Phase I/II Evaluation of Inotuzumab Ozogamicin Monotherapy and Combined Chemotherapy in Pediatric CD22-Positive Relapsed/Refractory Acute Lymphoblastic Leukemia

Trial ID: 2023-504694-20-00
Sponsor: Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

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Diseases & Conditions

Acute lymphocytic leukaemia recurrent

Objectives

The primary objective of this study is to establish the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of **inotuzumab ozogamicin** (InO) as a single agent in pediatric patients with CD22-positive relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This is clinically relevant as determining the optimal dosing is crucial for maximizing therapeutic efficacy while minimizing adverse effects in this vulnerable population. Additionally, the study aims to establish the preliminary clinical activity, specifically the overall response rate (ORR), of InO in these patients, which is essential for evaluating its potential as a treatment option.

The secondary objectives include: - Determining the safety and tolerability of InO, both as a single agent and in combination with chemotherapy, and assessing cumulative toxicities after multiple cycles and subsequent therapies such as allogeneic hematopoietic stem cell transplant (allo-HSCT) or CAR-T cell therapy. - Evaluating the overall hematological response rate and minimal residual disease (MRD) levels in responding patients, including the percentage achieving complete MRD response. - Describing the durability of response and long-term follow-up, including event-free survival (EFS) and overall survival (OS). - Assessing pharmacokinetic parameters of unconjugated calicheamicin and InO, and the relationship between CD22 receptor density, white blood cell count, cytogenetics, and in-vitro calicheamicin resistance to clinical response. - Investigating the persistence of B-cell aplasia and hypogammaglobulinemia, and the development of anti-drug antibodies (ADAs) and CD22-negative relapse.

Participants

The clinical trial involves a total of **16 participants** diagnosed with **pediatric CD22-positive relapsed/refractory Acute Lymphoblastic Leukemia**. The study population includes both male and female subjects, aged between **1 and 18 years**. Participants were selected based on specific inclusion criteria, including the presence of CD22-positive B-cell malignancies and a history of relapsed or refractory disease. The trial population is characterized by a vulnerable group, given the pediatric nature of the condition. Participants are required to have a performance level of **Karnofsky > 60%** for those over 16 years and **Lansky > 60%** for those 16 years or younger, with a life expectancy of at least six weeks. Prior to enrollment, participants must have recovered from acute toxic effects of previous therapies and meet renal, hepatic, and cardiac function criteria. Lifestyle considerations such as diet and physical activity are not specified, but reproductive function requirements are in place, including the use of effective contraception for participants of childbearing potential. The sponsor has not provided additional information regarding lifestyle factors or specific health status beyond the inclusion criteria.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **inotuzumab ozogamicin** as a single agent and in combination with chemotherapy for pediatric patients with CD22-positive relapsed/refractory **Acute Lymphoblastic Leukemia** (ALL). This is a Phase I/II trial, structured as a randomized, double-blind, controlled study. The trial is expected to run from August 2016 to October 2028, with participant involvement varying based on the specific stratum of the study.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis, and prior therapy. The trial includes multiple strata, each with specific objectives and endpoints. Stratum 1 focuses on determining the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of inotuzumab ozogamicin, while Stratum 2 explores safety and tolerability in other CD22-positive B-cell malignancies. Stratum 3 aims to establish preliminary clinical activity in very high-risk first relapse BCP-ALL patients.

Follow-up visits will be scheduled to monitor dose-limiting toxicities, overall response rate (ORR), and other safety and efficacy parameters. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any adverse events. The expected length of participant involvement will depend on the treatment cycle and response, with conditions for early termination including unacceptable toxicity, disease progression, or withdrawal of consent.

Key elements of the research methodology include the use of pharmacokinetic and pharmacodynamic assessments to understand the relationship between drug exposure and response. The trial will also evaluate secondary endpoints such as minimal residual disease (MRD) levels, duration of response, and overall survival. Participants will be closely monitored for adverse events, with safety assessments conducted throughout the study to ensure participant well-being.

