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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, pharmacokinetics, and efficacy of SM88 in patients with prostate cancer

Detailed Description
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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.

Official Title
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A Phase 1b/2, Open-Label, Dose Escalation Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of SM88 in Patients With Prostate Cancer

Conditions
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Prostate Cancer, Rising Prostate Specific Antigen (PSA)

Intervention / Treatment
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* Drug: SM88 (Cohort 1)
* Drug: SM88 (Cohort 2)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male ≥18 years of age. Histologically or cytologically confirmed prostate cancer (patients with neuroendocrine carcinoma of the prostate are excluded). Documented PSA progression. Pre-enrollment PSA progression will be as defined by the PCWG3 criteria, e.g. 3 values, increasing, each >7 days apart. ECOG performance status ≤1 Life expectancy >3 months, in the judgment of the investigator. Adequate organ function defined as follows: 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) Hepatic: aspartate transaminase (AST)/alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN); total or conjugated bilirubin ≤1.5 x ULN Renal: serum creatinine ≤1.5 x ULN or creatinine clearance (CrCl) ≥60 mL/min as calculated by the Cockroft-Gault method Coagulation: International normalized ratio (INR) ≤1.2 With or without one prior line of chemotherapy With or without prior or current ADT or hormone based therapy (up to 2 lines total) Cannot tolerate standard chemotherapy, hormone based therapy or ADT, or elects to opt out of standard therapies. 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. 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) 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): Oral, injectable, or implanted hormonal contraceptives Condom with a spermicidal foam, gel, film, cream, or suppository Occlusive cap (diaphragm or cervical/vault cap) with a spermicidal foam, gel, film, cream, or suppository Intrauterine device Intrauterine system (for example, progestin-releasing coil) Vasectomized male (as determined by the investigator) Able and willing to provide written informed consent to participate in this study Exclusion Criteria: PSA minimum starting value <1 ng/mL at trial entry. 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. 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. 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. 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 Local therapy such as radiation or surgery within 8 weeks of study baseline. Current use of a prohibited medication (see Section 8.5) or requires any of these medications during treatment phase 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 Minor surgical procedures within 7 days of baseline, or not yet recovered from prior surgery Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of any of the components of SM88, e.g. cirrhosis Known human immunodeficiency (HIV) virus infection Hepatitis B surface antigen (HBsAg) positive Hepatitis C virus (HCV) antibody positive Have previously been enrolled in this study or any other study investigating SM88 History of any drug allergies or significant adverse reactions to any of the components of SM88. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treated Group<br>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. | Drug: SM88 (Cohort 1)<br>* Tyrosine Isomers - 230 mg qd Phenytoin - 50 mg qd. Methoxsalen - 10 mg qd Sirolimus - 0.5 mg qd<br>* Other names: SM88;Drug: SM88 (Cohort 2)<br>* Tyrosine Isomers - 460 mg (230 mg bid) Phenytoin - 50 mg qd Methoxsalen - 10 mg qd Sirolimus - 0.5 mg qd<br>* Other names: SM88;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single dose pharmacokinetics (PK) of tyrosine based isomer alone and as a component of SM88 in patients with prostate cancer. | 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. | Six months | 
| Multi-dose PK of the individual isomers of tyrosine. | 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. | Six months | 
| Multi-dose steady state PK of all 4 components of SM88 in patients with prostate cancer. | 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. | Six months | 
| Safety and tolerability of SM88 in patients with prostate cancer. | Changes from baseline in blood work results and incidence of adverse events associated with treatment of SM88 in patients with prostate cancer. | Six months | 
| Anti-cancer activities of SM88 in patients with prostate cancer. | 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). | Six Months | 
| Correlation of toxicity and efficacy with cutaneous hyperpigmentation | 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. | Six Months | 
| Radiographic progression-free-survival (rPFS) | 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). | Six Months | 
| PSA doubling time before, during and after SM88 | PSA doubling time before, during and after SM88 treatment will be compared to evaluate disease progression rate associated with SM88 treatment. | Six Months | 
| 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. | 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). | Six Months | 
| Effect of SM88 on performance status in patients with prostate cancer. | Changes from baseline in the performance status (as measured by Eastern Cooperative Oncology Group (ECOG) score) in patients with prostate cancer. | Six months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, PSA, Androgen Deprivation Therapy (ADT)