pediatric CD22-positive relapsed/refractory Acute Lymphoblastic Leukemia MedDRA version: 21.0 Level: LLT Classification code 10063625 Term: Acute lymphoblastic leukemia recurrent System Organ Class: 100000004864
Conditions
Interventions
Trade Name: BESPONSA
Product Name: Inotuzumab Ozogamicin
Product Code: PF-05208773
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: INOTUZUMAB OZOGAMICIN
CAS
Sponsors
Erasmus Medical Center
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Age for all strata (Str1A, ph2, Str1B, Str2 and Str3): Patients must be = 1 and 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 a
Exclusion criteria
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).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary Objective Stratum 1 Stratum 1A: establish the MTD or RP2D of single agent InO when administered in children with CD22-positive relapsed/refractory BCP-ALL. Phase 2 Cohort: establish the activity (ORR) 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. Primary objective Stratum 2: 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). ;Secondary Objective: 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 ;Primary end point(s): Stratum 1A: Dose-limiting toxicities (DLTs) during the first cycle of therapy. Phase 2 cohort: Overall Response Rate (ORR), defined | — |
Secondary
| Measure | Time frame |
|---|---|
| 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. • | — |
Countries
Austria, Belgium, Czechia, Czech Republic, Denmark, Finland, France, Germany, Ireland, Israel, Italy, Netherlands, Norway, Poland, Portugal, Spain, Sweden, Switzerland, United Kingdom
Contacts
Public ContactTrial and datacenter
Prinses Maxima centrum
Outcome results
None listed