High Risk and/or relapsed/refractory Neuroblastoma MedDRA version: 20.0 Level: LLT Classification code 10019260 Term: Heart block AV third degree System Organ Class: 100000004849
Conditions
Interventions
Product Name: GD2-CART01
Pharmaceutical Form: Solution for infusion
Product Name: AP1903
Pharmaceutical Form: Solvent for solution for infusion
Product Name: Fludarabine
Product Code: L01BB05
Pharma
Sponsors
IRCCS Ospedale Pediatrico Bambino Gesù
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Procurement eligibility All the patients must meet the following eligibility inclusion criteri a at the time of procurement. l, Diagnosis of NBL that have been treated with frontline therapy and is judged to be incurable, based upon the following criteria: a, Relapse after first-line treatment, proved by a positive 123-I-mMIBG-scan b, Persistence/progression ofdisease after the initiation ofthe upfront treatment Treatment eligibility 3.2.1 Phase I -Patient Inelusion Criteria The patient must meet the following eligibility incJusion eriteria to be enrolled to receive treatment in the Phase I study. 1. Diagnosis ofNBL that have been treated with frontline therapy and is judged to be incurable, based upon the following criteria: a. Relapse after first-line treatment, proved by a positive 123-I-mMIBG-scan b. Persistenee/progression of disease after the initiation of the upfront treatment 2. Patients must have measurable or evaluable disease at the time of treatment enrollment, as shown by bone marrow biopsy/aspirate, US or CT/MRI sean or by 123I-mMrBG scano 3. Reeover from the toxic effeet of previous chemotherapies: grade 4 and or 3 nonhematologic toxicities must have resolved to grade :::2; if some effeets ofthe therapies have become chronic (Le. treatment associated thrombocytopenia), the patient must be clinical!y stable, according to the opinion of the treating physicians, and meet ali other eligibility criteria. 4. Age: 12 months -18 years. 5. Voluntary informed consent is given. For subjects 16 years of age: Karnofsky greater than or equa! to 60%; Patients less than or equal to 16 years ofage: Lansky scale greater than or equal to 60%. 7. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen. 8. Females ofchild-bearing potential must havea negative pregnancy test because ofthe potentially dangetous effects on the fetus. 3.2.2 Phase II -Patients Inclusion criteria The patient must meet the following eligibility inclusion criteria to be enrolled to receive treatmènt in the Phase n study. l. Diagnosis of NBL that have been treated with frontline therapy and is judged to be incurable, based upon the following criteria: a. Relapse after first-line treatment, proved by a positive MlBG-scan b. Persistence/progression ofdisease after the initiation of the upfront treatment OR 2. Diagnosis of High Risk NBL at high risk of relapse, defined by stage IIIIIV and MycN amplification, at the end of the first-line treatmentaccording to the Standard of Care, even ifNED. 3. Patients with relapsed/refractory disease must have measurable or evaluable disease at the time oftreatment enrollment, as shown by bone marrow biopsy/aspirate, US or CT/MRI scan or by MIBG-scan. 4. Recover from the toxic effect of previous chemotherapies: grade 4 and or 3 nonhematologic toxicities must have resolved to grade :::;2; if some effects ofthe therapies have become chronic (i.e. treatment associated thrombocytopenia), the patient must be clinically stable, according to the opinion of the treating physicians, and meet
Exclusion criteria
Exclusion criteria: Procurement eligibility Phase 1111 Exclusion Criteria l. Severe, uncontrolled active intercurrent infections 2. HIV or active HCV and/or HBV infection 3. Concurrent or recent prior therapies, before apheresis: a. Systemic steroids (at a dose equivalent to or greater 2 mg/kg prednisone) in the 2 weeks before apheresis collection. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary. b. Systemic chemotherapy in the 2 weeks preceding apberesis collection. c. Immunosuppressive agents in the 2 weekspreceding apheresis collection. d. Radiation therapy must have been completed at least 3 weeks prior to apheresis. e. Il3l MIBG therapy must have been completes at least 6 weeks prior to enrol1ment f. Anti-GD2 murinemonoclonal antibody (ch14.l8 antibody) in the 2 weeks preceding apheresis colleetion g. Other anti-neoplastic investigational agents currently or within 30 days prior to apheresis (Le. start of protoeol therapy); h. Exeeptions: i. Subjects receiving steroid therapy at physiologic replaeement doses only are allowed provided there has been no ìncrease in dose for at least 2 weeks prior to starting apheresis. Treatment eligibility Phase I/I1 ~ Patient Exclusion criteria l. Pregnant or lactating women 2. Severe, uncontro Iled acti ve intercurrent infections 3. Active hepatitis B or hepatitis C infection 4. HIV infection 5. Rapidly progressive disease with life-expectancy 4x upper limit of normal (ULN) or transaminase (ALT and AST) > 6 x ULN based on age and laboratory specific normal ranges 8. Renal function: serum creatinine > 3x ULN for age. 9. Blood oxygen saturation < 90%. lO. Cardiac function: Left ventricular ejection fraction )ower than 45% by ECHO. Il. Marrow function: ANC lower than 500/mm3 and/or platelets lower than 20.000 (not reached by transfusion). 