CAT-8015 in Children, Adolescents and Young Adults With Acute Lymphoblastic Leukemia or Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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A dose-escalation study to estimate maximum cummulative dose (MTCD) of CAT-8015 that can be safely administered to a participant.

Detailed Description
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A Phase 1, Multicenter, Dose Escalation Study of CAT-8015 in Children, Adolescents and Young Adults with Refractory CD22+ Acute Lymphoblastic Leukemia (ALL) or Non-Hodgkin Lymphoma (NHL) to estimate the maximum tolerated cummulative dose (MTCD), defined as the highest dose and number of doses that can be safely administered to a participant, and to establish a safe dose, based on the MTCD, for subsequent clinical testing.

Official Title
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A Phase 1, Multicenter, Dose Escalation Study of CAT-8015 in Children, Adolescents and Young Adults With Refractory CD22+ Acute Lymphoblastic Leukemia (ALL) or Non-Hodgkin Lymphoma (NHL)

Conditions
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Acute Lymphoblastic Leukemia, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: CAT-8015 (Moxetumomab Pasudotox)
* Drug: CAT-8015 (Moxetumomab Pasudotox)
* Drug: CAT-8015 (Moxetumomab Pasudotox)
* Drug: CAT-8015 (Moxetumomab Pasudotox)
* Drug: CAT-8015 (Moxetumomab Pasudotox)
* Drug: CAT-8015 (Moxetumomab Pasudotox)
* Drug: CAT-8015 (Moxetumomab Pasudotox)
* Drug: CAT-8015 (Moxetumomab Pasudotox)
* Drug: CAT-8015 (Moxetumomab Pasudotox)
* Drug: CAT-8015 (Moxetumomab Pasudotox)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Histologically confirmed diagnosis of acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) including lymphoblastic lymphoma, Burkitt's lymphoma, and large cell lymphoma; - Measurable or evaluable disease. - Evidence of CD22-positive malignancy by one of the following criteria: - greater than or equal to (>=) 30 % of malignant cells from a disease site cluster of differentiation 22+ (CD22+) by fluorescence-activated cell sorter (FACS) analysis or; ≥ 15 % of malignant cells from a disease site CD22+ by immunohistochemistry (IHC). Stage of disease: - Participants must have relapsed or refractory disease and have received at least one standard chemotherapy and one salvage regimen or allogeneic stem cell transplant; - Relapse after prior autologous or allogeneic HSCT is allowed. In the event of relapse after prior allogeneic HSCT, the participant must be at least 100 days post-transplant and have no evidence of ongoing active graft-vs-host disease; - Recovered from the acute toxic effects of all prior therapy before entry. Performance status: - Participants greater than or equal to (>=) 12 years of age: Eastern Cooperative Oncology Group (ECOG) score of 0, 1, 2, or 3; - Participants < 12 years of age: Lansky scale >= 50%; - Participants who are unable to walk because of paralysis, but who are up in a wheel chair will be considered ambulatory for the purpose of calculating the performance score. Participants with the following central nervous system (CNS) status, are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy. - Female and male participants with childbearing potential and their sexual partners must agree to use an approved method of contraception during the study. Exclusion Criteria: - Participants meeting any of the following criteria are not eligible for participation in the study: - Isolated testicular or CNS ALL; Hepatic function: - Inadequate liver function defined as total bilirubin > 2 × upper limit of normal (ULN) (except in the case of participants with documented Gilbert's disease > 5 × ULN) or transaminases (ALT and aspartate aminotransferase [AST]) > 5 × ULN based on age- and laboratory-specific normal ranges; Renal function: - With greater than age-adjusted normal serum creatinine (see Table below) and a creatinine clearance > 60 millilitre per minute mL/min/1.73 m2. - Age(Years)- Maximum Serum Creatinine (mg/dl)[≤5,0.8] [5 < age less than or equal to 10,1.0] [10 < age less than or equal to 15,1.2 [> 15, 1.5] Hematologic function: - For non-leukemic subjects only, absolute neutrophil count (ANC) < 1000/cmm, or platelet count < 50,000/cmm, if these cytopenias are not judged by the investigator to be due to underlying disease (ie potentially reversible with anti-neoplastic therapy); - Participants with CNS 3 disease; - Hyperleukocytosis (≥ 50,000 blasts/µL) or rapidly progressive disease (PD) that in the estimation of the investigator and sponsor would compromise ability to complete study therapy; - Prior treatment with CAT-3888 (BL22) or any pseudomonas-exotoxin-containing compound; - HIV positive serology (due to increased risk of severe infection and unknown interaction of CAT-8015 with antiretroviral drugs); - Active hepatitis B or C infection.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 25 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: 5 microgram per kilogram (mcg/kg)<br>Participants received intravenous infusion of 5 mcg/kg moxetumomab pasudotox (CAT-8015) without concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle. | Drug: CAT-8015 (Moxetumomab Pasudotox)<br>* Participants received intravenous infusion of 5 mcg/kg moxetumomab pasudotox (CAT-8015) without concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle.<br>|
