from baseline in CTCs, and PSA level per Prostate Cancer Working Group 3 (PCWG3) criteria and radiography per RECIST 1.1 criterial, stratified by circulating tumor cells (CTC) and other blood-based markers including lactate dehydrogenase (LDH), total alkaline phosphatase, bone-specific alkaline phosphatase, urine N-telopeptide, hemoglobin, and neutrophil:lymphocyte ratio (NLR).
  • Correlation of toxicity and efficacy with cutaneous hyperpigmentation [ Time Frame: Six Months ]
    The incident and severity (as assessed by CTCAE v4.0) of treatment-related adverse events and anticancer activities of SM88 are correlated with the degree of cutaneous pigmentation (measured by quantitative image analysis of subject skin color). The total number of subjects with adverse events and efficacy with changes in skin pigmentation during treatment will be reported in aggregate. We will evaluate cutaneous pigmentation as a biomarker in the treatment of prostate cancer by SM88 and stratify pigmentation and known risk factors for outcome analysis.
  • Radiographic progression-free-survival (rPFS) [ Time Frame: Six Months ]
    Duration of survival since treatment initiation with SM88 of study subjects who are without disease progression according to radiology, stratified by PSA level, CTC, and other blood-based markers (including LDH, total alkaline phosphatase, bone-specific alkaline phosphatase, urine N-telopeptide, hemoglobin, and NLR).
  • PSA doubling time before, during and after SM88 [ Time Frame: Six Months ]
    PSA doubling time before, during and after SM88 treatment will be compared to evaluate disease progression rate associated with SM88 treatment.
  • Effect of SM88 on patient-reported outcomes including quality of life (as measured by the EORTC QLQ-30 and EORTC QLQ-PR25) in patients with prostate cancer. [ Time Frame: Six Months ]
    Changes from baseline in the Quality-of-Life, as measured by EORTC QLQ-30 and QLQ-PR25, stratified by PSA level, CTC, and other blood-based markers (including LDH, total alkaline phosphatase, bone-specific alkaline phosphatase, urine N-telopeptide, hemoglobin, and NLR in patients with prostate cancer).
  • Effect of SM88 on performance status in patients with prostate cancer. [ Time Frame: Six months ]
    Changes from baseline in the performance status (as measured by Eastern Cooperative Oncology Group (ECOG) score) in patients with prostate cancer.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2016)
  • Single dose PK Maximum Plasma Concentration [Cmax] of Tyrosine Isomers [ Time Frame: Six months ]
    Evaluate the single dose PK Maximum Plasma Concentration [Cmax] of tyrosine isomer alone and as a component of SM88 in patients with prostate cancer.
  • Steady State PK Maximum Plasma Concentration [Cmax] of Tyrosine Isomers [ Time Frame: Six months ]
    Evaluate the steady state PK Maximum Plasma Concentration [Cmax] of tyrosine isomer alone and as a component of SM88 in patients with prostate cancer.
  • Single dose PK Area under the plasma concentration versus time curve (AUC) of Tyrosine Isomers [ Time Frame: Six months ]
    Evaluate the single dose PK Area under the plasma concentration versus time curve (AUC) of the individual isomers tyrosine.
  • Steady State PK Area under the plasma concentration versus time curve (AUC) of Tyrosine Isomers [ Time Frame: Six months ]
    Evaluate the steady state PK Area under the plasma concentration versus time curve (AUC) of the individual isomers tyrosine.
  • Single dose PK Maximum Plasma Concentration [Cmax] of all 4 components of SM88 [ Time Frame: Six months ]
    Evaluate the single dose PK Maximum Plasma Concentration [Cmax] of tyrosine isomer alone and as a component of SM88 in patients with prostate cancer. Evaluate the single dose PK of all 4 components of SM88 in patients with prostate cancer.
  • Steady State PK Maximum Plasma Concentration [Cmax] of all 4 components of SM88 [ Time Frame: Six Months ]
    Evaluate the steady state PK Maximum Plasma Concentration [Cmax] of tyrosine isomer alone and as a component of SM88 in patients with prostate cancer. Evaluate the single dose PK of all 4 components of SM88 in patients with prostate cancer.
  • Single Dose PK Area under the plasma concentration versus time curve (AUC) of tall 4 components of SM88 [ Time Frame: Six months ]
    Evaluate the single dose PK Maximum Plasma Concentration [Cmax] of tyrosine isomer alone and as a component of SM88 in patients with prostate cancer. Evaluate the single dose PK of all 4 components of SM88 in patients with prostate cancer.
  • Steady State PK Area under the plasma concentration versus time curve (AUC) of tall 4 components of SM88 [ Time Frame: Six months ]
    Evaluate the single dose PK Maximum Plasma Concentration [Cmax] of tyrosine isomer alone and as a component of SM88 in patients with prostate cancer. Evaluate the single dose PK of all 4 components of SM88 in patients with prostate cancer.
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Six months ]