12. Congestive heart failure, cardiac arrhythmia, psychiatric illness, or soci al situations that would limit compliance with study requirements or in the opinion ofthe PI would pose an unacceptable risk to the subject. ) 3. Untreated CNS metastasis; patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible. 14. Concurrent or recent prior therapies, before infusion: a. Systemic steroids (at a dose equivalent to or greater 2 mg/kg prednisone) in the 2 weeks before infusion. Recent or current use of inhaled/topicallnon~ absorbable steroids is not exclusionary. b. Systemic chemotherapy in the 2 weeks preceding infusion. c. Immunosuppressive agents less than or equal to 30 days. d. Radiation therapy must have been completed at least 3 weeks prior to enrollment. e. 1131 ~MIBG therapy must have been completed at least 6 weeks prior to enrollment f. Anti~GD2 murine monoclonal antibody (eh) 4. 18 antibody) in the 2 weeks preceding infusion g. Other anti-neoplastic investigational agents currently or within 30 days prior to start of protocol therapy; . h. Exceptions: i. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis;
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): Phase I primary end-points l. To evaluate the safety of the infusion of iC9-GD2-CAR T cells at different escalating/de-escalating doses and establish the dose limiting toxicity (DLT) of the cellular product. Toxicity will be evaluated according to the Common Terminology Criteria for Adverse Event (CTC AE) scale, version 4.0. DLT will be defined as any ofthe following that is not pre-existing, due to infection or to underlying malignancy and that may be considered possibly, probably or definitely related to the study cellular products. (l) Non-hematologic DLTois any grade 3 or 4 non-hematologic toxicity, nonresponsive to AP1903 infusions; (2) Hematologic DLT is defined as any grade 4hematologic toxicity, non-responsive to APl903 infusions; (3) Grade 4 reactions related to infusion; (4) Oeath related to iC9-G02-CAR T cells or to AP 1903 infusions. The incidence of grade 3-5 toxicities, with a main attention to severe CRS, will be evaluated. 2. To determine the optimal dose of iC9-G02-CAR transduced T cells resulting in the controI ofthe disease without inducing unacceptable levels oftoxicity (MTO) Phase II primary end-points l. To confirm the safety ofthe approaçh, using the recommended dose defined during the Phase I portion of the study. 2. To assess the antitumor effect of iC9-G02-CAR T cells at 6 weeks, 3 and 6 months post-infusion. The Best Overall Response Rate (BOR) and the proportion of patients achieving complete remission (CR) will be assessed according to both INRC and irRC;Timepoint(s) of evaluation of this end point: 6 weeks, 3 months and 6 months ;Main Objective: The primary objective ofthis study is to evaluate the safety and feasibility of iC9-GD2-CAR T cells infused in pediatric patients affected by relapsed/refractory NBL. The phase II extension is aimed at testing the efficacy of the treatment at the optimal dose defined in the phase I, including the patients with extremely High-Risk NBL, at greater risk of relapse (namely pati | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): l. To assess the in vivo persistence and expansion of the infused T cells in the peripheral blood (PB) and in the BM using immunoassays and transgene detection (Real Time qPCR), both for the whole population and the specific T cells subsets. 2. To evaluate the tumor infiftration ofthe infused T cells through Immunohistochemistry (IRC), flow cytometry and/or transgene detection (Real Time qPCR), whenever the tumor sample is available after the treatment.9. To assess the relapse rate ofthe high-risk patients treated with GD2 CAR T cells at the end ofthe first line treatment in NED. lO. To assess the disease outcome in patients treated with AP1903. 11.To assess the kinetic ofCAR T cells elimination after AP1903 infusion 12. To assess the clinical response and the kinetics of cytokine levels change in patients with CRS treated with AP 1903 13. To assess the outcome of patients treated in the presence of HAMA either pre-existing to the treatment, or detected after CAR T-celi infusion 3. To evaluate the activationand exhaustion ofthe infused T cells through immunoassays evaluating the expression of the specific markers and their activity through functional assays (such as EUSPOT for IFN-y release using G02-positive and G02-negative target cells, còmparing the response with the T cells at the moment of infusion, when possible) 4. To define the serum cytokine profile and its correlation with CRS in order to define a . possible predictive profile 5. To characterize the kinetic ofpentraxin 3 (PTX3) and its correlation with CRS to define its role as early predictive biomarker of CRS 6. To assess the long-term antitumor effect of the infused T cells at l, 3 and 5 years, without further therapy. 7. To assess relapse rate, time to progression (TIP) and event free survival (EFS) and OveraI! Survival (OS) at 6 months, l, 3 and 5 years post celi infusion. 8. To evaluate the ability of predicting the disease outcome by the response evaluati | — |
Countries
Italy
Contacts
Public ContactFrancesca Del Bufalo
OPBG
Outcome results
None listed