Study in Pediatrics With Relapsed or Refractory Pediatric Acute Lymphoblastic Leukemia (pALL) or Lymphoblastic Lymphoma

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of moxetumomab pasudotox in pediatric participants with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) or B-cell lymphoblastic lymphoma.

Detailed Description
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This is a global, multicenter, open-label, single-arm Phase 2 study to evaluate the efficacy and safety of moxetumomab pasudotox monotherapy in pediatric participants with relapsed or refractory B-cell ALL or B-cell lymphoblastic lymphoma. Participants will be enrolled at sites in North America, Europe, and Australia. This is an approximate 35 month study.

Official Title
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A Phase 2, Multicenter, Single-arm Study of Moxetumomab Pasudotox in Pediatric Subjects With Relapsed or Refractory Pediatric Acute Lymphoblastic Leukemia (pALL) or Lymphoblastic Lymphoma of B-cell Origin

Conditions
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B-Cell Pediatric ALL

Intervention / Treatment
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* Drug: Moxetumomab Pasudotox


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - Between the ages of greater or equal to (≥) 6 months and less than (<) 18 years of age Must have histologically proven B-cell acute lymphoblastic leukemia (ALL) or B-cell lymphoblastic lymphoma with marrow involvement All participants (both ALL and participants with lymphoblastic lymphoma) must have M2 or M3 bone marrow classification Disease status: a) Participants must have relapsed or refractory disease b) In the event of relapse after prior allogeneic hematopoietic stem cell transplant (HSCT), participants must be at least 3 months post-transplant and have no evidence of active graft-vs-host disease, and must have been off immunosuppression for at least 4 weeks, c) Must have resolution of the acute toxic effects to less than or equal to (≤) Grade 2 from prior chemotherapy before entry, in the opinion of the investigator Participants with the following central nervous system (CNS) 1 or 2 status are eligible only in the absence of neurologic symptoms Female participants of childbearing potential and post-pubertal male participants must use an approved method of contraception for the study. Exclusion Criteria Concurrent enrollment in another clinical study for cancer treatment, unless the subject is in the follow-up period from a previous study. Isolated testicular or CNS ALL Participants with mixed-lineage leukemia (MLL) gene rearrangement Inadequate Hepatic function Inadequate Renal function Radiologically-detected CNS lymphoma Participants with clear laboratory or clinical evidence of disseminated intravascular coagulation (DIC) Hyperleukocytosis or rapidly progressive disease that would compromise ability to complete study therapy QT interval corrected using Fridericia's formula (QTcF) greater than or equal to a Grade 2, confirmed by 2 additional seperate electrocardiographs (ECG's) within 28 days prior to starting study drug. The initial screening ECG need not be repeated for confirmation if the QTcF interval is <481 milliseconds. Pregnant or breast-feeding females Prior treatment with CAT-3888 (BL22), moxetumomab pasudotox, or any pseudomonas-exotoxin-containing compound Prior treatment with any anticancer biologic therapy within 2 weeks prior to starting study drug, including but not limited to therapeutic monoclonal antibodies or antibody-drug conjugates Systemic chemotherapy ≤ 2 weeks (6 weeks for nitrosoureas) and radiation therapy ≤ 3 weeks prior to starting study drug Clinically significant ophthalmologic findings (evidence of retinal damage or injury) during the screening Presence of a second invasive malignancy Uncontrolled pulmonary infection, presence of pulmonary edema Serum albumin < 2 gram per deciliter (g/dL). Albumin infusions for correction of hypoalbuminemia are allowed, but cannot have administered within 7 days prior to start of study drug Radioimmunotherapy within 2 years prior to study start of study drug Participants with prior history of thrombotic microangiopathy or hemolytic uremic syndrome (HUS) T-cell ALL or T-cell lymphoblastic lymphoma Participants currently receiving high-dose estrogen therapy defined as >0.625 milligram per day (mg/day) of an estrogen compound or within 2 weeks prior to starting study drug.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Moxetumomab Pasudotox 40 mcg/kg<br>Participants received 6 doses of moxetumomab pasudotox 40 microgram per kilogram (mcg/kg) intravenous infusion over 30 minutes every other day (Days 1, 3, 5, 7, 9, and 11) in 21-day treatment cycles until completion of a maximum of 6 cycles of therapy. | Drug: Moxetumomab Pasudotox<br>* Participants received 6 doses of moxetumomab pasudotox 40 microgram per kilogram (mcg/kg) intravenous infusion over 30 minutes every other day (Days 1, 3, 5, 7, 9, and 11) in 21-day treatment cycles until completion of a maximum of 6 cycles of therapy.