A phase I/II study of Inotuzumab Ozogamicin as a single agent and in combination with chemotherapy for pediatric CD22-positive relapsed/refractory Acute Lymphoblastic Leukemia
Study ITCC-059

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 6-18 yrs.
•Then at least 2 additional patients must be enrolled from age 1-6 yrs at the same dose level.
•After this: subsequent dose levels may enroll patients aged 1-18 yrs.
•In case 2 younger patients are not yet recruited, patients aged 6-18yrs may continue to be enrolled at dose level 1 until a maximum of 6 patients are enrolled. ;Stratum 1A: Diagnosis
First relapse of BCP-ALL post allogeneic HSCT or second or greater relapsed or refractory BCP-ALL, or refractory disease and must meet the following criteria:
•M2 or M3 marrow status (>= 5% blasts by morphology)
•CD22 surface antigen positive (either BM or PB)
•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
• First relapse of BCP-ALL post allogeneic HSCT or second or greater relapsed or refractory BCP-ALL, or refractory disease, and must meet the following criteria:
•M2 or M3 marrow status (>= 5% blasts by morphology)
•CD22 surface antigen positive (either BM or PB)
•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:
• 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.
• CD22 surface antigen positive (in either biopsy material, BM or PB) ;Performance Level and Life Expectancy:
•Karnofsky > 60% for patients > 16 years of age and Lansky > 60% for patients <= 16 years of age.
•life expectancy of at least 6 weeks.;Prior Therapy:
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy defined as resolution of all such non-hematologic toxicities to <= Grade 2 per the CTCAE 4.03.
•Chemotherapy: At least 7 days wash-out; except for hydroxyurea, 6-mp and steroids (wash-out 48 hrs) and intrathecal therapy (no wash-out). Patients who relapse while receiving maintenance chemotherapy will not be required to have a waiting period.
•Radiotherapy: At least 28 days must have elapsed since any prior radiation therapy.
•Hematopoietic Stem Cell Transplant: At least 90 days must have elapsed since previous allo-HSCT. No evidence of active GVHD; not receiving GVHD prophylaxis or treatment.
•Hematopoietic growth factors: At least 7 days wash-out of therapy with GCSF or other growth factors. At least 14 days wash-out of pegfilgrastim (Neulasta®).
•Immunotherapy: At least 42 days wash-out of any type of immunotherapy, e.g. CART therapy. No prior CD22-targeted therapy or anti-tumor vaccines permitted.
•Monoclonal antibodies: wash-out of at least 3 half-lives of the antibody (ie: Rituximab = 66 days, Epratuzumab = 69 days), with the exclusion of blinatumomab. Patients must have been off blinatumomab infusion for at least 14 days and all drug-related toxicity must have resolved to grade 2 or lower.
•Investigational drugs: At least 7 days or 5 drug half-lives (whichever is longer) must have elapsed since prior treatment with any experimental drug (with the exception of monoclonal antibodies).
•no prior treatment with a calicheamicin-conjugated antibody (e.g. gemtuzumab ozogamicin).
Renal and Hepatic Function:
•serum creatinine <= 1.5 x ULN according to age. If the serum creatinine is > than 1.5 xULN, the patient must have a radioisotope GFR >= 70mL/min/1.73m2.
•AST and ALT <= 2.5 x ULN.
•total bilirubin <= 1.5 x ULN (unless patient has documented Gilbert syndrome &AST and ALT are <=2.5 x ULN).
Cardiac Function:
•shortening fraction >= 30% by ECG or an ejection fraction > 50% by MUGA.
Reproductive Function:
•If applicable, negative urine or serum pregnancy test confirmed prior to enrollment.
•If applicable, agree not to breastfeed while on this study.
•If applicable, agree using effective method of contraception during the study and for 5 months (for male patients) or 8 months (for female patients) after the last dose of InO.

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.
•Children with Down syndrome are excluded from participation in the dose finding part (stratum 1A), but not in the stratum 1 phase 2 cohort.