International Study for Treatment of Childhood Relapsed Precursor B-Cell ALL 2020 (IntReALL BCP 2020)

Though survival of children with acute lymphoblastic leukemia (ALL) has considerably improved over the past few decades, relapsed ALL remains a leading cause of mortality in children with cancer. Prognostic factors for patients with relapsed ALL are duration of first remission, immunophenotype of the malignant clone, site of relapse, molecular response to induction therapy (i.e minimal/measurable residual disease, MRD) and very high risk genetic features. The prognosis of patients with relapsed ALL was substantially improved with intensive multidrug chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the majority of patients at the cost of acute and long-term toxicity, including early and late treatment-related deaths. Patients with precursor B-cell (BCP) ALL classified as standard risk (SR) with late isolated bone marrow (BM) or combined with extramedullary (EM) disease and without high risk genetic features achieve high remission rates (> 95%) and favorable event-free survival (EFS) rates (65%) with conventional consolidation and maintenance chemotherapy if, after induction therapy, the leukemia could be reduced below the MRD level of 10-3 or 10-4, depending on the induction regimen. About 50% of SR patients experience poor MRD response after conventional chemotherapy induction and require intensified consolidation through allo-HSCT with total body irradiation to achieve EFS rates comparable to that of SR patients with good MRD response. Patients classified as high risk (HR) with early BM/EM relapse still demonstrate poor CR rates of around 65-75% being treated on standard induction therapy, and high rates of subsequent relapse. Consequently, these patients all require allo-HSCT for consolidation of 2nd remission. Patients with isolated extramedullary relapse (IEM) had a better outcome with CNS directed induction / consolidation chemotherapy as provided with the ALL-REZ BFM backbone compared to conventional induction as provided with the ALL-R3 induction. Patients with very high risk (VHR) genetic features (KMT2A::AFF1, TCF3::PBX1, TCF3::HLF rearrangements, low hypodiploidy/near haploidy, TP53 alterations) and/or very early relapses (i.e. those occurring within 18 month after initial diagnosis) have a limited benefit from conventional chemotherapy followed by allo-HSCT since their EFS rates have been reported to be below 20%.

For SR and HR patients, there is a need to replace toxic induction/consolidation chemotherapy with targeted less toxic drugs and to improve the rates of MRD negative remission after induction. In SR patients, reduction of MRD after induction could result in a lower proportion of patients with indication for allo-HSCT, a treatment that - despite being efficacious - is associated with substantial long-term sequelae. For SR patients, there is a medical need to reduce toxic consolidation and maintenance chemotherapy with targeted less toxic and potentially more effective treatment. The CD3/19 directed bi-specific monoclonal antibody blinatumomab has shown better efficacy and less toxicity compared to conventional consolidation chemotherapy in children with relapsed B-cell precursor (BCP) ALL with and without extramedullary involvement in randomized trials. The superiority of blinatumomab has been shown for HR patients before receiving HSCT in a randomized trial in Europe and for HR/IR patients before receiving HSCT and SR patients with MRD good response in a randomized trial conducted by the Children's Oncology Group. In SR patients with MRD good response, a total of 3 courses of Blinatumomab has been applied partly replacing consolidation chemotherapy and partly as add on to the standard therapy. Thus, blinatumomab can be considered as best standard of care (SOC) for early consolidation in this indication. Blinatumomab is currently being developed for subcutaneous administration. This formulation is planned to be tested in phase I/II studies in children with BCP ALL at the end of 2025. Innovative, more efficacious therapies, such as CD19-targeting CAR T cells, are urgently needed for VHR patients, since conventional therapies, including allo-HSCT, have led to dismal results.

Inotuzumab ozogamicin (InO) is a CD22 directed humanized monoclonal antibody linked to the toxin calicheamicin, belonging to the class of antibody-drug conjugate (ADC). CD22 is expressed on nearly all BCP-ALLs. After antigen binding, InO is internalized and the toxin released causing DNA damage and inducing apoptosis. InO has shown high MRD negative remission rates compared to SOC in adult and pediatric patients with relapsed/refractory BCP ALL and a safe and effective dose has been identified in a pediatric phase I/II trial.