| Experimental: 10 microgram per kilogram (mcg/kg)<br>Participants received intravenous infusion of 10 mcg/kg moxetumomab pasudotox (CAT-8015) without concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle. | Drug: CAT-8015 (Moxetumomab Pasudotox)<br>* Participants received intravenous infusion of 10 mcg/kg moxetumomab pasudotox (CAT-8015) without concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle.<br>|
| Experimental: 20 microgram per kilogram (mcg/kg): Schema A<br>Participants received intravenous infusion of 20 mcg/kg moxetumomab pasudotox (CAT-8015) without concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle. | Drug: CAT-8015 (Moxetumomab Pasudotox)<br>* Participants received intravenous infusion of 20 mcg/kg moxetumomab pasudotox (CAT-8015) without concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle.<br>|
| Experimental: 20 microgram per kilogram (mcg/kg): Schema B<br>Participants received intravenous infusion of 20 mcg/kg moxetumomab pasudotox (CAT-8015) with concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle. | Drug: CAT-8015 (Moxetumomab Pasudotox)<br>* Participants received intravenous infusion of 20 mcg/kg moxetumomab pasudotox (CAT-8015) with concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle.<br>|
| Experimental: 30 microgram per kilogram (mcg/kg): Schema A<br>Participants received intravenous infusion of 30 mcg/kg moxetumomab pasudotox (CAT-8015) without concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle. | Drug: CAT-8015 (Moxetumomab Pasudotox)<br>* Participants received intravenous infusion of 30 mcg/kg moxetumomab pasudotox (CAT-8015) without concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle.<br>|
| Experimental: 30 microgram per kilogram (mcg/kg): Schema B<br>Participants received intravenous infusion of 30 mcg/kg moxetumomab pasudotox (CAT-8015) with concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle. | Drug: CAT-8015 (Moxetumomab Pasudotox)<br>* Participants received intravenous infusion of 30 mcg/kg moxetumomab pasudotox (CAT-8015) with concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle.<br>|
| Experimental: 40 microgram per kilogram (mcg/kg): Schema B<br>Participants received intravenous infusion of 40 mcg/kg moxetumomab pasudotox (CAT-8015) with concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle. | Drug: CAT-8015 (Moxetumomab Pasudotox)<br>* Participants received intravenous infusion of 40 mcg/kg moxetumomab pasudotox (CAT-8015) with concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle.<br>|
| Experimental: 32 microgram per kilogram (mcg/kg): Schema C<br>Participants received intravenous infusion of 32 mcg/kg moxetumomab pasudotox (CAT-8015) of process 3 material every other day (QoD) in a 21-day cycle for a total of 10 doses per cycle. | Drug: CAT-8015 (Moxetumomab Pasudotox)<br>* Participants received intravenous infusion of 32 mcg/kg moxetumomab pasudotox (CAT-8015) of process 3 material every other day (QoD) in a 21-day cycle for a total of 10 doses per cycle.<br>|
| Experimental: 50 microgram per kilogram (mcg/kg): Schema B<br>Participants received intravenous infusion of 50 mcg/kg moxetumomab pasudotox (CAT-8015) without concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle. | Drug: CAT-8015 (Moxetumomab Pasudotox)<br>* Participants received intravenous infusion of 50 mcg/kg moxetumomab pasudotox (CAT-8015) without concomitant corticosteroid administration every other day (QoD) in a 21-day cycle for a total of 6 doses per cycle.<br>|