    Evaluate the safety and tolerability of SM88 in patients with prostate cancer. Collate the adverse events that develop in subjects on trial.
  • PSA progression [ Time Frame: Six Months ]
    Evaluate the efficacy of SM88 as measured by PSA progression. Evaluate the efficacy if SM88 as measured by PSA level, stratified by circulating tumor cells (CTC), and other blood-based markers (including lactate dehydrogenase [LDH], total alkaline phosphatase, bone-specific alkaline phosphatase, urine N-telopeptide, hemoglobin, and neutrophil:lymphocyte ratio [NLR]) of SM88
  • Metastases free survival [ Time Frame: Six Months ]
    Evaluate the efficacy if SM88 as measured by metastases free survival stratified by PSA level, circulating tumor cells (CTC), and other blood-based markers (including lactate dehydrogenase [LDH], total alkaline phosphatase, bone-specific alkaline phosphatase, urine N-telopeptide, hemoglobin, and neutrophil:lymphocyte ratio [NLR]) of SM88
  • EORTC QLQ-PR25 [ Time Frame: Six Months ]
    Evaluate the quality of life efficacy of SM88 as measured by EORTC QLQ-PR25. Evaluate the efficacy of SM88 as measured by EORTC QLQ-PR25 stratified by PSA level, circulating tumor cells (CTC), and other blood-based markers (including lactate dehydrogenase [LDH], total alkaline phosphatase, bone-specific alkaline phosphatase, urine N-telopeptide, hemoglobin, and neutrophil:lymphocyte ratio [NLR]) of SM88
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 correlated with cutaneous pigmentation. [ Time Frame: Six Months ]
    All adverse events will be coded as present or absent. The total count of the number of participants with treatment-related adverse events as assessed by CTCAE v4.0 will be reported according to the degree of cutaneous pigmentation. Toxicity (yes or no) and efficacy (yes or no) of SM88 will be reported according to the degree of cutaneous pigmentation as measured by quantitative image analysis of subject skin color. The total number of subjects with adverse events with changes in skin pigmentation during treatment will be reported in aggregate. We will evaluate cutaneous pigmentation as a biomarker in the treatment of prostate cancer by SM88 and stratify pigmentation and known risk factors for outcome analysis.
  • EORTC QLQ-30 [ Time Frame: Six months ]
    Patient-reported outcomes using the EORTC QLQ-30. Evaluate the effect of SM88 on patient-reported outcomes including quality of life (as measured by the EORTC QLQ-30 and EORTC QLQ-PR25) in patients with prostate cancer. Patient reported outcomes will be presented using the validated aggregate score of this established research tool.
  • EORTC QLQ-PR25 [ Time Frame: Six months ]
    Patient-reported using the EORTC QLQ-PR25 validated aggregate score. Evaluate the effect of SM88 on patient-reported outcomes including quality of life (as measured by the EORTC QLQ-30 and EORTC QLQ-PR25) in patients with prostate cancer. Patient reported outcomes will be presented as the validated aggregate score of this established research tool.
  • Eastern Cooperative Oncology Group [ECOG] score) [ Time Frame: Six months ]
    Measure performance status to evaluate the effect of SM88 on performance status (as measured by Eastern Cooperative Oncology Group [ECOG] score) in patients with prostate cancer.
Current Other Pre-specified Outcome Measures
 (submitted: November 26, 2016)
  • Cutaneous hyperpigmentation as a biomarker in the treatment of prostate cancer by SM88. [ Time Frame: Six months ]
    Correlation between the anti-cancer activities of SM88 vs. the degree of cutaneous pigmentation (measured by quantitative image analysis of subject skin color). The total number of subjects with efficacy and changes in skin pigmentation during treatment will be reported in aggregate. We will evaluate cutaneous pigmentation as a biomarker for the efficacy of SM88 treatment in patients with prostate cancer.
  • Collection of lymphocyte counts as a biomarker for efficacy. [ Time Frame: Six months ]
    The efficacy of SM88 will be correlated with lymphocyte counts. The total number of subjects with efficacy and lymphocyte counts during treatment will be reported in aggregate. We will evaluate lymphocyte counts as a biomarker for the efficacy of SM88 treatment in patients with prostate cancer.
  • Stratification of outcome with known risk factors for prostate cancer. [ Time Frame: Six months ]
    Stratification of anticancer activities with known risk factors for prostate cancer.
  • Duration of time when a subsequent therapy is needed after treatment with SM88. [ Time Frame: Six months ]
    The duration in time for another therapy due to recurrence of disease.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of the Efficacy, Safety, and Pharmacokinetics of SM88 in Patients With Prostate Cancer
Official Title  ICMJE A Phase 1b/2, Open-Label, Dose Escalation Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of SM88 in Patients With Prostate Cancer
Brief Summary The purpose of this study is to evaluate the safety, pharmacokinetics, and efficacy of SM88 in patients with prostate cancer
Detailed Description

