| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| pediatric CD22-positive relapsed/refractory Acute Lymphoblastic Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pediatric relapsed Acute Lymphoblastic Leukemia |
|
| 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 | 21.0 |
| 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 |
|
| 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 1B (and 1B-ASP): 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.
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.
Primary objective Stratum 3: establish the preliminary efficacy (ORR)
with respect to ORR of single agent InO in children with CD22-positive Very High Risk 1st relapse BCP-ALl (excluding patients transplanted in 1st CR). |
|
| E.2.2 | Secondary objectives of the trial |
All strata
•(hematological) response rate
•MRD levels, % of patients with complete MRD (not Stratum 2)
•durability of response / long-term FUP
Str1A&Ph2:
•safety & tolerability of InO
•relation of CD22 receptor density, WBC-Count, CD22 saturation
kinetics, cytogenetics, in-vitro calicheamicin resistance to response
•persistence of B-Cell aplasia, hypogammaglobulinemia
•nr of patients developing ADAs
•serum PK parameters
Str1B and Stratum 1B-ASP:
•safety & tolerability of InO in combination with backbone regimen
•relationship of CD22 expr to response
•nr of patients developing CD22-neg relapse
•serum PK parameters
Str2:
•persistence of B-Cell aplasia, hypogammaglobulinemia
•nr of patients developing ADA
•serum PK parameters
Str3:
•safety & tolerability of InO
•relation of CD22 receptor density, WBC-Count, cytogenetics, in-vitro
calicheamicin resistance to response.
•persistence of B-Cell aplasia, MRD negativity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligibility:
Age for all strata (Str1A, ph2, Str1B, Str2 and Str3): Patients must be ≥
1 and < 18 years of age
Patients with Down syndrome are excluded in Stratum 1A and 1B/1B-ASP but not in the phase 2 cohort and Stratum 3.
Additional criteria for Stratum 1A and 1B:
•First 3 patients on dose level 1 must be 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, phase 2 and stratum 1B/1B-ASP: Diagnosis
Patients must have either 1st relapsed BCP-ALL after allo-HSCT or 2nd or greater relapsed or refractory BCP-ALL, or refractory disease (after at least 2 prior regimens):
•M2 or M3 marrow status (≥ 5% blasts by morphology)
•CD22 surface antigen positive (either BM or PB)
•Stratum 1 only: The first 6 patients must have M3 marrow status (≥ 25% blasts by morphology).
Stratum 2: Diagnosis
Patients must have 2nd 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
•Evaluable or measurable disease (by radiographic criteria or BM disease present)
• CD22 surface antigen positive (either biopsy material, BM or PB)
Str3: diagnosis:
• 1st 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
• excluding patients transplanted in 1st CR.
• M2 or M3 marrow status (≥ 5% blasts by morphology)
• CD22 surface antigen positive (in either the BM or PB)
• Evidence of prior fusion gene abnormalities is acceptable
• cytogenetic-high risk characteristics determined by chromosome
banding analysis (CBA), FISH, PCR and/or Next Generation Sequencing
All strata:
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 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. |
|
| 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 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.
•Patients with Down syndrome are excluded in the dose finding parts (stratum 1A and 1B), but not in the phase 2 cohort or VHR cohort.
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.1 ). 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 consensus.1).
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). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Stratum 1A:
Dose-limiting toxicities (DLTs) during the first cycle 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 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 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 cycles 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.
• Cumulative incidence of non-relapse mortality
Str3 cohort:
• ORR: % of pats with CR, CRi, CRp, measured as best response to InO
Treatment as a single agent in CD22+ VHR 1st relapse BCP ALL patients. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Stratum 1A:
1. Safety and tolerability:
• AEs
• Occurrence of toxic death
• Occurrence of hepatic VOD/ SOS during or after therapy with InO
• Laboratory abnormalities
• Cumulative incidence of non-relapse mortality
2. Measures of anti-leukemic activity:
• ORR defined as CR, CRi, CRp , best response after C1 and over multiple cycles
• MRD levels, incl. % of pats who become MRD- (defined as an MRD-level < 1x10-4), after C1, as well as the best response (MRDnegativity) over multiple cycles.
