A Phase I/II study of Inotuzumab Ozogamicin (InO) as monotherapy and in combination with chemotherapy in children and adolescents with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL).

Identifiant de l'essai ICTRP
EUCTR2016-000227-71 (ICTRP)

Titre officiel (approuvé par le comité d'éthique)
A phase I/II study of Inotuzumab Ozogamicin (InO) as a single agent and in combination with chemotherapy for pediatric CD22-positive relapsed/refractory Acute Lymphoblastic Leukemia. Study ITCC-059 (BASEC)

Titre académique
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 - ITCC-059 (ICTRP)

Titre public
The safety and efficacy of the medicine Inotuzumab Ozogamicin in children with relapsed/refractory acute lymphatic leukemia (ALL) (ICTRP)

Maladie en cours d'investigation
pediatric CD22-positive relapsed/refractory Acute Lymphoblastic Leukemia
MedDRA version: 20.0Level: LLTClassification code 10063625Term: Acute lymphoblastic leukemia recurrentSystem Organ Class: 100000004864;Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15] (ICTRP)

Intervention étudiée

Product Name: Inotuzumab Ozogamicin
Product Code: PF-05208773
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: Inotuzumab Ozogamicin
CAS Number: 635715-01-4
Other descriptive name: INOTUZUMAB OZOGAMICIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 0.25-

(ICTRP)

Type d'essai
Interventional clinical trial of medicinal product (ICTRP)

Plan de l'étude
Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no (ICTRP)

Critères d'inclusion/exclusion
Gender:
Female: yes
Male: yes

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 180 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. (ICTRP)

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 for the phase 1 dose finding part (stratum 1A), but not in the stratum 1 phase 2 cohort.




Critères d'évaluation principaux et secondaires
Main Objective: Primary objective Stratum 1A:
To establish the maximum tolerated dose of single agent InO when administered in children with CD22-positive relapsed/refractory BCP-ALL.

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. ;Secondary Objective: 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;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.
;Timepoint(s) of evaluation of this end point: After course 1 (ICTRP)

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.
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.;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 (ICTRP)

Date d'enregistrement
03.01.2018 (ICTRP)

Inclusion du premier participant
14.12.2017 (ICTRP)

Sponsors secondaires
non disponible

Contacts supplémentaires
Prof. Dr. CM Zwaan, c.m.zwaan@erasmusmc.nl, +31(0)107036691, ErasmusMC (ICTRP)

ID secondaires
ITCC-059, NTR5736, 2016-000227-71-NL (ICTRP)

Résultats-Données individuelles des participants
non disponible

Informations complémentaires sur l'essai
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000227-71 (ICTRP)