The trial IntReALL BCP 2020 aims at integrating these recent developments and findings and at increasing the use of promising new immune-therapeutic drugs replacing toxic SOC chemotherapy elements. SR patients with bone marrow relapse will randomly receive the SOC induction ALLR3 with Mitoxantrone or InO monotherapy. Post induction, they will receive a 1st consolidation chemotherapy element (SCB1). Patients with MRD good response (< 10-4) will receive 3 courses of blinatumomab during consolidation and maintenance therapy, the 1st replacing the consolidation chemotherapy element SCB2, the 2nd added on after the 3rd consolidation chemotherapy element SCB3, and the 3rd added on after the 4rth consolidation element SCB4 and 8 weeks of conventional maintenance therapy, which, at difference of the IntReALL 2010 trial will not include vincristine/dexamethasone pulses. SR patients with MRD poor response will receive SCB1 and one blinatumomab course followed by allo-HSCT. During the course of the trial, the protocol is planned to be amended changing the blinatumomab formulation from IV to SC as soon as the latter becomes available. .

HR patients with bone marrow relapse will be included into an industry sponsored induction window trial and will join the academic IntReALL BCP 2020 study only for consolidation, since all HR patients have an indication for allo-HSCT. HR patients in CR2 after induction will receive one course of consolidation chemotherapy (HC1), one course of blinatumomab as recently established SOC followed by allo-HSCT. Whereas for the European Blina-215 trial (randomized blinatumomab versus HC3) 2 courses HC1 and HC2 were given as standard early consolidation, in the COG trial (AALL1331) the whole consolidation chemotherapy has been replaced by blinatumomab. One standard chemotherapy consolidation course HC1 is considered as feasible compromise and provides time for B-cell regeneration after InO as prerequisite for T-cell expansion during the blinatumomab consolidation course.

Patients with IEM will receive the IntReALL SR2010 arm A backbone with blinatumomab replacing the chemotherapy element SCA3 as bridge to allo-HSCT in those with early relapse or to further consolidation therapy in those with late relapse.

The hypotheses addressed within the IntReALL BCP 2020 trial are, that:

• EFS-probability in SR patients will be improved in the InO arm leading to higher CR rates, better MRD response and to less patients requiring allo-HSCT compared to standard of care induction chemotherapy ALL R3 in a prospective randomized trial.
• SR patients with MRD good response will have a better DFS probability with 3 courses of blinatumomab, the 1st replacing the consolidation chemotherapy element SCB2, the 2nd added on after the consolidation chemotherapy element SCB3, and the 3rd added on after the consolidation element SCB4 and 8 weeks of conventional maintenance therapy, followed by maintenance therapy until week 132, being applied without vincristine/dexamethasone pulses, as compared to historical controls. Blinatumomab given subcutaneously is planned to be investigated accordingly after finalization of the recruitment for the IV trial within a planned amendment of the study.
• HR patients with CR2 after induction will have a non-inferior DFS with HC1 and blinatumomab compared to historical controls with HC1, HC2 and blinatumomab.
• EFS probability in patients with IEM relapse will be improved and toxicity will be reduced with blinatumomab as late consolidation element compared to historical controls (ALL-REZ BFM 2002).

The IntReALL BCP 2020 trial has the potential to improve CR and EFS rates for all SR and HR groups, as well as in patients with IEM relapse, by replacing toxic chemotherapy with targeted less toxic immunotherapy strategies and may establish these new approaches as SOC for children with relapsed BCP ALL in future. In addition, the IntReALL BCP 2020 trial has the ambition to reduce the proportion of SR patients in need of an allograft for consolidation therapy.

Inclusion criteria

For all study questions:

• Confirmed diagnosis of 1st relapsed B-cell precursor ALL
• Patients ≥ 1 year and less than 18 years of age at diagnosis of primary ALL and less than 21 years of age at date of inclusion into the study
• Patient enrolled in a participating center
• Written informed consent (IC)
• Start of treatment falling into the study period
• No participation in other clinical trials 30 days prior to study enrolment that interfere with this protocol, except trials for primary ALL

Specific for SR induction randomization:

• Meeting SR criteria
• BM involvement (≥ 5% or ≥ 1% leukemic blasts confirmed by 2 quantitative methods)
• CD22 positive ALL (>80% confirmed by flow-cytometry)
• No previous history of veno-occlusive disease (VOD)/ sinusoidal obstruction syndrome (SOS)

Specific for SR MRD poor response consolidation:

• Meeting SR criteria with bone marrow involvement at relapse diagnosis
• M1/CR2 and MRD ≥ 10-4 after induction
• CD19 positive ALL at relapse (>10%)

Specific for SR MRD good response consolidation:

• Meeting SR criteria with bone marrow involvement at relapse diagnosis
• M1/CR2 and MRD < 10-4 after induction
• CD19 positive ALL at relapse (>10%) Specific for HR consolidation arm
• Meeting HR or VHR (in case of no possibility to be treated with CAR T cells) criteria
• M1/CR2 after induction therapy
• CD19 positive ALL at relapse (>10%)

