Phase 2 Randomized Study of Inotuzumab Ozogamicin Monotherapy Versus ALLR3 Regimen in Pediatric High-Risk First Relapse CD22-Positive B-Cell Precursor Acute Lymphoblastic Leukemia
- Trial ID
- 2023-509810-13-00
- Protocol
- B1931036
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the superiority of **Inotuzumab Ozogamicin** (InO) monotherapy compared to the ALLR3 induction regimen in pediatric participants aged 1 to less than 18 years with high-risk first bone marrow relapse of CD22-positive B-cell precursor **Acute Lymphoblastic Leukemia** (BCP ALL). This objective is clinically relevant as it aims to establish a more effective treatment option for this specific patient population, potentially improving outcomes in terms of remission and survival rates.
Secondary objectives include evaluating the long-term efficacy of InO monotherapy versus the ALLR3 regimen with respect to several clinical endpoints:
- Event-free survival (EFS)
- Duration of response (DOR)
- Hematopoietic stem cell transplant (HSCT) rate
- Chimeric antigen receptor (CAR) T-cell therapy rate
- Overall survival (OS)
Participants
The clinical trial involves a total of **9 participants** diagnosed with **Acute Lymphoblastic Leukemia (ALL)**. The study population comprises both male and female pediatric participants aged between 1 and less than 18 years. Participants were selected based on a morphologically confirmed diagnosis of first relapse high-risk B-cell precursor ALL, characterized by CD22-positive status and bone marrow involvement of ≥ 5% leukemic blasts. The trial includes individuals who have experienced a relapse within 18 to 30 months of the original diagnosis or within 6 months of completing primary therapy, without any identified very high-risk genetic abnormalities. Participants are required to have adequate serum chemistry parameters, including an estimated glomerular filtration rate or creatinine clearance of ≥ 30 mL/min, and liver function tests within specified limits. The study also considers prior history of thrombosis during corticosteroid use and/or asparaginase, provided anticoagulant prophylaxis is administered. Cardiac function is assessed with a requirement of a cardiac shortening fraction of ≥ 30% or an ejection fraction > 50%. The trial population includes a vulnerable group, reflecting the pediatric nature of the study.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, phase 2 study to evaluate the efficacy of **Inotuzumab Ozogamicin** monotherapy compared to the ALLR3 regimen for induction treatment in pediatric patients with high-risk first relapse B-cell precursor **Acute Lymphoblastic Leukemia** (ALL). The trial aims to demonstrate the superiority of Inotuzumab Ozogamicin in achieving minimal residual disease (MRD)-negative complete remission (CR) at the end of induction therapy. The study is expected to run until July 2031, with recruitment starting in July 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease characteristics, and adequate serum chemistry parameters. Following randomization, participants will receive treatment according to their assigned group. The trial includes multiple follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will assess the primary and secondary endpoints, including event-free survival (EFS), duration of response (DOR), and overall survival (OS).
The expected duration of participant involvement is up to 28 days for the treatment period, with additional time for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or failure to adhere to the study protocol. The trial will ensure rigorous monitoring to maintain participant safety and data integrity throughout the study duration.
Treatment
The clinical trial involves the use of several treatments, including both experimental and non-experimental medications. **BESPONSA** (inotuzumab ozogamicin) is the primary experimental medication. It is provided as a 1 mg powder for concentrate for solution for infusion, intended for **intravenous use**. The maximum daily dose is 0.8 mg/m², with a total dose not exceeding 0.8 mg/m² over a treatment period of 28 days. This biologic agent is manufactured by Pfizer Europe MA EEIG and is used to evaluate its efficacy in treating childhood high-risk first relapse B-cell precursor acute lymphoblastic leukemia (BCP ALL).
**Dexamethasone** is used in various forms as a non-experimental treatment. It is available as a 3.3 mg/mL solution for injection, a 2.0 mg tablet, and a 0.5 mg and 4 mg tablet. The solution for injection is administered intravenously, while the tablets are taken orally. The maximum daily dose for dexamethasone in any form is 20 mg/m², with a total dose not exceeding 40 mg/m² over a 28-day period. The manufacturers include Noridem Enterprises Ltd, Aspen Pharma Trading Limited, and MIBE GmbH Arzneimittel.
**Mitoxantrone Hydrochloride** is another comparator treatment, provided as a concentrate for solution for infusion. It is administered intravenously with a maximum daily and total dose of 10 mg/m² over 28 days. This chemical agent is used to compare its effects against the experimental treatment.
**Vincristine Sulfate** is supplied as a 1 mg/mL solution for injection, administered intravenously. The maximum daily dose is 1.5 mg/m², with a total dose not exceeding 2 mg/m² over the 28-day treatment period. This chemical agent is produced by Hospira UK Limited.
**Oncaspar** (pegaspargase) is provided as a 750 U/mL powder for solution for injection/infusion, administered intravenously. The maximum daily and total dose is 1000 U/mL over a 28-day period. This biologic agent is manufactured by Les Laboratoires Servier (Suresnes).