Treatment

The clinical trial involves the administration of **BESPONSA**, which contains the active substance **inotuzumab ozogamicin**. This medication is provided as a powder for concentrate for solution for infusion, specifically formulated for pediatric use. It is administered intravenously. The study aims to establish the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) for children with CD22-positive relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The dosing schedule and frequency are determined based on the study protocol, with compliance monitored through standard clinical trial procedures.

**Dexamethasone** is used as a non-experimental treatment in the study. It is available as a solution for injection or infusion, containing **dexamethasone sodium phosphate**. This glucocorticoid is administered intravenously, and its role in the trial is auxiliary. The dosing regimen follows standard clinical guidelines for glucocorticoid use, and participant adherence is monitored accordingly.

**Methotrexate** is another auxiliary treatment in the trial, classified as an immunosuppressant. It is administered intrathecally, with the pharmaceutical form designated as PHF00231MIG. The administration schedule is aligned with the trial's protocol, ensuring participant safety and compliance.

**Prednisolone**, containing **abiraterone acetate**, is administered intravenously as part of the trial's auxiliary treatments. The pharmaceutical form is PHF00082MIG, and it is categorized as a glucocorticoid. The dosing and administration are conducted in accordance with the trial's guidelines.

**Vincristine**, with the active substance **vinblastine sulfate**, is provided as a solution for infusion. It is classified as an antineoplastic agent and is administered intravenously. The trial protocol specifies the dosing schedule, ensuring adherence to safety standards.

**Cytarabine**, containing **citalopram**, is administered intrathecally as an auxiliary treatment. The pharmaceutical form is PHF675, and it is categorized as an antineoplastic agent. The administration follows the trial's protocol, with compliance monitored through established procedures.

**Hydrocortisone**, with the active substance **hydrocortisone**, is administered intrathecally. It is provided in the pharmaceutical form PHF00099MIG and is classified as a corticosteroid. The dosing and administration are conducted according to the trial's guidelines, ensuring participant safety and adherence.

Efficacy

The efficacy of the clinical trial will be assessed through various parameters and endpoints tailored to the specific strata of the study. For Stratum 1A, the primary endpoint is the occurrence of dose-limiting toxicities (DLTs) during the first cycle of therapy. In the Phase 2 cohort, the primary endpoint is the overall response rate (ORR), defined as the percentage of patients achieving complete remission (CR), complete remission with incomplete hematologic recovery (CRi), or complete remission with partial hematologic recovery (CRp) as the best response during treatment with **Inotuzumab Ozogamicin** (InO). Stratum 1B and 1B-ASP will also focus on DLTs during the first cycle of InO when combined with a modified UKALL-R3 re-induction chemotherapy regimen.

Secondary endpoints across the strata include safety and tolerability measures such as adverse events (AEs) characterized by type, frequency, severity, timing, seriousness, and relation to study therapy. The occurrence of toxic deaths and hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) during or after therapy with InO will also be monitored. Additional measures of anti-leukemic activity include minimal residual disease (MRD) levels, duration of response, event-free survival (EFS), and overall survival. Pharmacokinetic and pharmacodynamic parameters will be evaluated, including serum levels of InO and unconjugated calicheamicin, and the relationship between response and CD22 expression levels.