Specific for IEM arm:

• Histology or cytology proven extramedullary relapse
• No bone marrow involvement (M1 at relapse diagnosis) and bone marrow MRD <1%
• CD19 positive ALL at relapse (>10%)

Exclusion criteria

• Known hypersensitivity to the active substances or excipients of the IMP's or the SOC drugs, except to PEG-asparaginase which can be replaced by Erwinase
• Left ventricular ejection fraction (LVEF) < 50% or fractional shortening < 25%, and/or current or prior treatment for cardiomyopathy and/or history of clinically significant arrhythmias
• Pregnancy or positive pregnancy test in female patients (urine sample positive for β-HCG > 10 U/l) at screening or within 7 days prior to the initiation of study treatment
• Sexually active adolescents and adults not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy
• Women not willing to refrain from breast feeding until 12 months after end of anti-leukemic therapy
• Relapse post allogeneic HSCT
• Relapse post chimeric antigen receptor T-cell (CAR-T) therapy
• The whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian
• Objection to the study participation by a minor patient
• Patients in a dependent or subordinate relationship to the investigator or site staff (e.g. employees, relatives, or students)
• No consent is given for saving and propagation of pseudonymized medical data for study reasons
• Patients with any concurrent medical condition, laboratory abnormality, concomitant treatment, or comorbidity that, in the investigator's clinical judgment would

• compromise the patient's ability to safely receive or tolerate inotuzumab ozogamicin and/or blinatumomab
• significantly interfere with assessment of treatment efficacy or safety
• make it unlikely that the patient would derive clinical benefit from protocol therapy
• preclude adherence to study procedures or follow-up requirements
• Subjects unwilling or unable to comply with the study procedures
• Subjects who are legally detained in an official institute

Specific for SR induction randomization:

• Prior confirmed severe (grade 3 or 4) or ongoing VOD/SOS
• Serious ongoing hepatic disease (e.g., cirrhosis, active hepatitis) not related to the current ALL relapse or current diagnostic/therapeutic measures
• ALT > 2,5 x ULN (at relapse diagnosis before start of cytoreduction) and/or bilirubin > 1.5 x ULN
• Patients with intolerance to PEG-asparagniase and also to Erwinase are stratified to the inotuzumab arm
• Patients with insufficient expression of CD22 (< 80%) on leukemic blasts, they are assigned to the control chemotherapy arrm

Specific for blinatumomab treatment:

• Clinically relevant CNS pathology requiring treatment (eg, unstable epilepsy)
• Evidence of current CNS (CNS 2, CNS 3) involvement by ALL. Subjects with CNS relapse at the time of relapse are eligible if CNS is successfully treated prior to enrollment

Allowed systemic diseases and concomitant medication

• Patients with Down Syndrome (DS) can be included as separate and descriptive population, not joining the study questions. Those with BM involvement receive inotuzumab ozogamicin for induction without randomization. HR patients and SR patients with MRD poor response will be allocated to allo-HSCT indication, or in case CD19 directed CAR-T-cell therapy off-protocol as individualized treatment approach. Patients with MRD good response will get the SR consolidation and maintenance therapy. Those with IEM profile will be treated according to the IEM stratum. Patients not expressing sufficiently CD22 and/or CD19 will receive the respective chemotherapy strategy.
• Patients with BCR::ABL positive (Ph+) or BCR::ABL like (Ph-like) BCP ALL with TKI treatment option can be included as separate and descriptive population, not joining the study questions. Those with BM involvement receive inotuzumab ozogamicin plus TKI (investigators choice) without randomization for induction followed by HC1 and blinatumomab plus TKI followed by allo-HSCT. Those with IEM profile will be treated according to the IEM stratum plus TKI. Patients not expressing sufficiently CD22 and/or CD19 will receive the respective chemotherapy strategy.
• Patients with systemic diseases such as cystic fibrosis or diabetes may be eligible for enrolment in this study only if they presumably will tolerate the protocol treatment and primary dose reductions would not be necessary.
• Any kind of concomitant medication given due to medical reasons is allowed. Incompatibilities and drug interactions with the study medications are listed in the appendix. In case of expected adverse interactions, concomitant therapies should be changed to alternative less problematic agents if possible

Prohibited medication

• Antileukemic therapy other than scheduled in the protocol (except cytoreductive pre-phase with dexamethasone)
• Investigational drugs other than scheduled in the protocol
• Attenuated live vaccines which are strictly prohibited during and until 6 months after end of chemotherapy or 18 months after allo-HSCT