A Study of NT-175 in Adult Participants With Advanced Malignancies That Are Positive for HLA-A*02:01 and the TP53 R175H Mutation

Official title

An Open-label, Phase 1, Multicentre Platform Study to Evaluate the Safety and Preliminary Anti-tumour Activity of NT-175 in Human Leukocyte Antigen-A*02:01-Positive Adult Participants With Advanced Malignancies That Are Positive for the TP53 R175H Mutation

Overview

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 malignancies

Detailed description

This is a Phase 1, open-label, multicentre platform study to evaluate the safety and preliminary antitumour activity of NT-175 in HLA-A\*02:01 participants with advanced malignancies that are positive for the TP53 R175H mutation.

Dose Escalation will investigate escalating doses of NT-175 in adult subjects with eligible histologies and will evaluate the safety and MTD and/or RDE/RP2D.

Cohort expansion will further evaluate the safety and preliminary anti-tumour activity at or below the MTD in disease specific histologies and determine the RP2D.

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

Interventions

• Biological NT-175
  * Pre-conditioning by non-myeloablative chemotherapy with fludarabine and cyclophosphamide * Single infusion Autologous, engineered T Cells targeting TP53 R175H * Post-infusion recombinant interleukin-2 (rIL-2)

Primary outcome measures

• Module 1, Part 1: Safety of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours [Time frame: 28 days after infusion]
• Module 1, Part 1: Safety of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours [Time frame: Up to 24 months post-infusion]
• Module 1, Part 2: Preliminary anti-tumour activity of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours [Time frame: Up to 24 months after infusion]
• Module 2: Safety of NT-175 in participants with haematological malignancies [Time frame: Up to 28 days after infusion]
• Module 2: Safety of NT-175 in participants with haematological malignancies [Time frame: Up to 24 months after infusion]

Secondary outcome measures (2)

• Module 1, Part 1: Preliminary anti-tumor activity of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours [Time frame: Up to 24 months after infusion]
• Module 2: Evaluate preliminary anti-tumour activity in participants with AML or MDS [Time frame: Up to 24 months after infusion]

Eligibility criteria

Key Inclusion Criteria (Module 1)

• Subjects must be at least 18 years of age
• 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)
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Adequate hematological, renal, hepatic, pulmonary, and cardiac function

Key Exclusion Criteria (Module 1)

• Any another primary malignancy within the 3 years prior to enrollment
• 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 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.
• Any form of primary immunodeficiency.
• Known to have Li-Fraumeni syndrome or is known to have relatives who are diagnosed with Li-Fraumeni syndrome.

Key Inclusion Criteria (Module 2 - hematological malignancies)

• At least 18 years of age
• Diagnosis of AML or MDS that allows for efficacy assessments
• Confirmation of TP53 R175H variant mutation in cancer cells
• Subject must be HLA-A\*02:01 positive (at least 1 allele)
• ECOG performance status of 0 to 1

Key Exclusion Criteria (Module 2 - hematological malignancy)

• Acute promyelocytic leukaemia or isolated extramedullary disease
• Another primary malignancy within 2 years (with exceptions)
• HSCT within 100 days or immunosuppression for GvHD within 4 weeks
• History of CNS or other extramedullary leukaemic involvement unless a lumbar puncture is negative for leukemic cells
• Prior stroke, ischemic attack, significant cardiac disease, heart failure
• Prior adoptive modified cell therapy
• Known to have Li-Fraumeni syndrome or is known to have relatives who are diagnosed with Li-Fraumeni syndrome.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 18 centers

• Research Site — Gilbert
• Research Site — Duarte
• Research Site — Newport Beach
• Research Site — Santa Monica
• Research Site — Jacksonville
• Research Site — Miami
• Research Site — Tampa
• Research Site — Boston
• … and 10 more centers

Identifiers

NCT: NCT05877599 · NT-175-201 · D8690C00001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