• Duration of response
• Nr and % of pats being transplanted or having received CAR-T
• Event-free survival (EFS)
• Overall survival
• Cumulative incidence of non-response or relapse
3. Serum PK parameters of InO and unconjugated calicheamicin.
4. 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
• % of pats 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. pats having received HSCT or CAR-T).
• % of pats with anti-drug antibodies (ADA).
Phase 2 cohort:
1. Safety:
• AEs
• Occurrence of toxic death
• Occurrence of VOD/SOS during or after therapy with InO.
• Laboratory abnormalities
• Cumulative incidence of non-relapse mortality
2. Other measures of anti-leukemic activity:
• ORR after C1
• MRD levels, including % of pats who become MRD- , after C1, as well as the best response (MRD-negativity) over multiple cycles.
• Duration of response
• Nr and % of pats being transplanted or having received CAR-T cells after treatment with Ino.
• EFS
• Survival
• Cumulative incidence of non-response or relapse
3. Serum PK parameters of InO and unconjugated calicheamicin
4. PD 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
• The % of pats 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. pats from the date of HSCT or CAR-T cell therapy)
• % of pats who exhibit ADA
Stratum 1B and 1B-ASP:
1. Safety:
• AEs
• Occurrence of toxic death (death attributable to InO)
• Occurrence of hepatic VOD/SOS during or after InO.
• Laboratory abnormalities
• Cumulative incidence of non-relapse mortality
2. Other measures of anti-leukemic activity:
• ORR
• MRD levels
• Duration of response
• Nr and % of pats who undergo HSCT and those receiving CAR-T cell therapy
• EFS
• Overall survival
• Cumulative incidence of non-response or relapse
3. Serum PK parameters of InO and unconjugated calicheamicin during treatment combined with modified UKALL-R3 re-induction regimen both with and without pegylated asparaginase
4. PD parameters
• Relationship between response (ORR) and CD22 expression levels
• Clonal evolution (CD22-negativity) and relation to loss of response
Stratum 2:
1. Measures of anti-tumor activity:
• ORR (CR and PR) both after C1 as well as overall best response in patients receiving multiple cycles of InO therapy
• Duration of response
• Nr and % of pats being transplanted or having received CAR-T cell
therapy after treatment with Ino.
• EFS
• Overall survival
• Cumulative incidence of non-response or relapse.
2. Serum pharmacokinetic parameters of InO and unconjugated calicheamicin.
3. Other
• The % of pats 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 pats from the date having received HSCT or CAR-T)
• % of pats who exhibit ADA.
Stratum3:
1. Safety:
• AEs
• induction death and/or toxic death.
• VOD/SOS during or after InO.
• Laboratory abnormalities
• The cumulative incidence of non-relapse mortality.
2. Other measures of anti-leukemic activity:
• ORR after cycle 1
• MRD levels, incl % of pats who become MRD- after C1, best
response (MRD-negativity) over multiple cycles.
• Duration of response
• Nr and % of pats being transplanted and/or receiving CAR T-cells.
• EFS, Survival
• cumulative incidence of non-response or relapse.
• Interval between InO re-induction and CAR-T cells therapy based on
MRD negativity and B cell aplasia after InO re-induction.
3. PD parameters
• Relationship between response (ORR) and CD22 expr, WBC, and
calicheamicin sensitivity.
• Clonal evolution (CD22-negativity) and relation to loss of response.
4. Other
• % of pats responding to InO without adequate recovery of CD19-
positive B-cells and CD4+/CD8+ T-cells or immunoglobulins at 4,6,8 and
10 weeks, 3, 6 and 12 months after treatment with InO, excl pats from
the date of HSCT or CAR T-cell infusion. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Response: After cycle 1, after each subsequent cycle of therapy,
Immunology: at 4wks, 10wks, 3months, 6 months and 9 months of FUP.
For str3 pats also at 6 and 8 wks of FUP.
Survival/remission status: monthly in the 1st yr, once every 3 months in the 2nd and 3rd yr of FUP.
|
|
| 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 |
|
| 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 | 28 |
| 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 |
| Israel |
| Switzerland |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Spain |
| Sweden |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
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