| 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 |
Stratum 1
- Stratum 1A:
To establish the maximum tolerated dose of single agent InO when administered in children with CD22-positive relapsed/refractory BCP-ALL.
- Phase 2 Cohort:
To establish the activity (overall response rate, defined as CR, CRi and CRp) of single agent InO when administered in children with CD22-positive relapsed/refractory BCP-ALL.
-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.
- 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. |
|
| E.2.2 | Secondary objectives of the trial |
Stratum 1A and Phase 2: determine
•safety and tolerability of InO single agent (during course 1 cum. tox. and after subsequent allo-HSCT or CAR-T)
•relationship between CD22 receptor density, WBC-Count, CD22 saturation kinetics, cytogenetics, in-vitro calicheamicin resistance to clinical response.
•persistence of B-Cell aplasia and hypogammaglobulinemia in responding patients.
•nr of patients developing ADAs
Stratum 1B: determine
•safety and tolerability of InO in combination with modified UKALL-R3 re-induction CT regimen
•relationship between CD22 expression and clinical response
•nr of patients developing CD22-negative relapse
Stratum 2: To determine
•persistence of B-Cell aplasia and hypogammaglobulinemia in responding patients
•nr of patients developing ADA
All strata: To determine
•(hematological) response rate
•MRD levels, % of patients with complete MRD
•durability of response and long-term FUP
•serum PK parameters
•nr of patients developing ADAs
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age: Patients must be ≥ 1 and < 18 years of age
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)
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
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 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 (male patients) or 8 months (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 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 and 1B), but not in the stratum 1 phase 2 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoints for patients enrolled in Stratum 1A:
Dose-limiting toxicities (DLTs) during the first course of therapy.
Primary endpoints for patients enrolled in 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.
Primary endpoint for patients enrolled in 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.
- The cumulative incidence of non-relapse mortality, defined as the cumulative probability of non-relapse mortality, with time calculated between start of study treatment and death due to other causes than relapsed or refractory leukemia or lymphoma, accounting for competing events. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After first cycle regarding DLTs. Response is assessed at end of cycle 1, 2, 4 and 6. |
|
| 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 VOD/ 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 C1, as well as the best response (MRDnegativity) over multiple courses.
• Duration of response (time between achieving response (CR, CRi or CRp) after starting study treatment and documented relapse or death).
• Nr and % of patients being transplanted or having received CAR-T
• 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 2nd malignancies
• Overall survival, defined as time to death following start of study treatment.
3. Serum PK 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. patients having received HSCT or CAR-T).
• % of patients with anti-drug antibodies (ADA).
Phase 2 cohort:
1. 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 C1
• MRD levels, including % of patients who become MRD-negative , after C1, as well as the best response (MRD-negativity) over multiple courses.
• Duration of response
• Nr and % of patients being transplanted or having received CAR-T cells after treatment with Ino.
• Event-free survival (EFS).
• Survival
3. Serum PK parameters of InO and unconjugated calicheamicin
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 % 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. patients from the date of HSCT or CAR-T cell therapy)
• Percentage of patients 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 patients who undergo HSCT and those receiving CAR-T cell therapy
• Event-free survival
• 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. Pharmacodynamic 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:
• Overall remission rate (CR and PR) both after C1 as well as overall best response in patients receiving multiple courses of InO therapy
• Duration of response
• Nr and % of patients being transplanted or having received CAR-T cell
therapy after treatment with Ino.
• Event-free survival (EFS).
• Overall survival.
2. Serum pharmacokinetic parameters of InO and unconjugated calicheamicin.
3. Other endpoints:
• The % 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 patients from the date having received HSCT or CAR-T)
• Percentage of patients who exhibit ADA.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Starting from screening visit, during treatment, until end of treatment visit.
Further follow up:
1-safety evaluation of adverse events will be followed up every month until 12 months post last InO dose (starting after week 10 safety visit)
2-Number of CD19+ B-Cells and serum Ig levels will be followed up every 3 months until 12 months post last InO dose (starting after week 10 safety visit)
For details please refer to Table 8 (page 62) in protocol V1.1 18Aug2016: Table 8:Schedule of events for all BCP-ALL patients |
|
| 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 | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| 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 |
| Norway |
| Spain |
| Sweden |
| Switzerland |
| 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
|
End of trial:LVLS
Premature end of trial:Premature termination of this study may occur because of a regulatory authority decision, change in opinion of the IRB/EC, or significant safety of efficacy concerns. The conditions to discontinue may not conflict with the clinical study agreement. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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