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 (EPITOME-1015-I)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Epithelial Ovarian Cancer; Myxoid Liposarcoma; Synovial Sarcoma; Gastro-esophageal Junction Cancer; Soft Tissue Sarcoma (STS)
• Intervention / Treatment: Drug: Lymphodepletion; Biological: TCR-T cells (MDG1015)

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

• Study Type: Interventional
• Enrollment (Estimated): 55
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kirsty Dr. Crame, MD; Phone Number: +49892000330; Email: k.crame@medigene.com
• Study Contact Backup: Name: Marianne Seibt, BA; Email: m.seibt@medigene.com

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Administration of MDG1015; MDG1015 is a first-in-class, 3rd generation TCR-T therapy consisting of autologous, patient-derived CD8+ T cells that are transduced with a New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/ L antigen family member-1a (LAGE-1a)-specific, human leukocyte antigen (HLA)-A*02:01-restricted T cell receptor (TCR) and the costimulatory switch protein (CSP) programmed cell death protein 1 (PD1)-41BB administered following lymphodepletion chemotherapy.

Drug: Lymphodepletion; Cylcophosamide and Fludarabine; Biological: TCR-T cells (MDG1015); TCR-T cells (MDG1015)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DE Segment: Adverse Events and Dose Limiting Toxicities (Safety and Tolerability)	Incidence and severity of adverse events to establish RP2D measured by dose limiting toxicities (DLTs) up to 28 days post infusion	28 days
Exp Segment: Adverse Events (Safety)	Incidence of (S)AEs by type, grade and duration	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Proportion of Subjects having a confirmed complete response (CR) or partial response (PR) per RECIST v1.1	12 months
Correlation of blood levels and the onset and/or severity of IP-related toxicities	Correlation of certain blood levels in serum over time and any correlation between these levels and the onset and/or severity of IP-related toxicities	12 months
Clinical benefit rate (CBR)	Proportion of Subjects having a sustained confirmed stable disease (SD) or a confirmed PR or CR for any duration of time per RECIST v1.1	12 months
Overall survival (OS)	The interval between MDG1015 infusion and date of death by any cause	15 years
Assess feasibility of MDG1015 generation in study population	Number of MDG1015 products manufactured which comply with the pre-defined release specifications	2 years
Progression Free Survival (PFS)	The interval between MDG1015 infusion and date of disease progression or death per RECIST v1.1	12 months
Duration of response (DOR)	The interval between the first documented response following MDG1015 infusion until first documented disease progression or death	12 months
Best overall response (BOR)	The best response recorded from the start of the treatment until disease progression (taking as reference for progressive disease (PD) the smallest measurements recorded since the treatment started)	12 months
Time to response (TTR)	The interval between MDG1015 infusion and first documented CR or PR per RECIST v1.1	12 months
Levels of MDG1015 in blood over time		12 months

Collaborators and Investigators

• Sponsor: Medigene AG
• Investigators: Principal Investigator: David Dr. Zhen, MD, Fred Hutch Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): August 1, 2042

Study Registration Dates

• First Submitted: December 12, 2024
• First Submitted That Met QC Criteria: December 23, 2024
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 23, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: solid tumors; phase I; open label; First-in-human; dose escalation; NY-ESO-1; LAGE-1a; single arm; Enhancement; TCR-T Therapy; Third Generation TCR-T Therapy; autologous, patient derived CD8+ T cells; BOIN design; PD1-41BB; Costimulatory Switch Protein; Armoring
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Genital Diseases, Female; Endocrine Gland Neoplasms; Neoplasms, Glandular and Epithelial; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Carcinoma; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Neoplasms, Adipose Tissue; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Adenocarcinoma; Sarcoma; Liposarcoma; Sarcoma, Synovial; Liposarcoma, Myxoid
• Other Study ID Numbers: CD-TCR-004; 2024-516787-28-00 (Ctis); 2024-516787-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No