A Study of NT-175 in Adult Subjects With Unresectable, Advanced, and/or Metastatic Solid Tumors That Are Positive for HLA-A*02:01 and the TP53 R175H Mutation

Study Overview
=================
Brief Summary
-----------------
Phase I Study of NT-175, an autologous T cell therapy product genetically engineered to express an HLA-A*02:01-restricted T cell receptor (TCR), targeting TP53 R175H mutant solid tumors.

Detailed Description
-----------------
This is a Phase 1, open-label, multicenter study to evaluate the safety and preliminary antitumor activity of NT-175 in HLA-A*02:01 subjects with unresectable, advanced, and/or metastatic NSCLC, colorectal adenocarcinoma, HNSCC, pancreatic adenocarcinoma, breast cancer, or any other solid tumor histologies that are positive for the TP53 R175H mutation.

Official Title
-----------------
An Open-label, Phase 1, Multicenter Study to Evaluate the Safety and Preliminary Anti-tumor Activity of NT-175 in Human Leukocyte Antigen-A*02:01-Positive Adult Subjects With Unresectable, Advanced and/or Metastatic Solid Tumors That Are Positive for the TP53 R175H Mutation

Conditions
-----------------
Colorectal Carcinoma, Non-small Cell Lung Cancer, Head and Neck Squamous Cell Carcinoma, Pancreatic Adenocarcinoma, Breast Cancer, Other Solid Tumors

Intervention / Treatment
-----------------
* Biological: Autologous, engineered T Cells targeting TP53 R175H


Participation Criteria
=================
Eligibility Criteria
-----------------
Subjects must be at least 18 years of age, at the time of signing the informed consent. Subjects must be capable of giving signed informed consent Subject must be diagnosed with one of the histologies below: NSCLC Colorectal adenocarcinoma HNSCC Pancreatic adenocarcinoma Breast cancer Any other solid tumor Tumors must harbor a TP53 R175H variant mutation (confirmed by an FDA-approved test), and subject must be HLA-A*02:01 positive (at least 1 allele). Subject has advanced solid cancer, defined as unresectable, advanced, and/or metastatic disease (Stage III or IV) after at least 1 line of approved systemic standard of care (SOC) treatment regimen and for which there are no available curative treatment options. Subject has at least 1 measurable lesion per computed tomography (CT) scan or magnetic resonance imaging (MRI). Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at the time of enrollment Adequate hematological, renal, hepatic, pulmonary, and cardiac function Per Investigator judgement, subject is likely to complete study visits and/or procedures per the protocol and comply with study requirements for study participation Exclusion Criteria: Any another primary malignancy within the 3 years prior to enrollment (except for non-melanoma skin cancer, carcinoma in situ (eg, cervix, bladder, breast) or low-grade prostate cancer Known, active primary central nervous system (CNS) malignancy History of prior adoptive cell and gene therapy, allogeneic stem cell transplant or solid organ transplantation. History of stroke or transient ischemic attack within the 12 months prior to enrollment. History of clinically significant cardiac disease within the 6 months prior to enrollment or heart failure at any time prior to enrollment. Systemic therapy within at least 2 weeks or 3 half-lives, whichever is shorter, prior to enrollment. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or rIL-2; or known sensitivity or allergy to methotrexate, gentamicin, or other aminoglycosides. Any form of primary immunodeficiency. Live vaccine ≤ 4 weeks prior to enrollment or plans to have a live vaccine prior to planned lymphodepleting chemotherapy and/or NT-175 treatment. Active immune-mediated disease requiring systemic steroids or other immunosuppressive treatment (except if related to prior checkpoint inhibitor therapy) Female of childbearing potential who is lactating or breast feeding at the time of enrollment. Known to have Li-Fraumeni syndrome or is known to have relatives who are diagnosed with Li-Fraumeni syndrome.

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

Sexes Eligible for Study
-----------------
All

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Dose Escalation of TCR T cell product | Biological: Autologous, engineered T Cells targeting TP53 R175H<br>* Pre-conditioning by non-myeloablative chemotherapy with fludarabine and cyclophosphamide Single infusion TCR T cells Post-infusion recombinant interleukin-2 (rIL-2)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors | Incidence of dose-limiting toxicities (DLTs) after the infusion of NT-175 | 28 days after infusion | 
| Adverse events and serious adverse events | Incidence of adverse events and serious adverse events by dose level | Up to 24 months post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors | Objective Response Rate (ORR) per RECIST V1.1 determined by Investigator assessment. | Up to 24 months after infusion | 
| Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors | Best Overall Response (BOR) per RECIST V1.1 determined by Investigator assessment. | Up to 24 months after infusion | 
| Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors | Duration of Response (DOR) per RECIST V1.1 determined by Investigator assessment. | Up to 24 months after infusion | 
| Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors | Clinical Benefit Rate (CBR) per RECIST V1.1 determined by Investigator assessment. | Up to 24 months after infusion | 
| Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors | Time to Response (TTR) per RECIST V1.1 determined by Investigator assessment. | Up to 24 months after infusion | 
| Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors | Progression-free survival (PFS) per RECIST V1.1 determined by Investigator assessment. | Up to 24 months after infusion |