Clinical trial NCT05430555: A Phase 1/ 2, First-in-Human, Open-Label, Accelerated-Titration, Two-Part Clinical Trial of TK-8001 in Patients With HLA-A*02:01 Genotype and Advanced-Stage/ Metastatic MAGE-A1+ Solid Tumors
Official title: A Phase 1/2, First-in-Human, Open-Label, Accelerated-Titration, Two-Part Clinical Trial of TK-8001 (MAGE-A1-Directed TCR-Transduced Autologous CD8+ T-cells) in Patients With HLA-A*02:01 Genotype and Advanced-Stage/Metastatic, MAGE-A1+ Solid Tumors That Either Have No Further Approved Therapeutic Alternative(s) or Are Not Eligible for Them or Are in a Non- Curable State and Have Received a Minimum of Two Lines of Systemic Therapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors
Keywords: Advanced stage solid tumors
MAGE-A1
TCR-transgenic T-cells
Lead sponsor: T-knife GmbH
Sponsor class: INDUSTRY
First posted: 2022-06-24
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: This 2-part trial consists of Phase 1 dose-escalation and expansion and Phase 2. In escalation, 6-18 subjects will receive TK-8001 across 3 dose levels (DL). In expansion, subjects will be treated with the DL selected in escalation. Subjects without brain metastasis (Cohort 1) and subjects with brain metastases (Cohort 2) will both be included in expansion if DL3 is declared safe. Cohort 1 will include melanoma \[skin or uveal\], NSCLC, urothelial, breast, gastric esophageal, sarcoma, HNSCC, HCC, biliary tract, cervical, and salivary gland cancer subjects. Cohort 2 will only include melanoma \[skin or uveal\], NSCLC, urothelial, or breast cancer. In expansion, up to 20 additional subjects may be treated on DL3 if cleared during escalation. Up to 10 additional Cohort 2 subjects may be treated on DL3 if cleared during escalation. 33 subjects maximum may be treated on DL3 during Phase 1. If DL2 was safely completed the maximum total number of subjects to be treated on DL2 would be 12.
Primary purpose: TREATMENT

Brief summary: The aim of this study is to determine the safety, tolerability and anti-tumoral activity of autologous T cells transduced with a T cell receptor specific for MAGE-A1 in eligible patients with advanced solid tumors.

Detailed description: This is a Phase 1/2, first-in-human, open-label, accelerated titration, two-part clinical trial of TK-8001 (MAGE-A1-directed TCR-transduced autologous CD8+ T-cells) in subjects with HLA-A\*02:01 genotype and advanced stage/metastatic, MAGE-A1+ solid tumors (including but not limited to melanoma \[skin or uveal\], NSCLC, urothelial, breast, gastric \[including gastroesophageal junction\], esophageal, sarcoma, HNSCC, HCC, biliary tract, cervical, and salivary gland cancer) that either have no further approved therapeutic alternative or are not eligible for them or that are in a non-curable state as per the Investigator's assessment and have received a minimum of two lines of systemic therapy.

This two-part clinical trial will consist of a Phase 1 Part, which includes dose-escalation and expansion, and a Phase 2 Part.

In the Phase 1 Part dose-escalation, at least 6 subjects and up to 18 subjects (if DLT occurs) will receive escalating doses of TK-8001, with up to three dose levels explored. During the Phase 1 Part expansion, up to 20 additional subjects may be treated on DL3 if cleared during dose escalation to further evaluate the safety and efficacy of TK-8001 (Cohort 1).

An additional cohort of up to 10 subjects with brain metastases (Cohort 2) may also be treated on DL3 if cleared during dose-escalation. The maximum total number of subjects to be treated on DL3 during Phase 1 will be 33 subjects.

In the Phase 2 Part, up to 30 patients will receive TK-8001 to further evaluate the efficacy and safety of TK-8001 and to confirm the RP2D.

