pediatric CD22-positive relapsed / refractory Acute Lymphoblastic Leukemia
Conditions
Interventions
A course of therapy is defined as 3 doses of InO administered weekly on days 1, 8 and 15. Course 1 will last 22 days (with delays allowed up to 42 days, depending on response and recovery from toxicit
Sponsors
ErasmusMC, Rotterdam
Eligibility
Inclusion criteria
Inclusion criteria: Age Patients must be ≥ 1 and < 18 years of age at the time of enrollment. • The first 3 BCP-ALL patients on dose level 1 must be aged 6 years to less than 18 years. • Then at least 2 additional patients must be enrolled from age 1 year to less than 6 years at the same dose level. • After this requirement is met, subsequent dose levels may enroll patients aged 1 year to less than 18 years. • In case 2 younger patients are not yet recruited, patients aged 6 to less than 18 years may continue to be enrolled at dose level 1 until a maximum of 6 patients are enrolled. Stratum 1A and 1B: Diagnosis Patients must have either second or greater relapsed or refractory BCP-ALL, or refractory disease as defined below, and must meet the following criteria: • Patients must have M2 or M3 marrow status (≥ 5% blasts by morphology) • The malignant clone needs to be CD22 surface antigen positive (in either the bone marrow or peripheral blood) by institutional standards as determined by the local immunophenotyping laboratory. • The first 6 patients must have M3 marrow status (≥ 25% blasts by morphology). • Refractory is defined as newly diagnosed patients who are induction failures after at least 2 previous regimens without attainment of remission, or patients with refractory first relapse after 1 previous reinduction regimen without attainment of remission. Phase 2 Cohort: Diagnosis Patients must have either second or greater relapsed or refractory BCP-ALL, or refractory disease as defined below, and must meet the following criteria: • Patients must have M2 or M3 marrow status (≥ 5% blasts by morphology) • The malignant clone needs to be CD22 surface antigen positive (in either the bone marrow or peripheral blood) by institutional standards as determined by the local immunophenotyping laboratory. • The first 6 patients must have M3 marrow status (≥ 25% blasts by morphology). • Refractory is defined as newly diagnosed patients who are induction failures after at least 2 previous regimens without attainment of remission, or patients with refractory first relapse after 1 previous reinduction regimen without attainment of remission. Stratum 2: Diagnosis Patients must have second or greater relapsed or refractory CD22-positive B-cell malignancy including but not limited to diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), Burkitt lymphoma, Burkitt leukemia or B-cell precursor lymphoblastic lymphoma: • There must be histologic verification of disease at original diagnosis or subsequent relapse. • Patient must have evaluable or measurable disease documented by radiographic criteria or bone marrow disease present at study entry. • The malignant cells need to be CD22 surface antigen positive (in either biopsy material, the bone marrow or peripheral blood) by institutional standards as determined by the local immunophenotyping laboratory. Stratum 3: Diagnosis Patients must have 1st BM or combined relapsed of VHR CD22-positive BCP-ALL defined as: • any relapse <18 months from initial diagnosis and/or • cytogenetic-high risk characteristics: KTM2A/AF4, E2A/TCF3-PBX1, t(1;19) or E2A/TCF3-HLF t(17;19), hypodiploidy (less than 40 chromosomes), TP53 mutation and/or deletion. • excluding patients trans
Exclusion criteria
Exclusion criteria: Isolated extramedullary relapse Patients with isolated extramedullary disease are excluded (not applicable to lymphoma patients except for isolated CNS-relapse)   VOD/SOS Patients with any history of prior or ongoing VOD/SOS per the modified Seattle criteria are excluded, as specified in appendix 3, or prior liver-failure [defined as severe acute liver injury with encephalopathy and impaired synthetic function (INR of ≥1.5)]. Infection Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient may not have: • A requirement for vasopressors; • Positive blood culture within 48 hours of study enrollment; • Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability. • A positive fungal culture within 30 days of study enrollment. • Active fungal, viral, bacterial, or protozoal infection requiring IV or oral treatment. Chronic prophylaxis therapy to prevent infections is allowed. Other anti-cancer therapy Patients will be excluded if there is a plan to administer non-protocol anti-cancer therapy including but not limited to chemotherapy, radiation therapy, or immunotherapy during the study period. Allergic reaction Patients with prior Grade 3/4 allergic reaction to a monoclonal antibody are excluded. Concurrent disease Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with protocol therapy, interfere with consent, study participation, follow up, or interpretation of study results.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| In stratum 1A: Dose-limiting toxicities (DLTs) during the first course of therapy. In phase 2 cohort: Overall Response Rate, measured as best response during InO treatment Stratum 2: Safety and tolerability Stratum 1B and 1B-ASP: Dose-limiting toxicities (DLTs) during the first cycle of InO when added to a modified UKALL-R3 re-induction chemotherapy regimen without or with ASP. Stratum 3: ORR: % of pats with CR, CRi, CRp, measured as best response to InO treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| In stratum 1A: Safety and tolerability, Measures of anti-leukemic activity, Serum pharmacokinetic parameters of InO and unconjugated calicheamicin, Pharmacodynamic parameters. Phase 2 cohort: safety, other measures of anti-leukemic activity, Serum pharmacokinetic parameters of InO and unconjugated calicheamicin, Pharmacodynamic parameters. Stratum 2: Measures of anti-tumor activity , Serum pharmacokinetic parameters of InO and unconjugated calicheamicin Stratum 1B and 1B-ASP: Safety and tolerability, Measures of anti-leukemic activity, Serum pharmacokinetic parameters of InO and unconjugated calicheamicin, Pharmacodynamic parameters. Stratum 3: Safety, other measures of anti-tumor activity, Pharmacodynamic parameters | — |
Contacts
Public ContactC.M. Zwaan
Erasmus Medisch Centrum
Outcome results
None listed