**Crisantaspase** is used as a comparator treatment, available as a powder for solution for injection/infusion. It is administered intravenously with a maximum daily dose of 20,000 U/mL and a total dose of 120,000 U/mL over a 6-day period. This protein-based agent is included to evaluate its comparative efficacy.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. All medications are subject to secondary packaging and/or labeling changes as part of the trial requirements.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the achievement of **Minimal Residual Disease (MRD)**-negative complete remission (CR), complete remission with incomplete platelet recovery (CRp), or complete remission with incomplete hematologic recovery (CRi) at the end of induction therapy. MRD negativity is determined by a central laboratory and defined as leukemic blasts less than 1x10-4 as measured by real-time quantitative polymerase chain reaction (RQ-PCR), with a reflex to flow cytometry (FC) if MRD is non-evaluable by RQ-PCR.
Secondary endpoints include Event-Free Survival (EFS), which is defined as the time from randomization until objective progression, relapse from CR/CRp/CRi, failure to achieve CR/CRp/CRi by the end of induction, MRD persistence prior to hematopoietic stem cell transplantation (HSCT), second malignancy, or death due to any cause. Duration of Response (DOR) is measured from the date of first documented response to the date of first documented objective progression, relapse, MRD persistence prior to HSCT, or death. The rate of HSCT and CAR T-cell therapy is also evaluated, defined as the number and percentage of participants receiving these treatments after the study interventions. Overall Survival (OS) is assessed from the date of randomization to the date of death from any cause. Additionally, the incidence and severity of adverse events (AEs) are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Pharmacokinetic parameters such as maximum concentration (Cmax) and trough concentration (Ctrough) are also measured.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female participants between 1 and less than 18 years of age.
- Type of Participant and Disease Characteristics: Morphologically confirmed diagnosis of first relapse HR BCP ALL or VHR BCP ALL; HR first relapse is defined as: i. relapse occurring within 18 to 30 months of original diagnosis of ALL or within 6 months of completion of primary therapy, and ii. lacking any identified very high-risk genetic abnormalities at original diagnosis or at relapse (Groeneveld-Krentz et al, 2019) (ie, KMT2A::AFF1 fusion [t(4;11)(q21;q23)], TCF3-HLF fusion [t(17;19)(q22;p13)], TCF3- PBX1 fusion [t(1;19)(q23;p13.3)], hypodiploidy [<40 chromosomes] or masked low hypodiploidy (Molina et al, 2021), TP53 alteration). VHR is defined as: i. relapse within 18 months of original diagnosis of ALL and/or ii. with any of the following genetic abnormalities at original diagnosis or at relapse (Groeneveld-Krentz et al, 2019) (ie, KMT2A::AFF1 fusion [t(4;11)(q21;q23)], TCF3-HLF fusion [t(17;19)(q22;p13)], TCF3-PBX1 fusion [t(1;19)(q23;p13.3)], hypodiploidy [<40 chromosomes] or masked low hypodiploidy (Molina et al, 2021), TP53 alteration). • CD22-positive ALL as defined by local institution • Bone marrow involvement of ≥5% leukemic blasts (≥M2 status).
- Other Inclusion Criteria: Adequate serum chemistry parameters: • An estimated glomerular filtration rate (eGFR) in participants 1 to less than 2 years of age, or estimated creatinine clearance (eCrCl) in those 2 to less than 18 years of age, ≥30 mL/min using the recommended formula • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × institutional ULN at the time of randomization or precytoreduction/ general anesthesia; • Total bilirubin ≤1.5 × institutional ULN unless the participant has documented Gilbert's syndrome;
- Prior history of thrombosis during corticosteroid use and/or asparaginase are eligible provided the participant receives anticoagulant prophylaxis per institutional guidelines.
- Cardiac shortening fraction ≥ 30% by echocardiogram or ejection fraction > 50% by MUGA.
Exclusion Criteria
- Any history of: • Prior or ongoing hepatic SOS or prior liver failure [defined as severe acute liver injury with encephalopathy and impaired synthetic function (INR of ≥1.5)]; • Prior allo-HSCT or CAR T-cell therapy; • Isolated extramedullary leukemia; • Philadelphia-chromosome positive ALL, ie. BCR-ABL/t(9;22) present; • Presence of Grade 3 or Grade 4 peripheral neuropathy as defined in the Delphi consensus of acute toxic effects for childhood ALL; • Hypersensitivity to the active ingredient of InO or any of its excipients; • Hypersensitivity/allergy to both PEG-ASP and Erwinia-ASP; • Intolerance to any of the ALLR3 agents (mitoxantrone, vincristine, dexamethasone, asparaginase); • Grade 3 or Grade 4 pancreatitis due to any cause, as defined by CTCAE v4.03; • Grade 3 or Grade 4 allergic reaction to a monoclonal antibody; • Participants not 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 NCI CTCAE v 4.03 prior to randomization, with the exception of the laboratory abnormalities as defined by other inclusion/exclusion criteria; • Down syndrome; • Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study; • Charcot-Marie-Tooth disease.
