E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
pediatric CD22-positive relapsed/refractory Acute Lymphoblastic Leukemia |
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E.1.1.1 | Medical condition in easily understood language |
Pediatric relapsed Acute Lymphoblastic Leukemia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063625 |
E.1.2 | Term | Acute lymphoblastic leukemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objective Stratum 1A: To establish the maximum tolerated dose of single agent InO when administered in children with CD22-positive relapsed/refractory BCPALL. Primary objective Phase 2 Cohort: To establish the activity (ORR) of single agent InO when administered in children with CD22-positive relapsed/refractory BCP-ALL. Primary objective Stratum 2: To explore the safety and tolerability of InO as a single agent in children with relapsed/refractory other CD22 positive B-cell malignancies. |
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E.2.2 | Secondary objectives of the trial |
Stratum 1A and Phase 2 cohort: To determine: •safety and tolerability of InO as a single agent (during course 1, cumulative toxicity, and after subsequent allo-HSCT). •hematological response rate (Stratum 1A only) •MRD levels in responding patients, % of patients with complete MRD. •durability of response and long-term FUP (relapse-rates, HSCT-nrs, overall survival). •serum PK parameters •the relationship between CD22 receptor density, WBC-Count at start of treatment, CD22 saturation kinetics, cytogenetics, and in-vitro calicheamicin resistance to clinical response. •persistence of B-Cell aplasia and hypogammaglobulinemia in responding patients. •nr of patients developing ADAs Stratum 2 (Other B-cell malignancies): to determine •response rates •durability of response and long-term FUP (SCT-nrs, relapse, overall survival) •serum PK parameters •persistence of B-Cell aplasia and hypogammaglobulinemia in responding patients •nr of patients developing ADA |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 6-18 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 Patients must have either first relapsed BCP-ALL after allo-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 Patients must have either first relapsed BCP-ALL after allo-HSCT or second or greater relapsed or refractory BCP-ALL, or refractory disease as defined below, 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 first relapsed BCP-ALL after allo-HSCT or 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 relapsed 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 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. |
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E.4 | Principal 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 liverfailure [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. •Patients with Down syndrome are excluded for the phase 1 dose finding part (stratum 1A), but not in the stratum 1 phase 2 cohort. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Stratum 1A: Dose-limiting toxicities (DLTs) during the first course of therapy.
Phase 2 cohort: Overall Response Rate (ORR), defined as CR, CRi, CRp, measured as best response during InO treatment (see Appendix 2 for definitions).
Stratum 2: Safety and tolerability: • AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy, during the first and subsequent courses of therapy. • Occurrence of toxic death; i.e., death attributable to InO therapy. • Occurrence of hepatic VOD/SOS during or after therapy with InO. • Laboratory abnormalities as characterized by type, frequency, severity and timing.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Stratum 1A: 1. Safety and tolerability: • AEs (type, frequency, severity, timing, seriousness, and relation to study therapy. • Occurrence of toxic death • Occurrence of hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) during or after therapy with InO. • Laboratory abnormalities (type, frequency, severity and timing). 2. Measures of anti-leukemic activity: • Overall Response Rate (ORR), defined as CR, CRi, CRp , best response over multiple courses • MRD levels, incl. % of patients who become MRD-negative (defined as an MRD-level < 1x10-4), after course 1, as well as the best response (MRD-negativity) over multiple courses. • Duration of response (time between achieving response (CR, CRi or CRp) after starting study treatment and documented relapse or death). • Number and percentage of patients being transplanted after treatment with Ino. • Event-free survival (EFS), defined as the time between start of study treatment and first event including failure to achieve CR/CRp/CRi (calculated as an event on day 0), relapse, death of any cause and second malignancies. • Overall survival, defined as time to death following start of study treatment. 3. Serum pharmacokinetic parameters of InO and unconjugated calicheamicin. 4. Pharmacodynamic parameters: • Relationship between response (ORR) and CD22 expression levels, WBC, CD22 saturation kinetic, calicheamicin sensitivity. • Clonal evolution (CD22-negativity) and relation to loss of response. 5. Other endpoints • % of patients responding to InO (ORR) without adequate recovery of CD19-positive B-cells or immunoglobulins following 4 wks, 10 wks, 3, 6 and 12 mnths after treatment (excl. HSCT patients). • % of patients with anti-drug antibodies (ADA). Phase 2 cohort: Safety: • AEs (type, frequency, severity, timing, seriousness, and relation to study therapy) • Occurrence of toxic death • Occurrence of VOD/SOS during or after therapy with InO. • Laboratory abnormalities (type, frequency, severity and timing). 2. Other measures of anti-leukemic activity: • Overall Response Rate (ORR) after course 1. • Minimal residual disease levels, including the percentage of patients who become MRD-negative , after course 1, as well as the best response (MRD-negativity) over multiple courses. • Duration of response (time between achieving response (CR, CRi or CRp) after starting study treatment and documented relapse or death). • Number and percentage of patients being transplanted after treatment with Ino. • Event-free survival (EFS), defined as the time between start of study treatment and first event including failure to achieve CR/CRp/CRi (calculated as an event on day 0), relapse, death of any cause and second malignancies. • Survival, defined as time to death following start of study treatment. 3. Serum pharmacokinetic parameters of InO and unconjugated calicheamicin. XML File Identifier: z/RnaKvMiw4PMlrszJ/ntM5p9mI= Page 14/28 4. Pharmacodynamic parameters: • Relationship between response (ORR) and CD22 expression levels, WBC, CD22 saturation kinetics and calicheamicin sensitivity. • Clonal evolution (CD22-negativity) and relation to loss of response. 5. Other endpoints • The percentage of patients responding to InO (ORR) without adequate recovery of CD19-positive B-cells or immunoglobulins following 4 wks, 10 wks, 3, 6 and 12 months after treatment with InO, (excl. HSCT patients from HSCT date) • Percentage of patients who exhibit ADA. Stratum 2 secondary endpoints: 1. Measures of anti-tumor activity: • Overall remission rate (CR and PR) both after course 1 as well as overall best response in patients receiving multiple courses of InO therapy (see Appendix 2 for definitions). • Duration of response (time between achieving response (CR and PR) after starting study treatment and documented relapse or death). • Number and percentage of patients being transplanted after treatment with Ino. • Event-free survival (EFS), defined as the time between start of study treatment and first event including failure to achieve CR/PR (calculated as an event on day 0), relapse, death of any cause and second malignancies. • Overall survival, defined as time to death following start of study treatment. 2. Serum pharmacokinetic parameters of InO and unconjugated calicheamicin. 3. Other endpoints: • The percentage of patients responding to InO (ORR) without adequate recovery of CD19-positive B-cells or immunoglobulins following 4 wks, 10 wks, 3, 6 and 12 mths after treatment, (excl HSCT patients from HSCT date). • Percentage of patients who exhibit ADA. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After course 1, after each subsequent course of therapy, and at 4wks, 10wks, 3months, 6 months and 9 months of FUP |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
First administration in pediatric population |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Czech Republic |
Denmark |
France |
Germany |
Ireland |
Israel |
Italy |
Netherlands |
Spain |
Sweden |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |