Epithelial Ovarian Cancer, Gastro-esophageal Junction Cancer, Soft Tissue Sarcoma (STS), Myxoid Liposarcoma, Synovial Sarcoma
Conditions
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
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
Interventions
DRUGLymphodepletion
Cylcophosamide and Fludarabine
BIOLOGICALTCR-T cells (MDG1015)
TCR-T cells (MDG1015)
Sponsors
Medigene AG
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single arm, open label, multicenter, phase I study following a Bayesian optimal interval (BOIN) design for dose escalation
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DE Segment: Adverse Events and Dose Limiting Toxicities (Safety and Tolerability) | 28 days | Incidence and severity of adverse events to establish RP2D measured by dose limiting toxicities (DLTs) up to 28 days post infusion |
| Exp Segment: Adverse Events (Safety) | 12 months | Incidence of (S)AEs by type, grade and duration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical benefit rate (CBR) | 12 months | 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 |
| Overall survival (OS) | 15 years | The interval between MDG1015 infusion and date of death by any cause |
| Assess feasibility of MDG1015 generation in study population | 2 years | Number of MDG1015 products manufactured which comply with the pre-defined release specifications |
| Progression Free Survival (PFS) | 12 months | The interval between MDG1015 infusion and date of disease progression or death per RECIST v1.1 |
| Objective response rate (ORR) | 12 months | Proportion of Subjects having a confirmed complete response (CR) or partial response (PR) per RECIST v1.1 |
| Best overall response (BOR) | 12 months | 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) |
| Time to response (TTR) | 12 months | The interval between MDG1015 infusion and first documented CR or PR per RECIST v1.1 |
| Levels of MDG1015 in blood over time | 12 months | — |
| Duration of response (DOR) | 12 months | The interval between the first documented response following MDG1015 infusion until first documented disease progression or death |
| Correlation of blood levels and the onset and/or severity of IP-related toxicities | 12 months | 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 |
Countries
United States
Contacts
Primary ContactKirsty Dr. Crame, MD
Backup ContactMarianne Seibt, BA
Outcome results
None listed