This is an open-label, multi-center, dose-escalating, dose-expansion study of SM88 in patients with prostate cancer. This study includes 2 phases, a dose-escalation phase that includes PK evaluation, and a dose-expansion phase.

During the first stage, at up to 2 institutions, up to 2 cohorts of 1 to 6 patients each will be enrolled.

During the second stage, the dose selected for evaluation from the Phase 1b will be administered for a total of 30 evaluable patients (inclusive of those treated at the same dose during the dose selection phase) for 6 cycles or until unacceptable toxicity, disease progression, or until any of the treatment discontinuation criteria are met.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Prostate Cancer
  • Rising Prostate Specific Antigen (PSA)
Intervention  ICMJE
  • Drug: SM88 (Cohort 1)
    • Tyrosine Isomers - 230 mg qd
    • Phenytoin - 50 mg qd.
    • Methoxsalen - 10 mg qd
    • Sirolimus - 0.5 mg qd
    Other Name: SM88
  • Drug: SM88 (Cohort 2)
    • Tyrosine Isomers - 460 mg (230 mg bid)
    • Phenytoin - 50 mg qd
    • Methoxsalen - 10 mg qd
    • Sirolimus - 0.5 mg qd
    Other Name: SM88
Study Arms  ICMJE Experimental: Treated Group

SM88 is a combination therapy consisting of 4 agents. One agent, the tyrosine isomer will be increased in each of 2 dose cohorts as follows:

Cohort 1:

  • Tyrosine isomers - 230 mg qd
  • Phenytoin - 50 mg qd.
  • Methoxsalen - 10 mg qd
  • Sirolimus - 0.5 mg qd

Cohort 2:

Cohort 2 has increasing tyrosine isomer from q.d. to b.i.d.

Expansion Cohort:

The optimum dose will be expanded in 2nd stage of the study to 30 subjects.

Interventions:
  • Drug: SM88 (Cohort 1)
  • Drug: SM88 (Cohort 2)
Publications *

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 26, 2016)
42
Original Estimated Enrollment  ICMJE
 (submitted: June 7, 2016)
54
Estimated Study Completion Date  ICMJE December 31, 2019
Estimated Primary Completion Date December 31, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male ≥18 years of age.
  2. Histologically or cytologically confirmed prostate cancer (patients with neuroendocrine carcinoma of the prostate are excluded).
  3. Documented PSA progression. Pre-enrollment PSA progression will be as defined by the PCWG3 criteria, e.g. 3 values, increasing, each >7 days apart.
  4. ECOG performance status ≤1
  5. Life expectancy >3 months, in the judgment of the investigator.
  6. Adequate organ function defined as follows:

