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

Withdrawn

Conditions: Solid Tumor
Malignant Solid Tumor
10027655

Registration Number: NL-OMON53302

Lead Sponsor: T-knife GmbH

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Withdrawn

Sex: Not specified

Target Recruitment: 3

Inclusion Criteria

Each subject must meet all of the following inclusion criteria to be eligible
to enroll in this trial and to proceed to TK-8001 treatment:
1. Ability to understand the intent of the trial and provision of a signed and
dated informed consent from the subject prior to performing any
protocol-related procedures (including screening evaluations), and ability to
comply with the trial procedures and any locally required authorization
2. Age >= 18 years
3. Presence of an advanced-stage/metastatic, solid tumor in non-curable state:
a. For which there is either no approved therapeutic alternative available or
the subject is not eligible for them or
b. For which the subject has received a minimum of two lines of approved
systemic therapy
NB: Screening I and apheresis may take place during the line of treatment
immediately preceding the planned TK-8001 treatment to avoid delays due to
manufacturing time in progressing subjects
4. HLA-A*02:01 genotype
5. MAGE-A1+ tumor as per IHC
6. As per most recent tumor assessment, presence of radiologically measurable
disease - with at least 1 lesion, not previously irradiated, that can be
accurately measured as per RECIST V1.1 with CT or MRI and that is not
considered for on-treatment biopsy
7. ECOG performance status <= 1
8. Life expectancy > 3 months as assessed by the Investigator
9. Adequate organ function, defined as:
a. Bone marrow function: hemoglobin >= 10 g/dL (equal to 6.2 mmol/L); platelet
count >= 100 × 109 /L; leukocyte count >= 3.0 × 109 /L; absolute lymphocyte count
>= 0.65 × 109/L. Note: absolute lymphocyte count >= 0.65 × 109/L criterion only
applies to Screening I.
b. Hepatic function: aspartate transaminase (AST) and alanine transaminase
(ALT) <= 3.0×upper limit of normal (ULN); bilirubin <= 2.0xULN
c. Renal function: serum creatinine < 1.5×ULN and/or creatinine clearance >= 50
mL/min (Cockcroft-Gault equation).
d. International normalized ratio (INR) < 1.5 and partial thromboplastin time
(PTT) within 1.25 × of upper and lower limit of normal
10. All toxicities related to prior radiotherapy, chemotherapy, or surgical
procedure must have recovered to baseline or Grade <= 1 based on the National
Cancer Institute - Common Terminology Criteria for AEs v5.0, except alopecia
(any grade), and AEs that are regarded clinically nonsignificant
or stable on supportive therapy as per treating physician's assessment
Note: In case of Screening I and apheresis taking place during a prior line of
treatment this criterion applies only to Screening II
11. Ongoing immune-related adverse events from previous therapies must have
recovered to baseline or Grade <= 1 except vitiligo, hair loss, and stable
endocrinopathies with physiologic hormone repletion
NB: In case of Screening I and apheresis taking place during a prior line of
treatment, this criterion applies only to Screening II
12. Women of non-childbearing potential due to surgical sterilization (at least
6 weeks following surgical bilateral oophorectomy with or without hysterectomy
or tubal ligation) confirmed by medical history or menopause (i.e., no
menstrual bleeding for more than 12 months in a woman aged >= 45 years).
13. Women of childbearing potential who test negative for pregnancy at
Screening based on serum pregnancy test must be using a highly effective method <b

