Table 3.
ALL PIP decisions: clinical studies
| Autologous T-cells transduced with lentiviral vector containing a chimeric antigen receptor directed against CD19 (CTL019), EMEA-001654-PIP01-14 | 1. OL SA posology-finding study to evaluate S and F of redirected autologous T-cells engineered to contain anti-CD19 attached to TCRzeta and 4-1BB signaling domains (CAR-19 cells) in patients 1 year to <18 years (and adults) with a CT-resistant or CT-refractory CD19+ leukemia or lymphoma |
| 2. OL SA, single-dose study to evaluate S and A of CTL019 in 2 years to <18 years at the time of initial diagnosis (and adults) with CD19+ B-cell acute LL/CD19+ B-cell lymphoblastic lymphoma refractory to standard CT, relapsed after SCT, or otherwise ineligible for allogeneic SCT | |
| 3. OL SA single-dose study to evaluate S and A of CTL019 in 3 years to <18 years (and adults) with | |
| 4. CD19+ B-cell ALL refractory to standard CT, relapsed after SCT, or ineligible for allogeneic SCT OL two-cohort study to evaluate manufacturing and S of CTL019 in <3 years, weighing ≥6 kg, with CD19+ B-cell ALL/CD19+ B-cell lymphoblastic lymphoma at high risk for relapse and at relapse or refractory stage | |
| Navitoclax (ABT-263), EMEA-000478-PIP01-08-M01 | 1. OL, S and PK study of ABT-263 single-agent and combination therapy in pediatric patients from 28 days to <18 years of age with relapsed or refractory lymphoblastic leukemia or lymphoblastic lymphoma |
| 2. R, controlled, S and A study of ABT-263 in combination with a chemotherapeutic backbone in patients with relapsed or refractory lymphoblastic leukemia or lymphoblastic lymphoma | |
| Blinatumomab, EMEA-000574-PIP02-12 | 1. MC, OL, multiple-dose, dose-escalation trial to evaluate PK, PD, toxicity, S, and antitumor activity of blinatumomab in children from birth to <18 years of age with a relapse of B-precursor ALL involving the bone marrow or a refractory ALL and for whom no effective treatment is known, with an extension phase R, controlled, adaptively designed, OL trial to evaluate the PK, S, and E of blinatumomab compared to multiagent consolidation CT in children from 1 month to <18 years of age with a first, high-risk relapse of B-precursor ALL PK–PD analysis to inform the dose for study 2 |
| Dasatinib, EMEA-000567-PIP01-09-M04 | 1. OL MC dose-escalation trial to evaluate PK and S of dasatinib in children from 2 years to <18 years (and in adults) with recurrent or refractory solid tumor or imatinib-resistant Ph+ leukemia |
| 2. OL MC dose-escalation trial to evaluate PK and S of dasatinib in children from 1 year to <18 years with Ph+ CML or acute leukemia | |
| 3. OL MC trial to evaluate PK, S, and E of dasatinib in children 1 year to <18 years with Ph+ CML of all phases (including treatment-naïve patients in chronic phase) or relapsed or refractory Ph+ ALL | |
| Imatinib, EMEA-000463-PIP01-08-M03 | 1. OL MC non-R dose-escalation trial to evaluate S and E of CT, hematopoietic SCT, and imatinib in children from 1 year to <18 years (and young adults) with ALL |
| 2. OL MC R trial to evaluate S, A, and E of imatinib on top of CT and in combination with hematopoietic SCT in children 1 year to <18 years with ALL | |
| 3. Development and validation of an integrated physiology-based PK and pop PK model | |
| 4. For the indications myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements, hypereosinophilic syndrome and/or chronic eosinophilic leukemia with FIP1L1-platelet-derived growth factor receptor alpha gene rearrangement, kit (CD 117)-positive gastrointestinal stromal tumors, and dermatofibrosarcoma protuberans, the following studies are separately listed | |
| • Study 3: same as for condition treatment of Philadelphia chromosome (BCR-ABL translocation)-positive ALL | |
| • Study 4: measure to extrapolate efficacy to the pediatric population | |
| l-Asparaginase encapsulated in erythrocytes, EMEA-000341-PIP02-09-M01 | 1. Double-blind, dose-comparative, R, repeat-dose, MC, active-controlled trial to evaluate PK, PD, S, and immunogenicity of l-asparaginase encapsulated in erythrocytes in children from 1 year to <18 years (and in adults) with ALL |
| 2. OL, R, single-dose, MC, active-controlled trial to evaluate PK, S, and PD activity of l-asparaginase encapsulated in erythrocytes in children from 1 year to <18 years (and in adults) with first relapse of ALL, with and without asparaginase hypersensitivity | |
| 3. OL, R, MC, active-controlled trial to evaluate S, PD equivalence/comparative efficacy of l-asparaginase encapsulated in erythrocytes in children from birth to <18 years with newly-diagnosed ALL | |
| Mercaptopurine, EMEA-000350-PIP01-08 | 1. OL, single-dose, single-center, R, crossover trial to assess the bioequivalence of oral mercaptopurine suspension to the tablet formulation in adults |
| Recombinant l-asparaginase, EMEA-000013-PIP01-07-M03 | 1. R, parallel-group, blinded, single-center, multiple-dose trial to evaluate PK, PD, A, and S of recombinant l-asparaginase compared to native Escherichia coli asparaginase in children from 1 year to <18 years of age (and adults) with newly-diagnosed ALL |
| 2. R, MC, double-blind trial to evaluate S, PD equivalence, and E of recombinant l-asparaginase compared to native E. coli asparaginase in children from 1 year to <18 years of age (and adults) with newly-diagnosed ALL | |
| 3. Noncontrolled, MC trial to evaluate PD, A, and S of recombinant l-asparaginase in children from birth to <1 year of age with newly-diagnosed ALL | |
| 4. Three studies, listed separately under lymphoblastic lymphoma: “same as for condition treatment of acute lymphoblastic leukaemia” | |
| Rituximab, EMEA-000308-PIP01-08-M02 | 1. OL R, controlled, parallel-group, MC trial to evaluate PK, PD, S, and E of rituximab add-on to standard CT in children 6 months to <18 years with advanced stage B-cell lymphoma (excluding primary mediastinal B-cell lymphoma), Burkitt and Burkitt-like lymphoma/leukemia |
Abbreviations: ALL, acute lymphoblastic leukemia; PIP, pediatric investigation plan; OL, open-label; SA, single-arm; S, safety; F, feasibility; A, activity; CT, chemotherapy; SCT, stem cell transplantation; MC, multicenter; PK, pharmacokinetics; Ph+, Philadelphia chromosome-positive; CML, chronic myeloid leukemia; E, efficacy; R, randomized; Pop, population; PD, pharmacodynamics; CAR, chimeric antigen receptor; LL, lymphoblastic lymphoma.