Study of INKmune in Patients With mCRPC (CaRe Prostate)

Study Overview
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Brief Summary
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This is an open-label, phase I/IIa dose escalation and expansion study of INKmune in men with mCRPC. INKmune is administered to patients intravenously over three doses, at least one-week apart. The study will consist of two stages.

Detailed Description
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This is an open-label, phase I/IIa dose escalation and expansion study of INKmune in men with mCRPC. INKmune is administered to patients intravenously over 3 doses. The 3 infusions will occur over a minimum of a 2-week period, with each infusion at least 1 week apart. The study will consist of 2 stages: Dose escalation: exploring dose levels of 1x10^8, 3x10^8 and 5x10^8 cells per infusion (18 patients projected). Dose expansion: following mBOIN termination and maximum tolerated dose (MTD) identification, 12 patients will be enrolled in up to 2 candidate optimal dose levels for final optimal dose determination. Eligible patients will sign informed consent prior to any study assessments being performed. Patients have up to 30 days in which to have all screening procedures and eligibility assessed. Patients will be infused with INKmune on Days 1, 8 and 15. Patients will also present to site on days 29, 57, 85, 113 and 141 to complete study assessments. Day 169 is the last study visit and patient will have completed trial after this visit has been completed. Option to enroll in the INKmune Long term Follow-up Registry will be presented at Day 169 visit.

Official Title
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An Open-label, Phase I/IIa Dose Escalation and Expansion Study to Determine the Safety and Clinical Activity of an Immune Priming Cell Therapy (INKmune) in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)

Conditions
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Cancer, Metastatic Castration-resistant Prostate Cancer, mCRPC

Intervention / Treatment
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* Biological: INKmune


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects over 18 years of age at time of screening. Blood Prostate Specific Antigen (PSA) of >1.0 ng/ml at time of screening. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 at time of screening. Histologic confirmation of adenocarcinoma prostate cancer. A diagnosis of progressive metastatic castrate resistant prostate cancer (mCRPC), as defined by Prostate Cancer Clinical Trials Working Group 3 (PCWG3), following androgen deprivation therapy (ADT) and at least one androgen receptor signaling inhibitor, but not more than 3 therapies in addition to ADT. Progressive disease at the time of study entry as indicated by at least one of the following: i. At least two rising PSA values at a minimum of a one-week interval. If PSA is the only measure of progression, then the minimum PSA value at the start of treatment must be ≥ 1 ng/mL. ii. Radiographic progression per RECIST1.1 for soft tissue (at least 1 measurable lesion per RECIST 1.1), and/or iii. Progression of bone metastases. Castrate level of testosterone of < 50 ng/dL. Adequate organ function indicated by the following laboratory parameters: i. Hemoglobin ≥ 8.0 g/dL. ii. White Blood Cell Count (WBC) ≥ 3.0 x 10⁹/L. iii. Lymphocytes ≥ 80% LLN iv. Absolute Neutrophil Count (ANC) ≥ 1.5 x 10⁹/L. v. Platelets ≥ 100 x 10⁹/L. vi. PT and APTT < 1.5x ULN (unless receiving therapeutic anticoagulation). vii. AST or ALT ≤ 2.5x ULN. AST or ALT ≤ 5x ULN for patients with liver metastases. viii. Bilirubin < 1.5x ULN (< 3x ULN in Gilbert's Syndrome). ix. Creatinine clearance/estimated GFR ≥ 50 mL/min (MDRD or Cockcroft-Gault). x. Resting room air PaO2 saturation of >95% as measured by pulse oximetry. Negative screen for Human Immunodeficiency virus (HIV), Hepatitis B virus (HBV) antigen, and Hepatitis C virus (HCV). If testing was done within the past three months, there is no need to repeat testing if documentation of results is provided to the study site. Subjects and their partners of reproductive potential must agree to use an effective form of contraception during the period of drug administration and for three months following the completion of the last administration of the study drug. An effective form of contraception is defined as oral contraceptives plus one form of barrier method or double barrier methods (condom with spermicide or condom with diaphragm). Subjects must be able to understand the potential risks and benefits of the study and be able to read and give written informed consent. Exclusion Criteria: The participant may not enter the study if ANY of the following apply: Diagnosis of small cell/neuroendocrine prostate cancer. Immunohistochemical staining for neuroendocrine markers (e.g., chromogranin A, neuron-specific enolase, and synaptophysin) is not sufficient to establish a small cell/neuroendocrine histology; morphologic features that are characteristic of small cell/neuroendocrine prostate cancer are required to confirm the presence of small cell/neuroendocrine prostate cancer. History of concurrent malignant cancer within previous 3 years, with the exception of in situ carcinomas and non-melanoma skin cancer. Uncontrolled autoimmune disease including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, temporal arteritis, and thyroiditis. Autoimmune conditions that are well-controlled in the opinion of the investigator must first be discussed with the Sponsor prior to enrollment. A requirement for daily systemic corticosteroids for any reason; or other immunosuppressive or immunomodulatory agents. Topical, nasal, modified-release oral, and/or physiologic corticosteroids may be permitted following discussion with the Sponsor. Clinically significant cardiac disease (New York Heart Association Class III/IV) or severe debilitating pulmonary disease. Patients with a current or recent history, as determined by the Investigator, of clinically significant, progressive, and/or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, gastroenterological, or neurological disease. Cytotoxic chemotherapy within three weeks prior to start of study treatment (Day 1). Radiation therapy within two weeks prior to start of study treatment (Day 1). Patients may not have received a previous NK based therapy. Evidence of central nervous system (CNS) metastatic disease at screening. Patients with an active infection requiring antibiotic treatment within seven days of starting study treatment (Day 1). Administration of live attenuated vaccines within eight weeks of start of study treatment (Day 1) and throughout the study. Any other medical condition that in the opinion of the Investigator may interfere with a subject's participation in, or compliance with, the study Participation in a therapeutic research study or receipt of an investigational drug within 4 weeks of start of treatment (Day 1) or 5 half-lives, whichever occurs first. Expected survival of less than six months

