GD2IL18CART Combined With Bevacizumab for Relapsed and Refractory GD2-positive Solid Tumors

Prior treatment

• Concurrent or recent prior therapies:
  • High-dose chemotherapy with autologous stem cell transplantation or requiring autologous stem cell rescue or anticancer biologicals (e.g. mifamurtide) or radiation therapy or major surgery within 30 days prior to leukapheresis.
  • CAR T cells within 3 months before leukapheresis.
  • Checkpoint inhibitors within less than 2 half lives prior to apheresis.
  • 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.
  • I-131 MIBG therapy (neuroblastoma) or other targeted radionuclide therapy must be completed at least 3 months prior to apheresis.
  • GD2-specific antibody therapy with dinutuximab beta or naxitamab within 40 days (5 half-lives) before apheresis.
  • Antiproliferative chemotherapy, epigenetic agents, antibody-drug conjugates, or antibodies targeting antigens other than GD2 within 3 weeks prior apheresis.
  • Immunosuppressive agents other than steroids within 2 weeks before apheresis.
  • Short-acting molecularly targeted agents (kinase inhibitors) within 7 days before apheresis.
  • Systemic corticosteroids, except physiologic replacement dosing, within 7 days before apheresis.
  • Live vaccines within 30 days before apheresis.
• Concurrent participation in another interventional trial that could interact with this trial, e.g. CAR T trials.

Other illness

• Active solid central nervous system (CNS) metastases or metabolically active metastatic disease in the skull with direct contact to the dura.
• Current autoimmune disease or history of autoimmune disease with potential CNS involvement.
• Active clinically significant CNS dysfunction, including but not limited to uncontrolled seizure disorders, cerebrovascular ischemia or hemorrhage, dementia, or paralysis.
• Pre-existing severe lung disease, oxygen requirement of \>28% inspired oxygen (O2) supplementation, or active pulmonary infiltrates on X-ray.
• Presence of any active infection.
• Rapidly progressive disease that in the estimation of the Investigator would compromise ability to complete study therapy.
• 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.

Lab values

• Cardiac function: Pediatric patients (˂18 yrs): fractional shortening \<28% or left ventricular ejection fraction \<50% by echocardiography, young adult patients (18-25 yrs): left ventricular ejection fraction \<50% by echocardiography.
• Renal function: GFR ≤29 mL/min/1.73 m22 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.
• Liver function: serum bilirubin \>3 times the upper limit of normal (ULN) or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>5 times ULN, unless attributable to liver infiltration by the underlying malignant disease.
• Hematological function: absolute neutrophil count (ANC) \<500/µL or platelet count \<50 × 10³/µL.
• Bevacizumab-specific exclusion criteria:
  • uncontrolled arterial hypertension, history of hypertensive crisis or hypertensive encephalopathy,
  • clinically significant proteinuria.
  • history of gastrointestinal perforation or clinically significant fistula, or current condition considered to confer a clinically relevant increased risk of gastrointestinal perforation,
  • clinically significant bleeding or coagulopathy, including recent clinically significant hemoptysis or pulmonary hemorrhage,
  • any history of clinically significant arterial thromboembolic event, including myocardial infarction, cerebrovascular accident, transient ischemic attack, or arterial thrombosis/embolism,
  • clinically significant venous thromboembolism within 6 months before the first dose of bevacizumab,
  • history of posterior reversible encephalopathy syndrome (PRES),
  • clinically significant cardiovascular disease beyond inadequate left ventricular ejection fraction, e.g., uncontrolled arrhythmia, congestive heart failure, unstable angina.

Age

• History of an additional malignancy other than non-melanoma skin cancer or carcinoma in situ unless disease-free for ≥3 years.

Other

• Pregnant or breast-feeding females.
• Contraindication to trial related procedures as judged by the Investigator, e.g., tumor biopsy.
• 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.
• Male patients of fathering 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.
• Cerebral dysfunction, legal incapacity of adult patients; Committal to an institution on judicial or official order.

• Participants must have relapsed and/or refractory neuroblastoma, osteosarcoma, or Ewing sarcoma judged to be incurable with conventional treatment and meet the following disease-specific requirements:
  • 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.
  • Osteosarcoma: Patients must have received frontline therapy and at least one prior line of relapse systemic anticancer therapy for relapsed or refractory disease. Patients with an isolated relapse manifestation (lung metastasis or local relapse) must have unresectable disease.
  • Ewing sarcoma: Patients must have received frontline therapy and at least one prior line of relapse chemotherapy according to standard regimens. Patients with an isolated lung relapse must have received pulmonary irradiation during frontline or relapse therapy.
• All participants must additionally meet the following criteria:
  • GD2 expression on tumor cells in an archival biopsy assessed by the central reference laboratory. GD2-positive tumor is defined as GD2 at least 50% of tumor cells expressing GD2 at an intensity of 2+ or higher, using an immunofluorescence assay for specific detection of GD2 expression in formalin-fixed, paraffin-embedded or frozen tumor tissue with semiquantitative evaluation.
  • Evaluable disease based on Response Evaluation Criteria in Solid Tumors for all disease entities or, in cases of diffuse bone/bone marrow metastases, by whole-body nuclear medicine imaging (e.g. metaiodobenzylguanidine (MIBG)) scan for neuroblastoma or positron emission tomography (PET) based imaging.
  • Age ≥1 year and ≤25 years.
  • Absolute cluster of differentiation 3 (CD3)-positive T-cell count ≥200/µL.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2 for participants \>16 years of age or Lansky performance score ≥60 for participants ≤16 years of age at screening.
  • No childbearing potential, or negative pregnancy test at screening and before chemotherapy in participants with childbearing potential.
  • Signed and dated informed consent/assent by participants and/or their caregivers before any trial-specific procedure.