<br>* Other names: CAT-8015;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Composite Complete Response (CRc) | The CRc is defined as achieving complete response (CR), or CR with incomplete count recovery [CRi]) in participants with relapsed or refractory B-cell ALL or B-cell lymphoblastic lymphoma. Complete response (CR) as per International Working Group (IWG) is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Morphologic CR with incomplete blood count recovery (CRi) is defined as the above CR criteria without specified blood counts. The efficacy assessments were evaluated as per investigator assessment. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Minimal Residual Disease (MRD)-Negative CRc Rate | The MRD-negative CRc rate was defined as the percentage of participants who achieved CRc and became MRD-negative as determined by flow cytometry performed by a central analysis laboratory. The CRc is defined as complete response (CR), or complete response with incomplete count recovery (CRi). Complete response (CR) as per International Working Group (IWG) is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Morphologic CR with incomplete blood count recovery (CRi) is defined as the above CR criteria without specified blood counts. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Overall Response Rate (ORR) | The ORR, defined as the percentage of participants with CRc or partial response (PR), was estimated; the Clopper Pearson (Exact) 95% CI was calculated. The CRc is defined as complete response (CR), or complete response with incomplete count recovery (CRi). Complete response (CR) as per International Working Group (IWG) is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Morphologic CR with incomplete blood count recovery (CRi) is defined as the above CR criteria without specified blood counts. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Time to Overall Response | Time to overall response was evaluated using the Kaplan-Meier method. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Best Overall Response (BOR) | The best overall response was calculated, based upon the disease assessments recorded during the study visits, and summarized with the number and percentage of participants for the following categories: CRc, PR, HA, SD, PD, and not evaluable. Overall best response is the best response observed for a participant during the study based on International Working Group (IWG) Response Criteria for malignant lymphoma. Complete response (CR) as per IWG is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. PR is a minimum of 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses and no increase in the size of other nodes and in size of liver or spleen. Stable disease (SD) is when a participant fails to attain the criteria needed for a CR or PR, but does not fulfill those for PD. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Bone Marrow Blast Percentage Change | Change in bone marrow blast percentage from baseline was evaluated. If the percentage (%) blasts (at least 200 cells counted) is less than (<) 5%, it is considered as M1, 5 to 25% considered as M2, greater than (>) 25% considered as M3. Stages with the higher blasts relate to worse outcomes. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Percentage of Participants Who Became Eligible to Receive an Stem Cell Transplant (SCT) After Treatment With Moxetumomab Pasudotox | The percentage of participants who became eligible for SCT after treatment with moxetumomab pasudotox were provided. The Clopper Pearson (Exact) 95% CI was calculated. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Time to Transplant to Receive an Stem Cell Transplant (SCT) After Treatment With Moxetumomab Pasudotox | The time to SCT was defined as the duration from the start of treatment with moxetumomab pasudotox until the date when the subject became eligible for SCT. The time to SCT was to be summarized using the Kaplan-Meier method, and was only to be evaluated for the subgroup of subjects who became eligible for SCT after treatment with moxetumomab pasudotox. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Percentage of Participants Who Were Neutropenic at Study Entry and Who Experienced Hematologic Activity (HA) | The percentage of participants who were neutropenic at study entry and experienced HA after treatment with moxetumomab pasudotox was evaluated. The Clopper Pearson (Exact) 95% CI was calculated. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Duration of Complete Response (DOCR) | DOCR was defined as the duration from the first documentation of CRc to the first documented disease progression.The CRc is defined as achieving complete response (CR), or CR with incomplete count recovery [CRi]) in participants with relapsed or refractory B-cell ALL or B-cell lymphoblastic lymphoma. Kaplan-Meier method was used for evaluation. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Duration of Overall Response (DOR) | DOR was to be defined as the duration from the first documentation of overall response to the first documented disease progression. Kaplan-Meier method was used for evaluation. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Progression-Free Survival (PFS) | PFS was measured from the start of treatment with moxetumomab pasudotox until the first documentation of disease progression or death due to any cause, whichever occurred first. Kaplan-Meier method was used for evaluation. | Prior to Cycle 1, and prior to every cycle, at the end of treatment, at post-treatment follow-up visits, and at the end of the study, up to 1 year | 