Both the Phase 1 Part and Phase 2 Part of the trial will consist of the following periods: Screening and Leukapheresis Period, Conditioning Period, TK-8001 Treatment Period, DLT Monitoring Period, Short-term Follow-up Period (Year 1), and Long-term Follow-up Period (Year 2 - 15).

Eligibility criteria: Inclusion Criteria:

* Able to understand and comply with study procedures
* At least 18 years old
* Phase 1 Part dose-escalation and Phase 1 Part expansion Cohort 1 only: Presence of an advanced-stage/metastatic, solid tumor in non-curable state as per current medical knowledge, for which there is either no further approved therapeutic alternative available or the subject is not eligible for them or, for which the subject has completed a minimum of two lines of approved systemic therapy in the advanced-stage/metastatic setting.
* Phase 1 Part expansion Cohort 2 only: Presence of an advanced-stage/metastatic disease of the following indications: melanoma (skin or uveal), NSCLC, urothelial, breast cancer in non-curable state as per current medical knowledge, for which there is either no further approved therapeutic alternative available or the subject is not eligible for them or, for which the subject has completed a minimum of two lines of approved systemic therapy in the advanced-stage/metastatic setting.
* HLA-A\*02:01 genotype.
* MAGE-A1+ tumor positive for MAGE-A1
* At least one measurable lesion, that can be accurately measured as per RECIST Version 1.1
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
* Life expectancy \> 3 months as assessed by the Investigator
* All toxicities related to prior therapy must have recovered to baseline or Grade ≤ 1 based on CTCAE v5.0
* Immune-related adverse events (irAEs) from previous therapies must have recovered to baseline or Grade ≤ 1

Exclusion Criteria:

* Any tumor-directed therapy within 14 days before start of conditioning therapy
* Any other MAGE-A1-targeting therapy.
* Pre-existing arrhythmia, uncontrolled angina pectoris, presently uncontrolled heart failure, or any myocardial infarction/coronary event as well as any thromboembolic event at any time \< 6 months prior to screening.
* Left ventricular ejection fraction (LVEF) \< 45% as measured by an echocardiogram
* History of CNS disease such as stroke, seizure, encephalitis, or multiple sclerosis (within 6 months prior to screening)
* Active allergy requiring continuous systemic medication or active infections requiring IV/PO anti-infectious therapy
* History of or clinical evidence of CNS primary tumors or metastases, unless they have been previously treated, and have been stable for at least 4 weeks prior to trial entry
* Major surgery within last 4 weeks prior to consent
* Active disease/ongoing infection with HIV, HBV, HCV, TB, syphilis, or SARS-CoV-2
* Receipt of any organ transplantation, except for transplants that do not require immunosuppression
* Any vaccine administration within 4 weeks of IP administration.

Primary outcomes:
measure: Safety and tolerability
timeFrame: Up to 15 years after TK-8001 treatment (1 year short-term follow-up, 14 years long-term follow up)
measure: Preliminary anti tumor activity
timeFrame: Up to 15 years after TK-8001 treatment, or until disease progression
Secondary outcomes:
measure: End of dose escalation
timeFrame: 28 days after TK-8001 treatment of last patient in Phase 1
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Universite Catholique de Louvain (UCL) - Cliniques Universitaires Saint-Luc - Institut Roi Albert II
city: Brussel
country: Belgium
facility: Universite Libre de Bruxelles (ULB) - Institut Jules Bordet Anderlecht
city: Ghent
country: Belgium
facility: University Hospital Ghent
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire (CHU) de Liège
city: Dresden
country: Germany
facility: Technische Universität Dresden (TU Dresden)
state: Sachsen
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin - Campus Benjamin Franklin
city: Frankfurt
country: Germany
facility: Universitatsklinikum Frankfurt, Goethe Universitat
city: Munich
country: Germany
facility: Klinikum der Universität München
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d´Hebrón
city: Madrid
country: Spain
facility: START Madrid-HM CIOCC
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: T-knife GmbH
name: Behzad K Masouleh, MD, PhD
role: STUDY_DIRECTOR
References: