Clinical trial NCT06748872: EPITOME-1015-I: a Study to Investigate the Safety and Tolerability of MDG1015 in Patients with Epithelial Ovarian Cancer, Gastroesophageal Adenocarcinoma, Round Cell Liposarcoma And/or Synovial Sarcoma
Official title: EPITOME-1015-I: a Phase I Study to Investigate the Safety, Tolerability and Preliminary Efficacy of a Third Generation TCR-T Therapy, MDG1015, in Epithelial Ovarian Carcinoma, Gastroesophageal (Junction) Adenocarcinoma, Myxoid (Round Cell) Liposarcoma And/or Synovial Sarcoma Subjects with Advanced Disease Expressing NY-ESO-1 And/or LAGE-1a
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Epithelial Ovarian Cancer
Gastro-esophageal Junction Cancer
Soft Tissue Sarcoma (STS)
Myxoid Liposarcoma
Synovial Sarcoma
Keywords: TCR-T Therapy
dose escalation
Third Generation TCR-T Therapy
autologous, patient derived CD8+ T cells
single arm
open label
phase I
BOIN design
NY-ESO-1
LAGE-1a
solid tumors
PD1-41BB
Costimulatory Switch Protein
Armoring
Enhancement
First-in-human
Lead sponsor: Medigene AG
Sponsor class: INDUSTRY
First posted: 2024-12-27
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single arm, open label, multicenter, phase I study following a Bayesian optimal interval (BOIN) design for dose escalation
Primary purpose: TREATMENT

Brief summary: MDG1015 is a third generation TCR-T therapy product targeting NY-ESO-1/LAGE-1a armored and enhanced by the PD1-41BB costimulatory switch protein (CSP). The study purpose is to establish the safety, tolerability and preliminary efficacy of MDG1015 in patients with epithelial ovarian cancer, gastroesophageal adenocarcinoma, round cell liposarcoma and/or synovial sarcoma that expresses NY-ESO-1 and/or LAGE-1a.

The main questions this clinical trial aims to answer are:

Can this TCR-T therapy MDG1015 be given to patients safely? What is the optimal dose of the TCR-T therapy MDG1015? If and what side effects do participants experience after receiving the TCR-T therapy MDG1015? Do participants experience a potential disease response after receiving the TCR-T therapy MDG1015?

Participants will:

Receive (in most cases) 1 single infusion of MDG1015 at a pre-defined dose level and will be followed up regularly up to 1 year. After one year, participants will enter the long term follow-up part up to 15 years after being treated. Any side effects and/or potential disease response will be documented during this period.

Detailed description: The clinical study consists of screening, leukapheresis of mononuclear cells, LDC, followed by a single MDG1015 infusion on Day 0 and a subsequent hospitalization period of at least 3 days for in-patient safety monitoring. All Subjects who have received an MDG1015 infusion will continue to be followed regularly for safety and efficacy assessments in a post-treatment follow-up through month 12 (Y1) and long-term follow-up (LTFU) through years 2 - 15 in an out-patient setting. Dose Escalation Segment (DE) will evaluate an anticipated number of 4 dose levels to establish the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). During the cohort expansion (CE) segment the MTD/RP2D will be confirmed

Eligibility criteria: Inclusion Criteria:

1. Adult, ≥ 18 years of age and weigh ≥ 40 kg for Dose levels 1-3 and ≥ 50 kg for Dose level 4
2. Subject must have a confirmed diagnosis of either High grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancer Gastric or esophageal (junction) adenocarcinoma Myxoid (round cell) liposarcoma Synovial sarcoma
3. Subject's must have tested positive for HLA-A\*02:01 genotype by a Sponsor designated central laboratory
4. Subject's tumor must have tested positive for NY-ESO-1 and/or LAGE-1a mRNA expression by a Sponsor designated central laboratory Both ≤1 year old archival tissue or fresh biopsy are allowed
5. Subjects diagnosed with an eligible indication must have exhausted treatment options with proven survival benefit
6. Subjects must have

   1. measurable disease
   2. Life expectancy ≥ 3 months per Investigator's opinion

8. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 9. Adequate vital organ function 10. Adequate bone marrow function 11. Adequate coagulation profile 12. Toxicities from prior/ongoing therapies must have recovered to ≤ Grade 2 according to the CTCAE v5.0 or Subject's baseline excluding alopecia 14. Prior toxicities related to surgical procedures should have recovered to Grade ≤ 1 15. Women of childbearing potential (WCBP) or men who can father children must be willing and able to use adequate (e.g. barrier or licensed hormonal methods)

Exclusion Criteria:

1. Any uncontrolled medical or psychiatric disorder that would preclude participation as outlined
2. HLA-A\*02:02 or HLA-A\*02:03 genotype
3. Pregnant or lactating women
4. Viral serology:

   1. Known infection with HIV-1/2, CMV (CMV required only for U.S. sites) or HTLV-1/2,
   2. Active infection with HBV or HCV
   3. Positive test for Mycoplasma or Treponema Pallidum
5. Uncontrolled infection(s) requiring intravenous anti-bacterial, anti-viral or anti-fungal treatment within 14 days prior to the first dose of LDC (patients receiving prophylactic antibiotics are eligible)
6. Inadequate venous access for or contraindications to leukapheresis
7. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to MDG1015 excipients, LDC agents, rasburicase, methylprednisolone or tocilizumab.
8. Untreated CNS metastases or active CNS metastases (progressing or requiring corticosteroids for symptoms control) and leptomeningeal disease
9. Unstable/active ulcer, varices, or digestive tract bleeding or recent digestive surgery that may have increased risk of bleeding
10. History of another primary malignancy that requires intervention beyond surveillance or that has not been in remission for at least 1 year. The following are exempt from the 1-year limit:

    1. non-melanoma skin cancer
    2. curatively treated localized prostate cancer
    3. carcinoma in situ (e.g. cervix, bladder, breast)
11. NYHA Class ≥ II, heart failure, unstable angina, a history of recent (≤ 6 months) arrythmias, myocardial infarction or sustained (\> 30 seconds) ventricular tachyarrhythmias
12. Subjects who are dependent on dialysis
13. Subjects with a history of pulmonary embolism or deep vein thrombosis that cannot safely withhold anti-coagulant therapy from leukapheresis until 7 days after administration of MDG1015 as determined by the Investigator
14. Active autoimmune disease requiring systemic therapy except for adequately controlled Type 1 diabetes mellitus, autoimmune hypothyroidism or Grave's disease
15. Previous allogeneic hematopoietic stem cell transplant within the last 5 years or solid organ transplant

    Specific to GAC/GEJ Subjects:
16. Positive history of esophageal or gastric resection that the Investigator considers is at increased risk of bleeding or perforation

Primary outcomes:
measure: DE Segment: Adverse Events and Dose Limiting Toxicities (Safety and Tolerability)
timeFrame: 28 days
measure: Exp Segment: Adverse Events (Safety)
timeFrame: 12 months
Secondary outcomes:
measure: Objective response rate (ORR)
timeFrame: 12 months
measure: Correlation of blood levels and the onset and/or severity of IP-related toxicities
timeFrame: 12 months
measure: Clinical benefit rate (CBR)
timeFrame: 12 months
measure: Overall survival (OS)
timeFrame: 15 years
measure: Assess feasibility of MDG1015 generation in study population
timeFrame: 2 years
measure: Progression Free Survival (PFS)
timeFrame: 12 months
measure: Duration of response (DOR)
timeFrame: 12 months
measure: Best overall response (BOR)
timeFrame: 12 months
measure: Time to response (TTR)
timeFrame: 12 months
measure: Levels of MDG1015 in blood over time
timeFrame: 12 months
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutch Cancer Center
state: Washington
Study officials:
affiliation: Fred Hutch Cancer Center
name: David Dr. Zhen, MD
role: PRINCIPAL_INVESTIGATOR
References: