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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Pancreatic Adenocarcinoma; Ovarian Cancer; Non-small Cell Lung Cancer; Head and Neck Squamous Cell Carcinoma; Colorectal Carcinoma; Other Solid Tumors
• Intervention / Treatment: Biological: Autologous, engineered T Cells targeting TP53 R175H

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, ovarian cancer, breast cancer, or any other solid tumor histologies that are positive for the TP53 R175H mutation.

Dose Escalation will investigate escalating doses of NT-175 in adult subjects with eligible solid tumor histologies and will evaluate the safety and MTD.

Disease Histology Evaluation will further evaluate the safety and preliminary anti-tumor activity at or below the MTD in disease specific histologies and determine the RP2D. .

Disease Cohort Expansion will further evaluate the preliminary anti-tumor activity and safety of NT-175 at the RP2D in disease specific settings.

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Recruiting
      • Research Site
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • Research Site
    • Newport Beach, California, United States, 92663
      • Recruiting
      • Research Site
    • Santa Monica, California, United States, 90404
      • Recruiting
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Research Site
    • Miami, Florida, United States, 33136
      • Withdrawn
      • Research Site
    • Tampa, Florida, United States, 33612
      • Withdrawn
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Research Site
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Recruiting
      • Research Site
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Withdrawn
      • Research Site
    • Winston-Salem, North Carolina, United States, 27103
      • Withdrawn
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97213
      • Recruiting
      • Research Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Recruiting
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Research Site
    • Round Rock, Texas, United States, 78665
      • Recruiting
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion 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
  • Ovarian cancer
  • Any other solid tumor
• Tumors must harbor a TP53 R175H variant mutation and subject must be HLA-A*02:01 positive (at least 1 allele) as confirmed by an CLIA-accredited laboratory-based test.
• 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) per RECIST version 1.1.
• 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

Key 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation and Expansion; Dose Escalation of TCR T cell product	Biological: Autologous, engineered T Cells targeting TP53 R175H; Pre-conditioning by non-myeloablative chemotherapy with fludarabine and cyclophosphamide; Single infusion TCR T cells; Post-infusion recombinant interleukin-2 (rIL-2)
Experimental: Part 1: Disease Histology Evaluation; TCR T Cell Product at the MTD	Biological: Autologous, engineered T Cells targeting TP53 R175H; Pre-conditioning by non-myeloablative chemotherapy with fludarabine and cyclophosphamide; Single infusion TCR T cells; Post-infusion recombinant interleukin-2 (rIL-2)
Experimental: Part 2: Disease Cohort Expansion; TCR T Cell Product at the RP2D	Biological: Autologous, engineered T Cells targeting TP53 R175H; Pre-conditioning by non-myeloablative chemotherapy with fludarabine and cyclophosphamide; Single infusion TCR T cells; Post-infusion recombinant interleukin-2 (rIL-2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: 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
Part 1: Safety of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors	Incidence of adverse events and serious adverse events	Up to 24 months post-infusion
Part 2: Further Evaluate the safety of NT-175 at the RP2D in subjects with unresectable, advanced, and/or metastatic solid tumors	Treatment-emergent adverse events, and serios adverse events	Up to 24 months after infusion
Part 2: 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
Part 2: 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
Part 2: 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
Part 2: 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
Part 2: 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
Part 2: 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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: 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
Part 1: 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
Part 1: 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
Part 1: 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
Part 1: 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
Part 1: 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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: AstraZeneca, AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2023
• Primary Completion (Estimated): July 31, 2029
• Study Completion (Estimated): July 31, 2029

Study Registration Dates

• First Submitted: May 17, 2023
• First Submitted That Met QC Criteria: May 17, 2023
• First Posted (Actual): May 26, 2023

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Breast Cancer; Solid tumors; Non-small cell lung cancer; Ovarian Cancer; TCR; Cell therapy; TP53; Pancreatic adenocarcinoma; Head and neck squamous cell carcinoma; Colorectal carcinoma
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Intestinal Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Genital Diseases, Female; Lung Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Lung Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Skin Diseases; Breast Diseases; Carcinoma; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Squamous Cell; Skin and Connective Tissue Diseases; Squamous Cell Carcinoma of Head and Neck; Colorectal Neoplasms; Ovarian Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: NT-175-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No