- Prior/Concomitant therapy with: • A calicheamicin-conjugated antibody (eg, InO or gemtuzumab ozogamicin) or prior therapy with a CD22-targeted therapy (immunotoxin or CAR T-cell therapy); • Cytotoxic therapy within 7 days prior to enrollment, with the exception of hydroxyurea and corticosteroids, which are permitted prior to initiating study intervention. Participants may have received intrathecal chemotherapy at any time prior to study entry. NOTE: No waiting period is required for participants who relapse while receiving first-line maintenance chemotherapy. • Any radiation therapy within 28 days prior to enrollment; • The last dose of granulocyte colony-stimulating factor (ie, Neupogen or equivalent) administered within 7 days prior to study enrollment and/or the last dose of pegfilgrastim (Neulasta®) given within 14 days prior to enrollment; • Less than 3 half-lives elapsed after the last dose of a mAb (eg, rituximab=66 days, epratuzumab=69 days). Participants must not have received blinatumomab within 4 weeks before study enrollment; • Current use of any prohibited concomitant medication(s) or participants unwilling/unable to use a permitted concomitant medication(s). Refer to Section 6.8,, Concomitant Therapy. • Any vaccination with live viral vaccines within 2 weeks of the start of study therapy.
- Administration of an IP (eg, drug or vaccine) concurrent with study intervention or within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). A participant may be eligible if they are in the follow-up phase of an investigational study if they meet the criterion for time elapsed from previous administration of IP. Cases must be discussed with sponsor's medical monitor to judge eligibility.
- Diagnostic Assessments: Serum or urine pregnancy test positive at screening.
- Baseline 12 lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF interval >470 msec, complete LBBB, signs of an acute or indeterminate age myocardial infarction, STT interval changes suggestive of myocardial ischemia, second- or thirddegree AV block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF >470 msec, the ECG should be repeated 2 more times the average of the 3 QTcF values should be used to determine the participant’s eligibility. Computer interpreted ECGs should be overread locally by a physician experienced in reading ECGs before excluding participants.
- Participants with active infection, including (but not limited to) HBV, HCV, and known HIV or AIDS-related illness. • HIV infection with CD4+ count <200/mm3 and viral load of >400 copies/mm3. Participants with stable well-controlled HIV infection may be eligible after consultation with the sponsor. HBV • Participants with a positive HBsAg (ie, either acute or chronic active hepatitis) are excluded. • Participants with HBV antibody positivity indicating immunity, either due to vaccination or prior natural infection, are eligible. •Participants with positive anti-HBcAb but negative HBsAg and anti- HBsAb profile, depending on clinical circumstances, may be eligible. Discussion with the sponsor is indicated. HCV • Participants with active HCV as determined by viral load.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 31 Jul 2023 | 3 |
 Belgium | Recruiting | 31 Jul 2023 | 3 |
 Czechia | Recruiting | 31 Jul 2023 | 4 |
 Denmark | Recruiting | 31 Jul 2023 | 3 |
 Finland | Recruiting | 31 Jul 2023 | 1 |
 France | Recruiting | 31 Jul 2023 | 15 |
 Germany | Recruiting | 31 Jul 2023 | 18 |
 Greece | Not Recruiting | 31 Jul 2023 | 3 |
 Hungary | Not Recruiting | 31 Jul 2023 | 3 |
 Italy | Recruiting | 31 Jul 2023 | 12 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Dexamethason 0,5 mg JENAPHARM® | Comparator | TABLET | ORAL USE | 20 | 28 | PRD988424 |
Dexamethason 4 mg JENAPHARM® | Comparator | TABLET | ORAL USE | 20 | 28 | PRD988426 |
Dexamethasone Tablets BP 2.0mg | Comparator | TABLETS | ORAL USE | 20 | 28 | PRD3570594 |
Vincristine Sulfate 1 mg/ml solution for injection | Comparator | SOLUTION FOR INJECTION | INTRAVENOUS USE | 1.5 | 28 | PRD993268 |
BESPONSA 1 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 0.8 | 28 | PRD6504828 |
MITOXANTRONE HYDROCHLORIDE | Comparator | — | INTRAVENOUS USE | 10 | 28 | SUB03309MIG |
CRISANTASPASE | Comparator | — | INTRAVENOUS USE | 20000 | 6 | SUB33789 |
Oncaspar 750 U/ml powder for solution for injection/infusion. | Comparator | POWDER FOR SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS USE | 1000 | 28 | PRD6822367 |
DEXAMETHASONE SODIUM PHOSPHATE | Comparator | — | INTRAVENOUS | 20 | 28 | SUB01615MIG |