CART-PSMA Cells for Advanced Prostate Cancer

Study Overview
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Brief Summary
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This is a single center, open-label phase 1 study to assess the safety and feasibility of PSMA-specific CAR modified autologous T cells (CART-PSMA cells) in patients with advanced prostate cancer.

Official Title
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Phase I Study of CART-PSMA Cells in Patients With Advanced Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: CART-PSMA cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants must have the ability to understand and the willingness to sign a written informed consent. Histologic confirmation of prostate cancer. Tumor expressing PSMA as demonstrated by immunohistochemistry analysis or other methods. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2. Under general air conditions, blood oxygen saturation >90%. Adequate liver function, specifically alanine aminotransferase (ALT) < 3 times of upper limit of normal (ULN), aspartate transferase (AST)< 3 times of ULN, serum bilirubin and alkaline phosphatase < 2 times of ULN. Adequate renal function, specifically serum creatinine < 2.0 mg/dl. Adequate cardiac function, specifically left ventricular ejection fraction (LVEF)≥50%. Hemoglobin concentration ≥80g/L. The side effects brought by the latest treatment should be recovered, and the latest chemotherapy should be at least 7 days before; At least three t½ have passed since the latest immunotherapy. Exclusion Criteria: Patients with other malignant tumors or major diseases. Patients who are already undergoing other clinical drug trials or other gene therapy or cell therapy. Patients with uncontrolled active infection. Patients with active hepatitis B or hepatitis C infection. Patients with human immunodeficiency virus (HIV) infection. Patients who are being treated with immunosuppressive agents or systemic steroids (other than inhalation therapy). Patients with various types of serious heart disease or a history of severe cerebrovascular disease. Patients with congenital immune deficiency diseases or bone marrow deficiency diseases. Patients with active autoimmune disease, including connective tissue disease, uveitis, inflammatory bowel disease, or multiple sclerosis; or a history of severe (as judged by the physician-investigator) autoimmune disease requiring prolonged immunosuppressive therapy. Patients with active medical condition that, in the opinion of the physician-investigator, would substantially increase the risk of uncontrollable CRS (cytokine release syndrome) or CAR Neurotoxicity.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 85 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: autologous CART-PSMA cells<br> | Drug: CART-PSMA cells<br>* This study consists of 2 parts: Part A (Dose Escalation): The investigators are looking the highest dose of the study intervention that can be administered safely without severe or unmanageable side effects in participants that advanced prostate cancer. Up to 4 dosing cohorts, with up to 3 subjects enrolled in each cohort, will be explored as follows: cohort 1： CART-PSMA cells 1-3x10^7 on Day 0; cohort 2： CART-PSMA cells 1-3x10^8 on Day 0; cohort 3： CART-PSMA cells 1-3x10^7 on Day 0,following lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days; cohort 4： CART-PSMA cells 1-3x10^8 on Day 0,following lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days; Part B (Expansion Cohort): Participants will be treated at the respective dose (at or below the Maximum Tolerated Dose), as determined during Part A (Dose Escalation).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of study related adverse events, laboratory toxicities and clinical events that are possibly, likely, or definitely related to study participation. | Assessing the type, frequency, severity, and duration of adverse events as a result of CART-PSMA cell infusion via physical, laboratory and imaging examination. | Up to 15 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The persistence, accumulation, and migration of CART-PSMA cells. | Assessing the trafficking of CART-PSMA cells in the peripheral blood by quantifying the mRNA of CAR gene at the time of each infusion as well as at each time of follow-up blood collection. Peripheral blood will be collected prior to the initial infusion and will be set as baseline. | Up to 2 years | 
| Overall survival (OS) | Estimating median OS from CART-PSMA cell infusion to the event date (death) or last contact date (censor date) by Kaplan Meier methods. | Up to 15 years | 
| Progression-free survival (PFS) | Estimating median PFS by survival without biochemical (PSA) or radiographic evidence of disease progression or relapse from CART-PSMA cell infusion to event date (progression/relapse or death); the censor date: off protocol therapy date (required disallowed treatment or withdrawal of consent for further therapy) or last contact date. | Up to 15 years | 
| Patterns of change in PSA (prostate-specific antigen) | Assessing PSA response by the percentage of change in PSA from baseline to the defined time-frame on therapy (or earlier if patients discontinue therapy prior to the time-frame) as well as the maximum decline in PSA that occurs at any point during CART-PSMA cell infusion. | Up to 5 years | 
| Serum cytokine profile | Assessing potential cytokine release syndrome (CRS) toxicity and CART cell effector function, sequential serum samples by analysis of Th1/Th2 cytokines (e.g., IL-2, IFNgamma, TNFalpha, IL-10, GMCSF, IL-6, MIP-1alpha) before and after CART-PSMA cell infusion. | Up to 2 years | 
| Phenotypes and frequencies of immune cell subsets in the peripheral blood pre- and post-therapy | Assessing phenotypes and frequencies of immune cell subsets in the peripheral blood, T cell subsets and phenotypes utilising groups of labelled antibodies. | Up to 2 years | 
| Changes in circulating tumor cells in peripheral blood | Assessing changes in levels of circulating tumor cells (CTC) to investigate if decreases in CTC levels correlate with response. | Up to 2 years | 
| Circulating cell-free deoxyribonucleic acid (cfDNA) in peripheral blood | Assessing changes in levels of cfDNA to investigate if decreases in cfDNA levels correlate with response. | Up to 2 years |