A phase I safety, dose finding and feasibility trial of GD2IL18CART in patients with relapsed or refractory GD2 positive solid cancers

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaet Muenster

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Apr 2024 → ongoing

Decision date (initial)

2024-03-19

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Miltenyi Biotec B.V. & Co. KG · Bundesministerium für Bildung und Forschung

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Dose response

Primary objective: Assessment of safety and toxicity of GD2IL18CART
Dose-finding objective: Recommended dose (RD) of GD2IL18CART
Efficacy objective: Response to autologous GD2IL18CART

Secondary objectives 2

1. In vivo immune function of GD2IL18CART
2. Duration of response, relapse rate, survival

Conditions and MedDRA coding

Neuroblastoma

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Male or female patients must have a diagnosis of relapsed and/or refractory (r/r) neuroblastoma, Ewing sarcoma, osteosarcoma or advanced breast cancer, judged to be incurable with conventional treatment.  Among patients with advanced breast cancer,: ‐ patients with hormone receptor positive disease must have exhausted all endocrine therapy options including a combination with a CDK4/6 inhibitor and chemotherapy must not be a reasonable therapy option, ‐ patients with HER2 positive disease: Patients should have received Trastuzumab-Emtansin (T-DM1) and/or T-DXd in second line after a HER2 directed antibody in the (neo)adjuvant setting or in first line therapy, ‐ patients with triple negative disease must have received at least 2 prior lines of chemotherapy including Sacituzumab-Govitecan in the metastatic setting, and patients with combined positive score (CPS) >10 and/or immune cell score (IC)  1% should have received an immune checkpoint inhibitor previously.  For neuroblastoma, patients with locoregional recurrence must have received surgery and/or radiotherapy followed by relapse chemotherapy. Patients with metastatic recurrence after initial classification as intermediate risk must have received high risk therapy. Patients with recurrence after initial classification as high risk must have received relapse chemotherapy alone or combined with immunotherapy.  Patients with Ewing sarcoma must have received front-line therapy and at least one prior line of relapse chemotherapy according to standard regimens (alkylating agents in combination with topoisomerase inhibitors; irinotecan with temozolomide; gemcitabine and docetaxel; high-dose ifosfamide; carboplatin with etoposide. Patients with an isolated lung relapse must have received pulmonary irradiation either during frontline or relapse therapy.  Patients with osteosarcoma must have received front-line therapy and at least one prior line of relapse chemotherapy (alkylating agents and/or etoposide and/or carboplatin or gemcitabine and docetaxel). Patients with an isolated relapse manifestation (lung metastasis or local relapse) must have unresectable disease.
2. GD2 expression on tumor cells in archival biopsy in the central reference lab. GD2-positive tumor is defined as ≥ 50% of tumor cells expressing ≥ 2+ GD2 using an immunofluorescence staining (IF) assay for specific detection of GD2 expression in formalin-fixed, paraffin-embedded neoplastic tissue or frozen tumor tissue along with a semi- quantitative evaluation.
3. Evaluable disease based on RECIST v1.1 (all disease entities) or by MIBG-scan or PET-scan or bone marrow biopsy/aspirate (neuroblastoma)
4. Age ≥1 and <80 years
5. Absolute CD3+ T cell count ≥200/μl
6. ECOG performance score of 0-2 if >16 years old or Lansky performance score of ≥ 60 if ≤16 years old at screening
7. No childbearing potential or negative pregnancy test at screening and before chemotherapy in women with childbearing potential
8. Signed and dated informed consent/assent by patients and/or parents, before conduct of any trial-specific procedure.

