Authorised Phase I and Phase II (Integrated)- Other pediatric CD22-positive relapsed/refractory Acute Lymphoblastic Leukemia

Inotuzumab ozogamicin for Acute Lymphoblastic Leukemia

EU CTIS ID: 2023-504694-20-00

What this study is testing

STRATUM 1 Stratum 1A: To establish the MTD or the RP2D of single agent InO when administered in children with CD22-positive relapsed/refractory BCP-ALL (completed). Note that: o if the MTD is not reached at the highest tested dose, no further dose-escalation will be performed. o to establish the RP2D for further study in the Phase 2 cohort, additional modelling will be performed regarding cumulative toxicity (as described in Section 9) Phase 2 Cohort: To establish the preliminary clinical activity (efficacy) activity with respect to ORR of single agent InO when administered in children with CD22-positive relapsed/refractory BCP-ALL. (completed) Stratum 1B (and 1B-ASP): To determine the RP2D of InO in children with CD22-positive relapsed/refractory BCP-ALL in combination with a modified UKALL-R3 based re-induction regimen. (completed) STRATUM 2 (EXPLORATORY) To explore the safety and tolerability of InO as a single agent in children with relapsed/refractory other CD22 positive B-cell malignancies. (completed) STRATUM 3 To establish the preliminary clinical activity (efficacy) with respect to ORR of single agent InO when administered in children with CD22-positive VHR 1st relapse BCP-ALL, excluding patients transplanted in 1st CR. (enrolment completed) STRATUM 4 To establish the clinical activity (efficacy) with respect to ORR of single agent InO in pediatric patients with R/R CD22+ BCP ALL (including VHR 1st relapse BCP-ALL, ≥2nd relapse, relapse after HSCT and refractory disease).

  • Phase I and Phase II (Integrated)- Other

A plain-language read of the study's public EU CTIS listing. The study team confirms the details.

Who can take part

You may be able to join if

  • Age (for all patients) • Patients must be ≥ 1 and < 18 years of age at the time of enrollment. Additional criteria for limited to Stratum 1A and 1B only: • 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 years up to less than 18 years may continue to be enrolled at dose level 1 until a maximum of 6 patients are enrolled.
  • Stratum 4: Patients must have either: • 2nd or greater CD22 positive BCP-ALL relapse; • 1st VHR CD22 positive BCP-ALL relapse defined as isolated bone marrow or combined relapse occurring less than 18 months from initial diagnosis and/or with cytogenetic-high risk characteristics, including KTM2A/AF4, E2A/TCF3-PBX1 t(1;19), E2A/TCF3-HLF t(17;19), hypodiploidy (less than 40 chromosomes), TP53 mutation and/or deletion. Acceptable laboratory techniques to confirm these cytogenetic abnormalities include chromosome banding analysis (CBA), fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), and/or Next Generation Sequencing (based on local laboratory results); • Any relapse of BCP-ALL post HSCT; • Refractory disease, 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. AND must meet the following criteria: • Patients must have M2 or M3 marrow status (≥ 5% blasts by morphology). • The malignant clone must be CD22 surface antigen positive (in either bone marrow or peripheral blood) by institutional standards as determined by the local immunophenotyping laboratory. • For 1st VHR BCP-ALL relapse evidence of prior fusion gene abnormalities is acceptable as they tend to be stable during the course of the disease. Laboratory techniques acceptable to test the presence of the cytogenetic-high risk characteristics are chromosome banding analysis (CBA), FISH, PCR and/or Next Generation Sequencing (inclusion is based on local laboratory results).
  • Stratum 1A, Phase 2 and Stratum 1B/1B-ASP: Diagnosis Patients must have either • First relapse of BCP-ALL post allogeneic HSCT • Second or greater relapsed or refractory BCP-ALL • Refractory disease, 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. 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 (Stratum 1A only) must have M3 marrow status (≥ 25% blasts by morphology).
  • 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: • First BM or combined relapse of CD22+ VHR 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, as also shown in Table 2 (excluding patients who received a HSCT in 1st CR). 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. • Evidence of prior fusion gene abnormalities is acceptable as they tend to be stable during the course of the disease. • Laboratory techniques acceptable to test the presence of the above mentioned cytogenetic-high risk characteristics are chromosome banding analysis (CBA), FISH, PCR and/or Next Generation Sequencing (inclusion is based on local laboratory results).
  • For all patients Performance Level and Life Expectancy • Karnofsky > 60% for patients > 16 years of age and Lansky > 60% for patients ≤ 16 years of age. (See Appendix I for Performance Scales). • Patient must have a life expectancy of at least 6 weeks.