    1. Hematologic: Platelets ≥100 x 109 /L; Absolute Neutrophil Count (ANC) ≥1.5 x 109/L (without platelet transfusion or growth factors within the 7 days prior to the screening laboratory assessment)
    2. Hepatic: aspartate transaminase (AST)/alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN); total or conjugated bilirubin ≤1.5 x ULN
    3. Renal: serum creatinine ≤1.5 x ULN or creatinine clearance (CrCl) ≥60 mL/min as calculated by the Cockroft-Gault method
  7. Coagulation: International normalized ratio (INR) ≤1.2
  8. With or without one prior line of chemotherapy
  9. With or without prior or current ADT or hormone based therapy (up to 2 lines total)
  10. Cannot tolerate standard chemotherapy, hormone based therapy or ADT, or elects to opt out of standard therapies.
  11. Patients who are on ADT prior to the study need not discontinue such therapy during the study, but the use of ADT during the study must be documented.
  12. All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before baseline, with the exception of alopecia (Grade 1 or 2 permitted) and neurotoxicity (Grade 1 or 2 permitted)
  13. Male patients of fertile potential who engage in heterosexual intercourse with female partners of childbearing potential must agree to use highly effective contraception while enrolled in the study and for at least 6 months following the last dose of study drug. Highly effective birth control methods include the following (the patient should choose 2 to be used with their partner):

    1. Oral, injectable, or implanted hormonal contraceptives
    2. Condom with a spermicidal foam, gel, film, cream, or suppository
    3. Occlusive cap (diaphragm or cervical/vault cap) with a spermicidal foam, gel, film, cream, or suppository
    4. Intrauterine device
    5. Intrauterine system (for example, progestin-releasing coil)
    6. Vasectomized male (as determined by the investigator)
  14. Able and willing to provide written informed consent to participate in this study

Exclusion Criteria:

  1. PSA minimum starting value <1 ng/mL at trial entry.
  2. Metastatic disease as detected on bone scan, Computed Tomography (CT), Magnetic Resonance Imaging (MRI), or CT-positron emission tomography (PET) beyond the prostate or post-surgical prostate area.
  3. Any screening laboratory, electrocardiogram (ECG), or other findings that, in the opinion of the investigator or the sponsor, indicate an unacceptable risk for the patient's participation in the study.
  4. History or evidence of any clinically significant disorder, condition, or disease that, in the opinion of the investigator or medical monitor would pose a risk to the patient's safety or interfere with the study evaluations, procedures, or completion. Examples include intercurrent illness such as active uncontrolled infection, active or chronic bleeding event within 28 days of baseline, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements.
  5. History of a concurrent or second malignancy, except for adequately treated local basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, adequately treated Stage 1 or 2 cancer currently in complete remission; or any other cancer that has been in complete remission for ≥5 years
  6. Local therapy such as radiation or surgery within 8 weeks of study baseline.
  7. Current use of a prohibited medication (see Section 8.5) or requires any of these medications during treatment phase
  8. Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (i.e., larger than that required for placement of central venous access, percutaneous feeding tube, or biopsy) within 28 days of the first dose of study drug
  9. Minor surgical procedures within 7 days of baseline, or not yet recovered from prior surgery
  10. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of any of the components of SM88, e.g. cirrhosis
  11. Known human immunodeficiency (HIV) virus infection
  12. Hepatitis B surface antigen (HBsAg) positive
  13. Hepatitis C virus (HCV) antibody positive
  14. Have previously been enrolled in this study or any other study investigating SM88
  15. History of any drug allergies or significant adverse reactions to any of the components of SM88.
  16. Are currently enrolled in, or have discontinued within 30 days of screening, from a clinical trial involving an investigational product or non-approved use of a drug or device.
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: Avi Kamelhar 718.732.4010 Avi@axellaresearch.com
Contact: Carmen Vicuna 718-732-4078 cvicuna@nycancer.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02796898
Other Study ID Numbers  ICMJE Tyme 2016b
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Tyme, Inc
Study Sponsor  ICMJE Tyme, Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Giuseppe Del Priore, MD, MPH Chief Medical Officer TYME Inc.
PRS Account Tyme, Inc
Verification Date June 2018

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