| Overall Survival (OS) | OS was determined as the time from the start of treatment with moxetumomab pasudotox until death due to any cause. For participants who were alive at the end of the study or lost to follow-up, OS was censored on the last date when the participant was known be alive. Kaplan-Meier method was used for evaluation. | Baseline to end of study or last contact date, up to 1 year | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Treatment-emergent adverse events (TEAEs), were defined as events present at baseline that worsened in intensity after administration of investigational product or events absent at baseline that emerged after administration of study drug. | Baseline up to 30 days after the last dose of study drug, up to 1 year | 
| Number of Participants With Abnormal Clinical Laboratory Parameters Reported as Treatment-Emergent Adverse Events (TEAE) | Laboratory tests were grouped according to hematology, serum chemistry, and urinalysis. Laboratory abnormalities with toxicity grades according to NCI CTCAE Version 4.03 were derived according to laboratory values and reported as treatment-emergent adverse events. | Baseline up to 30 days after the last dose of study drug, up to 1 year | 
| Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | Participants were evaluated for ECG abnormalities. | Baseline up to 30 days after the last dose of study drug, up to 1 year | 
| Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events (TEAEs) | Participants who experienced vital signs abnormalities recorded as TEAEs were reported. | Baseline up to 30 days after the last dose of study drug, up to 1 year | 
| Number of Participants With Positive Anti-drug Antibody (ADA) and Neutralizing Antibodies (NAb) | Immunogenicity assessment included determination of antidrug (moxetumomab pasudotox) antibodies and neutralizing antidrug antibodies in serum samples. Titers and specificity were determined for NAb-positive participants. Specificity were observed in participants who had ADAs directed to the PE38 domain of moxetumomab pasudotox and increase in titers were observed in participants who tested ADA-positive at baseline. Moxetumomab pasudotox ADA-titer is a validated immunoassay, which determines titers or levels of ADAs present in ADA-positive samples. | Prior to the Start of Each Cycle for Cycles 1, 2, 3, and Subsequent Odd-Numbered Cycles, End of Treatment, and 30 Day Follow-up Visit, up to 1 year | 
| Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUC0-inf) After the First Dose of Cycle 1 | AUC (0-infinity) = Area under the serum concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-infinity). It is obtained from AUC (0-t) plus AUC (tinfinity). It was calculated by extrapolating the concentrationtime curve from time zero to infinity using the linear/log trapezoidal rule. | Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion of Day 1 of Cycle 1 | 
| Area Under the Concentration Versus Time Curve From Time Zero to Last Quantifiable Concentration [AUC0-last] After the First Dose of Cycle 1 | AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC0-t is defined as AUC from time zero to the last data point above the lower limit of quantification. | Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion at Day 1 of Cycle 1 | 
| Maximum Observed Drug Concentration in Plasma (Cmax) After the First Dose of Cycle 1 | Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. | Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion at Day 1 of Cycle 1 | 
| Time to Reach Maximum Drug Concentration in Plasma (Tmax) After the First Dose of Cycle 1 | Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. | Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion at Day 1 of Cycle 1 | 
| Terminal Phase Elimination Half Life (t1/2) After the First Dose of Cycle 1 | Terminal phase elimination half-life is the time measured for the serum/plasma concentration to decrease by one half, calculated as natural logarithmic (log)-transformed (ln) value of 2 divided by elimination rate constant (lambda); that is [ln(2)/lambda]. Elimination rate constant (lambda) was estimated via linear regression of the time versus log concentration. | Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion at Day 1 of Cycle 1 | 
| Systemic Clearance (CL) After the First Dose of Cycle 1 | CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]). | Pre-infusion, end of infusion (EOI); 1, 3, and 6 hours post-infusion at Day 1 of Cycle 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric cancer,pediatric acute lymphoblastic leukemia, lymphoblastic lymphoma, B-cell leukemia, ALL, moxetumomab pasudotox, CD22