You likely can't join if

  • 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 degrees Celsius 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. • Patients will be excluded if they have received prior treatment with anti-tumor vaccines.
  • 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 parts (stratum 1A and 1B), but not in the single-agent phase 2, stratum 3 and stratum 4.
See the full eligibility criteria
Who can join
  • Age (for all patients) • Patients must be ≥ 1 and < 18 years of age at the time of enrollment. Additional criteria for limited to Stratum 1A and 1B only: • 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 years up to less than 18 years may continue to be enrolled at dose level 1 until a maximum of 6 patients are enrolled.
  • Stratum 4: Patients must have either: • 2nd or greater CD22 positive BCP-ALL relapse; • 1st VHR CD22 positive BCP-ALL relapse defined as isolated bone marrow or combined relapse occurring less than 18 months from initial diagnosis and/or with cytogenetic-high risk characteristics, including KTM2A/AF4, E2A/TCF3-PBX1 t(1;19), E2A/TCF3-HLF t(17;19), hypodiploidy (less than 40 chromosomes), TP53 mutation and/or deletion. Acceptable laboratory techniques to confirm these cytogenetic abnormalities include chromosome banding analysis (CBA), fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), and/or Next Generation Sequencing (based on local laboratory results); • Any relapse of BCP-ALL post HSCT; • Refractory disease, 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. AND must meet the following criteria: • Patients must have M2 or M3 marrow status (≥ 5% blasts by morphology). • The malignant clone must be CD22 surface antigen positive (in either bone marrow or peripheral blood) by institutional standards as determined by the local immunophenotyping laboratory. • For 1st VHR BCP-ALL relapse evidence of prior fusion gene abnormalities is acceptable as they tend to be stable during the course of the disease. Laboratory techniques acceptable to test the presence of the cytogenetic-high risk characteristics are chromosome banding analysis (CBA), FISH, PCR and/or Next Generation Sequencing (inclusion is based on local laboratory results).
  • Stratum 1A, Phase 2 and Stratum 1B/1B-ASP: Diagnosis Patients must have either • First relapse of BCP-ALL post allogeneic HSCT • Second or greater relapsed or refractory BCP-ALL • Refractory disease, 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. 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 (Stratum 1A only) must have M3 marrow status (≥ 25% blasts by morphology).
  • 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: • First BM or combined relapse of CD22+ VHR 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, as also shown in Table 2 (excluding patients who received a HSCT in 1st CR). 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. • Evidence of prior fusion gene abnormalities is acceptable as they tend to be stable during the course of the disease. • Laboratory techniques acceptable to test the presence of the above mentioned cytogenetic-high risk characteristics are chromosome banding analysis (CBA), FISH, PCR and/or Next Generation Sequencing (inclusion is based on local laboratory results).
  • For all patients Performance Level and Life Expectancy • Karnofsky > 60% for patients > 16 years of age and Lansky > 60% for patients ≤ 16 years of age. (See Appendix I for Performance Scales). • Patient must have a life expectancy of at least 6 weeks.
  • For all patients 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 prior to entering this study, with the exception of the authorized laboratory abnormalities as defined in the inclusion/exclusion criteria. a. Chemotherapy: At least 7 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea, 6-mercaptopurine and steroids which are permitted up until 48 hours prior to initiating protocol therapy. Patients may have received intrathecal therapy at any time prior to study entry. Patients who relapse while receiving maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study. b. Radiotherapy: At least 28 days must have elapsed since any prior radiation therapy. c. Hematopoietic Stem Cell Transplant: At least 90 days must have elapsed since previous allo-HSCT. Patient must have no evidence of active graft vs. host disease. Patient must not be receiving GVHD prophylaxis or treatment. d. Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with GCSF or other growth factors at the time of enrollment. At least 14 days must have elapsed since the completion of therapy with pegfilgrastim (Neulasta®). e. Immunotherapy: At least 42 days must have elapsed after the completion of any type of immunotherapy, e.g. chimeric antigen receptor T cell (CART) therapy. Patients may not have received prior CD22- targeted therapy (immunotoxin or CART therapy). f. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of a monoclonal 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 as outlined in the inclusion and exclusion criteria. g. 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) under investigation. No residual toxicities should be observed following previous treatment. An experimental drug is defined as any drug that is not approved and licensed for sale by the FDA for institutions in the United States, by the EMA for institutions in Europe, by Health Canada for institutions in Canada and by The Therapeutic Goods Administration for institutions in Australia. h. Prior calicheamicin exposure: Patient has not received prior treatment with a calicheamicin-conjugated antibody (e.g. gemtuzumab ozogamicin).
  • For all patients Renal and Hepatic Function • Patient’s serum creatinine must be ≤ 1.5 x institutional upper limit of normal (ULN) according to age. If the serum creatinine is greater than 1.5 x institutional ULN, the patient must have a GFR ≥ 70mL/min/1.73 m2 estimated based on serum creatinine and/or cystatin C levels (e.g. Bedside Schwartz formula). • AST and ALT must be ≤ 5 x institutional ULN. (stratum 3 & 4) • Patient’s total total bilirubin must be ≤ 1.5 x institutional ULN unless the patient has documented Gilbert syndrome, in which case the AST and ALT must be ≤ 5 x ULN. (stratum 3 & 4)
  • For all patients Cardiac Function • Patient must have a shortening fraction ≥ 30% by echocardiogram or an ejection fraction > 50% by MUGA.
  • For all patients Reproductive Function • Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment. • Female patients with infants must agree not to breastfeed their infants while on this study. • Male and female patients of child-bearing potential must agree to use a highly effective method of contraception approved by the investigator during the study, following the CTFG recommendations, and for at least 8 months for females and for at least 5 months for males after the last dose of InO. • Highly effective methods of contraception include (but not exclusively) the following contraceptive methods: • combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation • progestogen-only hormonal contraception associated with inhibition of ovulation • intrauterine device (IUD) • intrauterine hormone-releasing system (IUS) • sexual abstinence.
What rules you out
  • 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 degrees Celsius 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. • Patients will be excluded if they have received prior treatment with anti-tumor vaccines.
  • 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 parts (stratum 1A and 1B), but not in the single-agent phase 2, stratum 3 and stratum 4.
  • Additional exclusion criteria for Stratum 1B • Patients with grade 3-4 peripheral neuropathy (as defined in the Delphi consensus of acute toxic effects for childhood ALL by Schmiegelow et al.12). • Patients with prior history of thrombosis during steroid and/or asparaginase are eligible provided they use adequate anti-coagulant prophylaxis, according to institutional guidelines. • Patients in whom prior experience suggests that a timely delivery of therapy is unlikely or associated with an undue risk because of intolerance.
  • Additional exclusion criteria for Stratum 1B-ASP cohort only • Patients with any history of PEG-asparaginase intolerance due to allergic reactions or silent inactivation during prior treatment. • Patients with any history of prior asparaginase-associated acute pancreatitis (any grade as defined in the Delphi consensus12. Patients who are excluded from Stratum 1B-ASP may potentially be enrolled in Stratum 1B expansion cohort.
  • Additional exclusion criteria for Stratum 3 (VHR cohort) only • Patients who are transplanted in CR1 (such patients are eligible for the phase 1B cohort).

The study team makes the final eligibility decision.

Where it's taking place

  • United Kingdom
  • Switzerland
  • Israel

Questions & answers

Do participants get paid in this trial?

This listing doesn't specify compensation. Many trials still reimburse travel or offer a stipend, so it's worth asking the study team when you connect.

Is it free to join, and do I need insurance?

Searching and applying through BridgeMD is free. In clinical trials the study-related treatment and visits are generally provided at no cost to you. You usually don't need insurance to take part - confirm specifics with the study team.

How long does this study last?

The listing doesn't state an exact length. The study team walks you through the schedule and number of visits before you decide to enroll.

Who can join this trial?

This study is enrolling all sexes, 0-17 years. The study team makes the final eligibility decision.

Where is this trial taking place?

Study sites include United Kingdom; Switzerland; Israel. Enter your location above to see the nearest site and check your eligibility.

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BridgeMD is an information and trial-matching tool - not medical advice, and not the study sponsor. Details come from EU CTIS; the study team decides eligibility.