Exclusion Criteria

Each subject fulfilling any of the following exclusion criteria is not eligible
to enroll in this trial and to proceed to TK-8001 treatment:
1. Has received any approved or non-approved tumor-directed therapy within 14
days before start of conditioning therapy
2. Has received any other MAGE-A1-targeting therapy
3. Pre-existing arrhythmia, considered to be of concern as per clinical
assessment (e.g. uncontrolled atrial fibrillation, significant ventricular
tachy-/arrhythmia [CTCAE Grade >= 2], significant bradycardia, or highergrade
AV-block among others) ,uncontrolled angina pectoris, diagnosed with at present
uncontrolled heart failure (New York Heart Association II-IV), or any
myocardial infarction/coronary event as well as any CNS-ischemic event and any
thromboembolic event within 6 months prior to screening
4. Left ventricular ejection fraction (LVEF) <45% as measured by an
echocardiogram or multigated acquisition (MUGA) scan
5. Corrected QT interval by the Fredericia formula (QTcF) >450 ms for men or
>470 ms for women
6. History of CNS disease such as stroke, seizure, encephalitis or multiple
sclerosis (within 6 months prior to screening)
7. Active allergy requiring continuous systemic medication or active infections
requiring IV/orally (PO) anti-infectious therapy within 7 days prior to
conditioning therapy
8. History of or clinical evidence of CNS primary tumors or metastases
(including leptomeningeal metastases), unless they have been previously treated
are asymptomatic, considered inactive by brain imaging and have been stable for
at least 4 weeks prior to trial entry/TK-8001 treatment
9. Systemic steroids at a daily dose of >5 mg of prednisolone except
non-systemic (inhaled, topical, or nasal), for the last 14 days prior to
planned date for leukapheresis
10. Evidence of any form of active rheumatoid arthritis or active joint
inflammation
11. Subjects with rapidly progressing disease (as per Investigator assessment),
which may predispose to inability to tolerate treatment and/or trial procedure
12. Major surgery within last 4 weeks prior to consent
13. Known/expected hypersensitivity against TK-8001, dimethyl sulfoxide (DMSO),
and/or other cellular therapy components
14. Active disease/ongoing infection in regard to human immunodeficiency virus
(HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), tuberculosis (TB),
syphilis (Treponema pallidum [TPHA]), or
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (by PCR)
15. Any other diseases, metabolic dysfunction, physical examination finding, or
clinical laboratory abnormality giving reasonable suspicion of a disease or
condition that in the opinion of the Investigator would contraindicate the use
of the IP
16. Receipt of any organ transplantation, including autologous or allogeneic
hematopoietic cell transplantation, but with the exception of transplants that
do not require immunosuppression (e.g., corneal transplant, hair transplant)
17. Any vaccine administration within 4 weeks of IP administration. Vaccination
with live vaccines while on trial is not permitted unless of vital medical
necessity and outside the Conditioning, TK-8001 Treatment, and Monitoring
Periods
18. Subject is pregnant or breastfeeding
19. Known active drug or alcohol abuse

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Phase 1 Part (Dose-escalation and Expansion):<br /><br><br /><br>• Incidence and grade of treatment-emergent adverse events (AEs) and serious<br /><br>adverse events (SAEs)<br /><br>• Number and type of dose limiting toxicities (DLT)<br /><br><br /><br>Phase 2 Part:<br /><br>• Evaluation of ORR, SD, PR, and CR rate of TK-8001 monotherapy, according to<br /><br>RECIST Version 1.1 and iRECIST<br /><br>• Incidence and grade of treatment-emergent AEs and SAEs</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Phase 1 Part (Dose-escalation and Expansion):<br /><br><br /><br>• Evaluation of overall response rate (ORR), stable disease rate (SD), partial<br /><br>response rate (PR), and complete response (CR) rate of TK-8001 monotherapy,<br /><br>according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1<br /><br>and modified Response Evaluation Criteria in Solid<br /><br>Tumors (RECIST, V1.1) in cancer immunotherapy trials (iRECIST)<br /><br>• Integrated evaluation of safety, efficacy and pharmacodynamic parameters<br /><br><br /><br>Phase 2 Part:<br /><br>• Evaluation of PK parameters of TK-8001, such as the number and persistence of<br /><br>TCR-transduced T-cells in peripheral blood (e.g., vector copy)<br /><br>• Evaluation of pharmacodynamic parameters of TK-8001, such as the<br /><br>treatment-emergent cytokine profile of TK-8001</p><br>