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RecruitingInterventionalPhase 1

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

NCT ID: NCT05877599Sponsor: AstraZenecaLast updated: 2026-06-10

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, 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.

Arms & interventions

  • BiologicalAutologous, 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)

Outcome measures

Primary

  • 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

    Time frame: 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

    Time frame: 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

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: Up to 24 months after infusion

Secondary

  • Part 1: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors

    Time frame: 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 frame: 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 frame: 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 frame: 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 frame: 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 frame: Up to 24 months after infusion

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No
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 locations (18)

Research Site

Gilbert, Arizona, 85234

Recruiting

Research Site

Duarte, California, 91010

Recruiting

Research Site

Newport Beach, California, 92663

Recruiting

Research Site

Santa Monica, California, 90404

Recruiting

Research Site

Jacksonville, Florida, 32224

Recruiting

Research Site

Miami, Florida, 33136

Withdrawn

Research Site

Tampa, Florida, 33612

Withdrawn

Research Site

Boston, Massachusetts, 02115

Recruiting

Research Site

New Brunswick, New Jersey, 08901

Recruiting

Research Site

New York, New York, 10065

Recruiting

Research Site

Charlotte, North Carolina, 28204

Withdrawn

Research Site

Winston-Salem, North Carolina, 27103

Withdrawn

Research Site

Portland, Oregon, 97213

Recruiting

Research Site

Pittsburgh, Pennsylvania, 15232

Recruiting

Research Site

Nashville, Tennessee, 37203

Recruiting

Research Site

Houston, Texas, 77030

Recruiting

Research Site

Round Rock, Texas, 78665

Recruiting

Research Site

Milwaukee, Wisconsin, 53226

Recruiting