Breast Cancer, Colorectal Carcinoma, Head and Neck Squamous Cell Carcinoma, Myeloid Neoplasms (AML/MDS), Non-small Cell Lung Cancer, Other Solid Tumors, Ovarian Cancer, Pancreatic Adenocarcinoma
Conditions
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, AML, MDS, TCR
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 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
BIOLOGICALNT-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)
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Platform Study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Module 1, Part 1: Safety of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours | 28 days after infusion | Incidence of dose-limiting toxicities (DLTs) after the infusion of NT-175 |
| Module 1, Part 2: Preliminary anti-tumour activity of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours | Up to 24 months after infusion | Per RECIST v1.1 determined by Investigator assessment: * Objective Response Rate (ORR) * Best Overall Response (BOR) * Duration of Response (DOR) * Clinical Benefit Rate (CBR) * Time to Response (TTR) * Progression-free survival (PFS) * Overall Survival (OS) |
| Module 2: Safety of NT-175 in participants with haematological malignancies | Up to 28 days after infusion | \- Incidence of dose-limiting toxicities (DLTs) after the infusion of NT-175 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Module 1, Part 1: Preliminary anti-tumor activity of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours | Up to 24 months after infusion | Per RECIST v1.1 determined by Investigator assessment: * Objective Response Rate (ORR) * Best Overall Response (BOR) * Duration of Response (DOR) * Clinical Benefit Rate (CBR) * Time to Response (TTR) * Progression-free survival (PFS) * Overall Survival (OS) |
| Module 2: Evaluate preliminary anti-tumour activity in participants with AML or MDS | Up to 24 months after infusion | Per ELN 2022 criteria for AML and per IWG 2023 criteria for MDS by Investigator assessment: * Objective Response Rate (ORR) * Time to Response (TTR) * Duration of Response (DOR) * Event-free survival (EFS) By Investigator assessment: * Transfusion Independence (TI) * Overall Survival (OS) * Complete Response (CR) + Complete response with partial haematological recover (CRh) * Complete Response with limited count recovery (CRL) (CRuni + CRbi) in MDS * MDS time to Progression to AML * Proportion of participants with subsequent Haematopoietic Stem Cell Transplantation (HSCT) |
Countries
United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
STUDY_DIRECTORAstraZeneca
AstraZeneca
Outcome results
None listed