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation using mBOIN design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: 1 x 10^8 INKmune<br>In Dose Escalation: INKmune therapy will be administered by a slow intravenous injection via conventional blood giving set. Approximately 18 patients will receive 3 weekly IV doses of INKmune on Day 1, 8, and 15 as per the below: In Cohort 1, the initial planned dose is 1 x 10^8 INKmune; In Cohort 2, the weekly dose will increase to 3 x 10^8 INKmune; In Cohort 3, the weekly dose will increase to 5 x 10^8 INKmune. In Dose Expansion: INKmune therapy will be administered by a slow intravenous injection via conventional blood giving set. Approximately 12 patients will receive 3 weekly IV doses of INKmune on Day 1, 8, and 15 as per the below: Following mBOIN termination and MTD identification, patients will be enrolled in up to two candidate optimal dose levels (no higher than the MTD) for final optimal dose determination. | Biological: INKmune<br>* INKmune is a patented biologic delivery system and method for cancer treatment using in vivo priming and activation of natural killer (NK) cells in order to achieve tumor cell lysis. INKmune is a suspension of INB16 cells which have been rendered replication incompetent that does not require donor matching.<br>|
| Experimental: Cohort 2: 3 x 10^8 INKmune<br>In Dose Escalation: INKmune therapy will be administered by a slow intravenous injection via conventional blood giving set. Approximately 18 patients will receive 3 weekly IV doses of INKmune on Day 1, 8, and 15 as per the below: In Cohort 1, the initial planned dose is 1 x 10^8 INKmune; In Cohort 2, the weekly dose will increase to 3 x 10^8 INKmune; In Cohort 3, the weekly dose will increase to 5 x 10^8 INKmune. In Dose Expansion: INKmune therapy will be administered by a slow intravenous injection via conventional blood giving set. Approximately 12 patients will receive 3 weekly IV doses of INKmune on Day 1, 8, and 15 as per the below: Following mBOIN termination and MTD identification, patients will be enrolled in up to two candidate optimal dose levels (no higher than the MTD) for final optimal dose determination. | Biological: INKmune<br>* INKmune is a patented biologic delivery system and method for cancer treatment using in vivo priming and activation of natural killer (NK) cells in order to achieve tumor cell lysis. INKmune is a suspension of INB16 cells which have been rendered replication incompetent that does not require donor matching.<br>|
| Experimental: Cohort 3: 5 x 10^8 INKmune<br>In Dose Escalation: INKmune therapy will be administered by a slow intravenous injection via conventional blood giving set. Approximately 18 patients will receive 3 weekly IV doses of INKmune on Day 1, 8, and 15 as per the below: In Cohort 1, the initial planned dose is 1 x 10^8 INKmune; In Cohort 2, the weekly dose will increase to 3 x 10^8 INKmune; In Cohort 3, the weekly dose will increase to 5 x 10^8 INKmune. In Dose Expansion: INKmune therapy will be administered by a slow intravenous injection via conventional blood giving set. Approximately 12 patients will receive 3 weekly IV doses of INKmune on Day 1, 8, and 15 as per the below: Following mBOIN termination and MTD identification, patients will be enrolled in up to two candidate optimal dose levels (no higher than the MTD) for final optimal dose determination. | Biological: INKmune<br>* INKmune is a patented biologic delivery system and method for cancer treatment using in vivo priming and activation of natural killer (NK) cells in order to achieve tumor cell lysis. INKmune is a suspension of INB16 cells which have been rendered replication incompetent that does not require donor matching.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the optimal concentration of INKmune therapy to be used in patients with mCRPC. | Measurement of peripheral blood activated NK cell (memory like NK cell phenotype) percentage by flow cytometry to >2 times pre-treatment percentage. | 2-3 years | 
| Determine the optimal concentration of INKmune therapy to be used in patients with mCRPC. | Measurement of Prostate Specific Antigen (PSA) to determine the percent of patients that decrease PSA by ≥30% during treatment. | 2-3 years | 
| Determine the optimal concentration of INKmune therapy to be used in patients with mCRPC. | Measurement of disease burden as determined by prostate-specific membrane antigen (PMSA) positron emission tomography (PET) scan. | 2-3 years | 
| Determine the optimal concentration of INKmune therapy to be used in patients with mCRPC. | Measurement of change in circulating tumor DNA (ctDNA). | 2-3 years | 
| Evaluate the safety and tolerability of INKmune therapy in patients with mCRPC. | Measurement of frequency and severity of Dose-Limiting Toxicities (DLT). | 2-3 years | 
| Evaluate the safety and tolerability of INKmune therapy in patients with mCRPC. | MTD identification, if available. | 2-3 years | 
| Evaluate the safety and tolerability of INKmune therapy in patients with mCRPC. | Measurement of frequency and severity of adverse events (AEs). | 2-3 years | 
| Evaluate the safety and tolerability of INKmune therapy in patients with mCRPC. | Measurement of frequency and severity of serious adverse events (SAEs). | 2-3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the overall clinical efficacy of INKmune treatment in patients utilizing RECIST. | Assessment based on current Prostate Cancer Working Group 3 (PCWG3) modified Response Evaluation Criteria (RECIST) Version 1.1, where applicable. | 2-3 years | 
| Evaluate the overall clinical efficacy of INKmune treatment in patients utilizing PSA. | Measurement of PSA response using PSA50 response rate. | 2-3 years | 
| Evaluate the overall clinical efficacy of INKmune treatment in patients utilizing PSA. | Measurement of the period of time PSA decrease by ≥30%. | 2-3 years | 
| Evaluate the overall clinical efficacy of INKmune treatment in patients utilizing PSA. | Measurement of the period of time PSA is below baseline. | 2-3 years | 
| Evaluate the overall clinical efficacy of INKmune treatment in patients utilizing survival data. | Measurement of Progression Free Survival (PFS). | 2-3 years | 
| Evaluate the overall clinical efficacy of INKmune treatment in patients utilizing survival data. | Measurement of Radiological Progression Free Survival (rPFS). | 2-3 years | 
| Evaluate the overall clinical efficacy of INKmune treatment in patients utilizing disease response. | Measurement of Objective response rate (ORR) | 2-3 years | 
| Evaluate the overall clinical efficacy of INKmune treatment in patients utilizing disease response. | Measurement of the Disease control rate. | 2-3 years | 
| Evaluate the overall clinical efficacy of INKmune treatment in patients utilizing survival data. | Measurement of Overall survival (OS). | 2-3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mCRPC, NK Cell Based Therapy, Immune Mediated Therapy, Cell Therapy