Exclusion criteria 19

1. Active solid central nervous system (CNS) metastases
2. Pregnant or breast-feeding females
3. Concurrent or recent prior therapies: o High-dose chemotherapy with autologous stem cell transplantation or requiring autologous stem cell rescue or anticancer biologicals (e.g. mifamurtide, interferons) or immune checkpoint inhibitors or radiation therapy or major surgery within 30 days prior to leukapheresis o Neuroblastoma patients who have relapsed after allogeneic or haploidentical stem cell transplantation must be at least 100 days posttransplant, with no evidence of GVHD and not taking immunosuppressive agents for at least 30 days prior to leukapheresis. o I131 MIBG therapy (neuroblastoma) or other targeted radionuclide therapy must be completed at least 3 months prior to apheresis. o GD2-specific antibody therapy with dinutuximab beta or naxitamab within 40 days (5 half lives) o Antiproliferative chemotherapies, epigenetic agents, antibody drug conjugates or antibodies targeting GD2 or alternative antigens (e.g. herceptin)alternative antigens than GD2 or epigenetic agents within 3 weeks prior to leukapheresis o Immunosuppressive agents other than steroids within 2 weeks prior to leukapheresis o Short-acting molecularly targeted agents (kinase inhibitors) within 7 days prior to leukapheresis o Systemic corticosteroids with the exception of physiologic replacement dosing within 7 days prior to leukapheresis o Live vaccines within 30 days prior to leukapheresis
4. Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory preparative chemotherapy, pre-medication for infusion, rescue medication/salvage therapies for treatment related toxicities
5. Contraindication of trial related procedures as judged by the Investigator, e.g. tumor biopsy
6. Female patients of child-bearing potential not willing to practice a highly effective form of birth control from the time of signing the informed consent form and for 12 months after dosing the IMP
7. Male patients of fathering potential not willing to practice a highly effective form of birth control from from the time of signing the informed consent form and for 12 months after dosing the IMP
8. Concurrent participation in another interventional trial that could interact with this trial, e.g. CAR T trials
9. Cerebral dysfunction, legal incapacity of adult patients; Committal to an institution on judicial or official order
10. Current autoimmune disease or history of autoimmune disease with potential CNS involvement
11. Active clinically significant CNS dysfunction (including but not limited to uncontrolled seizure disorders, cerebrovascular ischemia or hemorrhage, dementia, paralysis)
12. History of an additional malignancy other than non-melanoma skin cancer or carcinoma in situ unless disease free for ≥3 years
13. Pulmonary function: Patients with pre-existing severe lung disease or an oxygen requirement of >28% O2 supplementation or active pulmonary infiltrates on X-ray
14. Cardiac function: Pediatric patients: fractional shortening <28% or left ventricular ejection fraction <50% by echocardiography, adult patients: left ventricular ejection fraction <50% by echocardiography
15. Renal function: GFR ≤29 mL/min/1.73 m2 by CKD-EPI for patients ≥18 yrs or creatinine clearance ≤29 mL/min/1.73 m2 by Schwartz formula for patients <18 yrs of age
16. Liver function: Patients with a serum bilirubin >3 times upper limit of normal or an AST or ALT >5 times upper limit of normal, unless due to liver infiltration by the underlying malignant disease in the estimation of the Investigator
17. Rapidly progressive disease that in the estimation of the Investigator would compromise ability to complete study therapy
18. Hematological function: Patients must have an absolute neutrophil count (ANC) ≥ 500/μl and a platelet count ≥ 50 × 103/μl
19. Presence of any active infection

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Overall incidence and severity of AEs (CTCAE version 5.0)
2. Dose-finding part: RD of GD2IL18CART based on the maximum tolerated dose (MTD) selected by the Bayesian Optimal Interval (BOIN) Design decision rules (posterior DLT estimate closest to target toxicity, i.e. 20%) until day 28 after GD2IL18CART and on the basis of safety and efficacy.
3. Dose extension part: Overall response rate (ORR) defined as the rate of complete (CR) or partial (PR) remissions at week 12 by imRECIST.

Secondary endpoints 5

1. In vivo persistence/immune function of GD2IL18CART
2. Proportion of patients for whom a GD2IL18CART product can be generated
3. Best response
4. Duration of response, relapse rate and time to relapse
5. Disease-free and overall survival at 1 year

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaet Muenster

Sponsor organisation

Universitaet Muenster

Address

Schlossplatz 2, Schlossbezirk Schlossbezirk

City

Muenster

Postcode

48149

Country

Germany

Scientific contact point

Organisation

Westfaelische Wilhelms Universitaet Muenster

Contact name

Prof. Dr. med. Claudia Rössig

Public contact point

Organisation

Westfaelische Wilhelms Universitaet Muenster

Contact name

Prof. Dr. med. Claudia Rössig

Third parties 7

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Application history

8 submissions — initial application plus substantial / non-substantial modifications