Data collection will occur at specified intervals, including after cycle 1 and at the best response over multiple cycles. The analysis will involve validated scales and laboratory tests to ensure accuracy and reliability. The study will also explore the percentage of patients responding to InO without adequate recovery of CD19-positive B-cells or immunoglobulins, and the presence of anti-drug antibodies (ADA) in certain cohorts. These comprehensive assessments will provide insights into the efficacy and safety of InO in pediatric patients with CD22-positive relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and other B-cell malignancies.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age (for all patients) • Patients must be ≥ 1 and < 18 years of age at the time of enrollment. Additional criteria for limited to Stratum 1A and 1B only: • The first 3 BCP-ALL patients on dose level 1 must be aged 6 years to less than 18 years. • Then at least 2 additional patients must be enrolled from age 1 year to less than 6 years at the same dose level. • After this requirement is met, subsequent dose levels may enroll patients aged 1 year to less than 18 years. • In case 2 younger patients are not yet recruited, patients aged 6 years up to less than 18 years 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 • First relapse of BCP-ALL post allogeneic HSCT • Second or greater relapsed or refractory BCP-ALL • Refractory disease, 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. AND must meet the following criteria: • Patients must have M2 or M3 marrow status (≥ 5% blasts by morphology) • The malignant clone needs to be CD22 surface antigen positive (in either the bone marrow or peripheral blood) by institutional standards as determined by the local immunophenotyping laboratory. • The first 6 patients (Stratum 1A only) must have M3 marrow status (≥ 25% blasts by morphology).
Stratum 2: Diagnosis Patients must have 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: • There must be 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. • The malignant cells need to be CD22 surface antigen positive (in either biopsy material, the bone marrow or peripheral blood) by institutional standards as determined by the local immunophenotyping laboratory.
Stratum 3: Diagnosis; Patients must have: • First BM or combined relapse of CD22+ VHR BCP-ALL defined as any relapse <18 months from initial diagnosis and/or cytogenetic-high risk characteristics: KTM2A/AF4, E2A/TCF3-PBX1 t(1;19) or E2A/TCF3-HLF t(17;19), hypodiploidy (less than 40 chromosomes), TP53 mutation and/or deletion, as also shown in Table 2 (excluding patients who received a HSCT in 1st CR). AND must meet the following criteria: • Patients must have M2 or M3 marrow status (≥ 5% blasts by morphology) • The malignant clone needs to be CD22 surface antigen positive (in either the bone marrow or peripheral blood) by institutional standards as determined by the local immunophenotyping laboratory. • Evidence of prior fusion gene abnormalities is acceptable as they tend to be stable during the course of the disease. • Laboratory techniques acceptable to test the presence of the above mentioned cytogenetic-high risk characteristics are chromosome banding analysis (CBA), FISH, PCR and/or Next Generation Sequencing (inclusion is based on local laboratory results).
For all patients Performance Level and Life Expectancy • Karnofsky > 60% for patients > 16 years of age and Lansky > 60% for patients ≤ 16 years of age. (See Appendix I for Performance Scales). • Patient must have a life expectancy of at least 6 weeks.
For all patients 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 prior to entering this study, with the exception of the authorized laboratory abnormalities as defined in the inclusion/exclusion criteria. a. Chemotherapy: At least 7 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea, 6-mercaptopurine and steroids which are permitted up until 48 hours prior to initiating protocol therapy. Patients may have received intrathecal therapy at any time prior to study entry. Patients who relapse while receiving maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study. b. Radiotherapy: At least 28 days must have elapsed since any prior radiation therapy. c. Hematopoietic Stem Cell Transplant: At least 90 days must have elapsed since previous allo-HSCT. Patient must have no evidence of active graft vs. host disease. Patient must not be receiving GVHD prophylaxis or treatment. d. Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with GCSF or other growth factors at the time of enrollment. At least 14 days must have elapsed since the completion of therapy with pegfilgrastim (Neulasta®). e. Immunotherapy: At least 42 days must have elapsed after the completion of any type of immunotherapy, e.g. chimeric antigen receptor T cell (CART) therapy. Patients may not have received prior CD22- targeted therapy (immunotoxin or CART therapy). f. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of a monoclonal 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 as outlined in the inclusion and exclusion criteria. g. 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) under investigation. No residual toxicities should be observed following previous treatment. An experimental drug is defined as any drug that is not approved and licensed for sale by the FDA for institutions in the United States, by the EMA for institutions in Europe, by Health Canada for institutions in Canada and by The Therapeutic Goods Administration for institutions in Australia. h. Prior calicheamicin exposure: Patient has not received prior treatment with a calicheamicin-conjugated antibody (e.g. gemtuzumab ozogamicin).
For all patients Renal and Hepatic Function • Patient’s serum creatinine must be ≤ 1.5 x institutional upper limit of normal (ULN) according to age. If the serum creatinine is greater than 1.5 x institutional ULN, the patient must have a GFR ≥ 70mL/min/1.73 m2 estimated based on serum creatinine and/or cystatin C levels (e.g. Bedside Schwartz formula). • AST and ALT must be ≤ 5 x institutional ULN. (stratum 3 & 4) • Patient’s total total bilirubin must be ≤ 1.5 x institutional ULN unless the patient has documented Gilbert syndrome, in which case the AST and ALT must be ≤ 5 x ULN. (stratum 3 & 4)
For all patients Cardiac Function • Patient must have a shortening fraction ≥ 30% by echocardiogram or an ejection fraction > 50% by MUGA.
For all patients Reproductive Function • Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment. • Female patients with infants must agree not to breastfeed their infants while on this study. • Male and female patients of child-bearing potential must agree to use a highly effective method of contraception approved by the investigator during the study, following the CTFG recommendations, and for at least 8 months for females and for at least 5 months for males after the last dose of InO. • Highly effective methods of contraception include (but not exclusively) the following contraceptive methods: • combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation • progestogen-only hormonal contraception associated with inhibition of ovulation • intrauterine device (IUD) • intrauterine hormone-releasing system (IUS) • sexual abstinence.
Stratum 4: Patients must have either: • 2nd or greater CD22 positive BCP-ALL relapse; • 1st VHR CD22 positive BCP-ALL relapse defined as isolated bone marrow or combined relapse occurring less than 18 months from initial diagnosis and/or with cytogenetic-high risk characteristics, including KTM2A/AF4, E2A/TCF3-PBX1 t(1;19), E2A/TCF3-HLF t(17;19), hypodiploidy (less than 40 chromosomes), TP53 mutation and/or deletion. Acceptable laboratory techniques to confirm these cytogenetic abnormalities include chromosome banding analysis (CBA), fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), and/or Next Generation Sequencing (based on local laboratory results); • Any relapse of BCP-ALL post HSCT; • Refractory disease, 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. AND must meet the following criteria: • Patients must have M2 or M3 marrow status (≥ 5% blasts by morphology). • The malignant clone must be CD22 surface antigen positive (in either bone marrow or peripheral blood) by institutional standards as determined by the local immunophenotyping laboratory. • For 1st VHR BCP-ALL relapse evidence of prior fusion gene abnormalities is acceptable as they tend to be stable during the course of the disease. Laboratory techniques acceptable to test the presence of the cytogenetic-high risk characteristics are chromosome banding analysis (CBA), FISH, PCR and/or Next Generation Sequencing (inclusion is based on local laboratory results).

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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 degrees Celsius 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. • Patients will be excluded if they have received prior treatment with anti-tumor vaccines.
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. • Children with Down syndrome are excluded from participation in the dose finding parts (stratum 1A and 1B), but not in the single-agent phase 2, stratum 3 and stratum 4.
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.12). • 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 consensus12. 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).

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	01 Aug 2016	6
Belgium	Not Recruiting	01 Aug 2016	2
Czechia	Not Recruiting	01 Aug 2016	4
Denmark	Not Recruiting	01 Aug 2016	1
Finland	Not Recruiting	01 Aug 2016	4
France	Not Recruiting	01 Aug 2016	23
Germany	Not Recruiting	01 Aug 2016	22
Ireland	Not Recruiting	01 Aug 2016	2
Italy	Not Recruiting	01 Aug 2016	25
The Netherlands	Not Recruiting	01 Aug 2016	—