Clinical trial NCT05877599: 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
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Non-small Cell Lung Cancer
Head and Neck Squamous Cell Carcinoma
Colorectal Carcinoma
Pancreatic Adenocarcinoma
Breast Cancer
Other Solid Tumors
Ovarian Cancer
Keywords: Cell therapy
TP53
Solid tumors
Non-small cell lung cancer
Head and neck squamous cell carcinoma
Colorectal carcinoma
Pancreatic adenocarcinoma
Breast Cancer
Ovarian Cancer
TCR
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-05-26
Enrollment: 162
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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, 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Part 1: Safety of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: 28 days after infusion
measure: Part 1: Safety of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months post-infusion
measure: Part 2: Further Evaluate the safety of NT-175 at the RP2D in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 2: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 2: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 2: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 2: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 2: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 2: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
Secondary outcomes:
measure: Part 1: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 1: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 1: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 1: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 1: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
measure: Part 1: Preliminary anti-tumor activity of NT-175 in subjects with unresectable, advanced, and/or metastatic solid tumors
timeFrame: Up to 24 months after infusion
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Research Site
state: Arizona
city: Duarte
country: United States
facility: Research Site
state: California
city: Newport Beach
country: United States
facility: Research Site
state: California
city: Santa Monica
country: United States
facility: Research Site
state: California
city: Miami
country: United States
facility: Research Site
state: Florida
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New Brunswick
country: United States
facility: Research Site
state: New Jersey
city: New York
country: United States
facility: Research Site
state: New York
city: Charlotte
country: United States
facility: Research Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Research Site
state: North Carolina
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Houston
country: United States
facility: Research Site
state: Texas
city: Round Rock
country: United States
facility: Research Site
state: Texas
Study officials:
affiliation: AstraZeneca
name: AstraZeneca
role: STUDY_DIRECTOR
References: