A Phase 1b Dose Escalation Trial of PSK®/Placebo With Docetaxel to Treat Metastatic Castration-resistant Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
This is a phase 1b study that follows a 3+3 dose escalation design and consists of a 21-day lead-in period of oral Polysaccharide Krestin (PSK)/placebo (study drug) alone followed by the addition to study drug of standard intravenous docetaxel at 75 mg/m2 every 3 weeks for three cycles. Study drug will be discontinued on day 15 of the third docetaxel cycle to allow for a 7-day washout period before the fourth dose of docetaxel. Pharmacokinetic (PK) analysis of docetaxel will be conducted during docetaxel cycle 1 (combination therapy) and cycle 4 (docetaxel alone). Serum for future PSK PK analysis will be collected on days 1, 3, and 15 of PSK/placebo lead-in and during cycles 1 and 4.

Official Title
-----------------
A Phase 1b Dose Escalation Trial of PSK®/Placebo With Docetaxel to Treat Metastatic Castration-resistant Prostate Cancer

Conditions
-----------------
Prostatic Neoplasms

Intervention / Treatment
-----------------
* Drug: Docetaxel, PSK®
* Drug: Docetaxel, Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male patients 18 years or older Histologically confirmed diagnosis of adenocarcinoma of the prostate Evidence of metastatic disease by standard imaging studies (bone scan, Computerized Tomography Scan (CT) or Magnetic Resonance Imaging (MRI)) Testosterone levels <50 ng/dL Confirmed progressive disease defined by one or more of the following: an increase in PSA, > 2ng/dL x 2 or more values at least 1 week apart in the setting of metastatic disease appearance of new bone lesions on bone scan progression of soft tissue lesion defined by the Response Evaluation Criteria In Solid Tumors [RECIST] 1.1 criteria Concurrent use of an agent for testosterone suppression (e.g., Luteinizing Hormone Releasing Hormone [LHRH] agonist) if the patient is not surgically castrate Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 determined within 28 days before enrollment Recovery to CTCAE grade ≤ 1 toxicity, to patient's baseline status (except alopecia), or toxicities deemed irreversible from the effects of prior cancer therapy (CTCAEs grade > 1 that are not considered a safety risk by the investigator will be allowed) Adequate bone marrow function defined as: absolute neutrophil count (ANC) > 1500 cells/mm³ without growth factor support platelet count > 100,000 cells/mm³ without transfusion or growth factor support hemoglobin > 9g/dL without transfusion or growth factor support Adequate liver function defined as: total bilirubin < upper limit of normal (ULN) alanine aminotransferase (ALT) < 1.5 x ULN aspartate aminotransferase (AST) < 1.5 x ULN Adequate renal function defined as serum creatinine level within normal limits (WNL) At least a 6-month or greater life expectancy Ability to understand and sign a written informed consent, which will be obtained from study participants before undergoing any study-specific procedures Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures Suitable venous access for the study-required blood sampling (i.e., including PK sampling) Exclusion Criteria: Prior treatment with antineoplastic chemotherapy or radioisotopes for metastatic disease Prior adjuvant or neo-adjuvant chemotherapy within 12 months of study entry Last dose of sipuleucel-T therapy within 4 weeks of enrollment Any investigational therapies within 4 weeks of study entry Radiotherapy within 4 weeks of study entry Major surgery within 4 weeks of study entry, and not fully recovered to baseline or a stable clinical status Uncontrolled high blood pressure (systolic blood pressure > 160mmHg, diastolic blood pressure > 95mmHg) Receiving chronic steroid therapy. Topical and inhaled steroids are permitted Known severe hypersensitivity reactions to docetaxel or other drugs formulated in polysorbate 80, or to mushroom products Any comorbid condition or unresolved toxicity that would preclude administration of docetaxel Medical contraindication to any docetaxel pre-medications History of > grade 2 neurotoxicity or any toxicity from any cause that has not resolved to < grade 1 Brain or other CNS metastasis The need for chronic daily immunosuppressive therapy, including concurrent use of prednisone Evidence of active second malignancy, except non-melanoma skin cancer Infection requiring intravenous antibiotic therapy or other severe infection within 14 days preceding first dose of study drug Inability to swallow oral medication or maintain a fast, as required 2 hours before and 1 hour after PSK administration Uncontrolled pain at baseline, impending complication from bone metastasis and/or presence of urinary obstruction Other medical or psychiatric condition that may increase the risk associated with trial participation or any other condition in the judgment of the investigator that may interfere with the interpretation of trial results or would make the patient inappropriate for enrollment in this trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Docetaxel, PSK®<br>A 21-day lead-in oral PSK alone is followed by the addition of standard intravenous docetaxel at 75 mg/m2 evey 3 weeks for three cycles. After the third dose of docetaxel, study drug will be discontinued on day 14 to allow for a 7-day washout period before a fourth dose of docetaxel is administered. | Drug: Docetaxel, PSK®<br> <br> * Other names: Polysaccharide-Kureha;|
| Placebo Comparator: Docetaxel, Placebo<br>A 21-day lead-in oral placebo alone is followed by the addition of standard intravenous docetaxel at 75 mg/m2 every 3 weeks for three cycles. After the third dose of docetaxel, the placebo will be discontinued on day 14 to allow for a 7-day washout period before a fourth dose of docetaxel is administered. | Drug: Docetaxel, Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine tolerability dose of PSK alone and in combination with docetaxel | Adverse events are graded to determine a dose limiting toxicity of PSK during the lead-in PSK alone and during the docetaxel treatment in combination with PSK. | 42 days | 
| Determine maximum tolerated dose and recommended phase 2 dose of PSK in combination with docetaxel | When the maximum tolerated dose is determined, a total of 15 patients will be treated with the recommended phase 2 dose with the combination of docetaxel chemotherapy. | 106 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of docetaxel when combined with oral PSK | The plasma docetaxel levels are analyzed at eight time points during the cycle 1 of standard intravenous docetaxel at 75 mg/m2 with oral PSK/Placebo. After the seven-day washout of PSK/placebo at the cycle 3, the plasma docetaxel levels are analyzed again at eight time points during the cycle 4 of docetaxel treatment without PSK/Placebo. | 106 days | 
| Pharmacokinetics of oral PSK dosing and in combination with docetaxel | The serum PSK levels are analyzed at two time points during the lead-in cycle and eight time points during the cycle 1 of standard intravenous docetaxel at 75 mg/m2 with oral PSK/Placebo. After the seven-day washout of PSK/placebo at the cycle 3, the plasma docetaxel levels are analyzed again at eight time points during the cycle 4 of docetaxel treatment without PSK/Placebo. | 106 days | 
| Immunological laboratory analysis | Natural Killer (NK) cell functional activity, distributions of NK, B, and T cells, and IFN-gamma and TNF-alpha production capacity are analyzed and compared to those of the placebo group. | 106 days | 
| Clinical tumor markers | Circulating tumor cell (CTC) and prostate specific antigen (PSA) levels are compared to that of the placebo group during the oral PSK lead-in period and during the combination therapy with docetaxel and PSK. | 106 days | 
| Prostatic acid phosphatase | The serum level of prostatic acid phosphatase levels are compared to that of the placebo group during the oral PSK lead-in period and during the combination therapy with docetaxel and PSK. | 106 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PSK, Prostate, Neoplasm, Adenocarcinoma, Cancer, Metastatic, Castrate resistant, Docetaxel, Krestin, Trametes versicolor, Safety, Maximum tolerated dose, Mushroom, Natural, Immunotherapy