A Study of Gene Edited Autologous Neoantigen Targeted TCR T Cells With or Without Anti-PD-1 in Patients With Solid Tumors

Study Overview
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Brief Summary
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This is a first in human, single arm, open label, Phase 1a/1b study to determine the safety, feasibility, and efficacy of a single dose of NeoTCR-P1 T cells in participants with solid tumors.

Official Title
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A Phase 1a/1b, Open-label First-in-human Study of the Safety, Tolerability and Feasibility of Gene-edited Autologous NeoTCR-T Cells (NeoTCR-P1) Administered as a Single Agent or in Combination With Anti-PD-1 to Patients With Locally Advanced or Metastatic Solid Tumors

Conditions
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Solid Tumor

Intervention / Treatment
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* Biological: NeoTCR-P1 adoptive cell therapy
* Biological: nivolumab
* Biological: IL-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented incurable or metastatic solid tumors of the following types: melanoma, UC, ovarian cancer, colorectal cancer, breast cancer (HR+), or prostate cancer. Disease has progressed after at least one available standard therapy or no additional curative therapies are available. Measurable disease per RECIST v1.1 Eastern cooperative oncology group (ECOG) performance status of 0 or 1 Adequate hematologic and end organ function determined within 30 days prior to enrollment. Disease-specific criteria related to the specific tumor type are required. Note: There are additional inclusion criteria. The study center will determine if you meet all of the criteria. Exclusion Criteria: Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and/or inherited liver disease Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases Uncontrolled or symptomatic hypercalcemia Pregnancy, lactation, or breastfeeding Prior allogeneic stem cell transplant or solid organ transplant Prior chimeric antigen receptor therapy or other genetically modified T cell therapy Active HIV, Hepatitis B, or Hepatitis C infection Active tuberculosis Severe infection within 2 weeks prior to enrollment Major surgical procedure within 4 weeks prior to enrollment or anticipation of need for a major surgical procedure during the study. Note: There are additional exclusion criteria. The study center will determine if you meet all of the criteria.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NeoTCR-P1<br>Single dose of NeoTCR-P1 | Biological: NeoTCR-P1 adoptive cell therapy<br>* The investigational agent in this protocol is NeoTCR P1, an autologous adoptive T cell therapy (ACT) for patients with solid cancer. NeoTCR P1 is composed of apheresis derived CD8 and CD4 T cells that are precision genome engineered to express one autologous TCR of native sequence that targets a neoepitope (neoE) presented by human leukocyte antigen (HLA) receptors exclusively on the surface of that patient's tumor cells and not on other cells in the body.<br>|
| Experimental: NeoTCR-P1 plus nivolumab<br>Single dose of NeoTCR-P1 plus nivolumab 480mg IV every four weeks for up to 6 doses. | Biological: NeoTCR-P1 adoptive cell therapy<br>* The investigational agent in this protocol is NeoTCR P1, an autologous adoptive T cell therapy (ACT) for patients with solid cancer. NeoTCR P1 is composed of apheresis derived CD8 and CD4 T cells that are precision genome engineered to express one autologous TCR of native sequence that targets a neoepitope (neoE) presented by human leukocyte antigen (HLA) receptors exclusively on the surface of that patient's tumor cells and not on other cells in the body.<br>Biological: nivolumab<br>* Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody<br>* Other names: Opdivo;|
| Experimental: NeoTCR-P1 plus IL-2<br>Single dose of NeoTCR-P1 plus IL-2 500,000 IU/m2 SC twice daily (BID) for 7 days. | Biological: NeoTCR-P1 adoptive cell therapy<br>* The investigational agent in this protocol is NeoTCR P1, an autologous adoptive T cell therapy (ACT) for patients with solid cancer. NeoTCR P1 is composed of apheresis derived CD8 and CD4 T cells that are precision genome engineered to express one autologous TCR of native sequence that targets a neoepitope (neoE) presented by human leukocyte antigen (HLA) receptors exclusively on the surface of that patient's tumor cells and not on other cells in the body.<br>Biological: IL-2<br>* IL-2 is a biologic response modifier. It is a type of protein called a cytokine.<br>* Other names: interleukin-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events as defined as DLTs | Dose limiting toxicity (DLT) is defined as protocol-defined adverse events that occur within 28 days following infusion of Neo-TCR-P1 administered as a single agent without or with IL-2, or in combination with nivolumab. | 28 days | 
| Number of participants with adverse events as a measure of safety and tolerability of NeoTCR-P1 or NeoTCR-P1 in combination with nivolumab | Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Cytokine release syndrome (CRS) and neurotoxicity associated with NeoTCR-P1 will be graded according to ASBMT consensus grading. | 2 years | 
| Maximum Tolerated Dose (MTD) of NeoTCR-P1 | The MTD is defined as the highest dose with an observed incidence of DLT in no more than one out of six patients treated at a particular dose level. | 2 years | 
| Feasibility of manufacturing NeoTCR-P1 | Percent of screened patients that enroll on study and receive NeoTCR-P1 | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration of NeoTCR-P1 (Cmax) in the peripheral blood |  | 2 years | 
| Area-under-the-concentration-vs-time-curve (AUC) in the peripheral blood |  | 28 days | 
| Persistence of NeoTCR-P1 in samples of peripheral blood |  | 2 years | 
| Objective Response Rate (ORR) in participants with solid tumors following infusion of NeoTCR-P1 as a single agent or in combination with nivolumab | ORR will be defined as Complete Response (CR) or Partial Response (PR) per RECIST v1.1, as determined by the investigator | 2 years | 
| Duration of Response mediated by neoTCR-P1 administered as a single agent or in combination with nivolumab to participants with solid tumors | Duration of response, defined as time from the first occurrence of a documented objective response to the time of relapse or death from any cause | 2 years | 
| Progression free survival (PFS) in participants with solid tumors following infusion of NeoTCR-P1 as a single agent or in combination with nivolumab | PFS is defined from date of administration of NeoTCR-P1 cell infusion to the date of disease progression per the RECIST v1.1 or death as a result of any cause. Subjects who do not meet criteria for progression by the analysis data cut-off date will be censored at their last evaluable disease assessment date | 2 years | 
| Overall survival (OS) in participants with solid tumors following infusion of NeoTCR-P1 as a single agent or in combination with nivolumab | OS will be measured from the date of administration of NeoTCR-P1 to the date of death. Subjects who have not died by the analysis data cut-off date will be censored at their last date of contact. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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melanoma, HR+ breast cancer, ovarian cancer, prostate cancer, colorectal cancer, urothelial carcinoma, adoptive cell therapy, neoantigen, T cell receptor, T lymphocyte, TCR-engineered T cells, personalized cell therapy, cell therapy, immunotherapy, gene therapy, PD-1, non-small cell lung cancer, head and neck squamous carcinoma, HER2 negative breast cancer, triple negative breast cancer, IL-2