| Experimental: 50 microgram per kilogram (mcg/kg): Schema C<br>Participants received intravenous infusion of 50 mcg/kg moxetumomab pasudotox (CAT-8015) continuous every other day (QoD) in a 21-day cycle for a total of 10 doses per cycle. | Drug: CAT-8015 (Moxetumomab Pasudotox)<br>* Participants received intravenous infusion of 50 mcg/kg moxetumomab pasudotox (CAT-8015) continuous every other day (QoD) in a 21-day cycle for a total of 10 doses per cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | Adverse events that were suspected of a relationship to moxetumomab pasudotox and were greater than or equal to (>=) Grade 3 in severity were considered DLTs with the following additional criteria or exceptions: Participants with hematologic abnormalities of any grade, Grade 2 allergic reactions of bronchospasm or urticaria, or any Grade ≥ 3 allergic reaction, in the presence of premedication. | Day 1 up to 21 days of Cycle 1 (each cycle duration was of 21 days) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received investigational product. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between administration of investigational product and 30 days after the last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. | From start of study drug administration until 30 days after the last dose of study drug | 
| Number of Participants With Vital Signs Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs) | Vital signs included parameters as heart rate, blood pressure, temperature, weight, pulse oximetry and respiratory rate. TEAEs were events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug, for the period extending to 30 days after the last dose of study drug. | From start of study drug administration until 30 days after the last dose of study drug | 
| Number of Participants With Clinically Significant Laboratory Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs) | An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation were reported as an adverse event. Treatment-emergent were events between first dose of study drug and 30 days after the last dose that were absent before treatment or that worsened relative to pretreatment state. Number of participants with grade 3 or higher treatment-emergent adverse events (5% cut off) for laboratory abnormalities were reported as clinically relevant laboratory changes. | From start of study drug administration up to 30 days after the last dose of study drug | 
| Treatment-Emergent Adverse Events (TEAEs) Related to Chemistry Abnormalities Occurring in Greater Than (>) 5 Percent of Participants | An abnormal chemistry finding which required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation were reported as an adverse event. Treatment-emergent were events between first dose of study drug and 30 days after the last dose that were absent before treatment or that worsened relative to pretreatment state. | From start of study drug administration up to 30 days after the last dose of study drug | 
| Number of Participants With Abnormalities in Ophthalmologic Examination at End of Treatment That Were Not Present at Baseline | Ophthalmologic examination included evaluation of retinal, corneal and lens abnormalities at baseline and end of treatment that were not present at screening. Participants who experienced abnormalitities during ophthalmologic examination recorded and reported. | Baseline and end of treatment (up to 1 year after the last participants begins study drug treatment) | 
| Number of Participants With Change From Baseline in Normal Sinus Rhythm Findings in ECG | Number of participants with abnormal ECG changes (compared with baseline) as assessed by study cardiologist | Baseline and end of treatment (up to 1 year after the last participant begins study drug treatment) | 
| Change From Baseline to End of Treatment in Clinical Findings in Electrocardiogram (ECG) QT, QTC Interval and Ventricular Rate | The 12-lead ECG data were summarized and evaluated for the following parameters: ,QT, QTC intervals and ventricular rate. Change from baseline in these parameters were reported. | Baseline and end of treatment (up to 1 year after the last participants begins study drug treatment) | 
| Best Overall Tumor Response | Antitumor activity was assessed by best overall tumor response. | Baseline and end of treatment (up to 1 year after the last participant begins study drug treatment) | 
| Objective Response Rate (ORR) | Objective response based on assessment of confirmed composite complete response (CRc) or partial response (PR) according to disease specific criteria [modified criteria for response in acute lymphoblastic leukemia (ALL)]. | Baseline until end of treatment (up to 1 year after the last participant begins study drug treatment) | 
| Percentage of Participants With Relapse of Disease | Relapse is defined as progressive disease (PD) following complete response (CR). Rate of relapse was only calculated for the subgroup of participants with complete response. | Baseline until end of treatment (up to 1 year after the last participant begins study drug treatment) | 
| Time to Disease Response | Time to disease response was measured from the start of moxetumomab pasudotox administration to the first documentation of response (CR or PR) and was assessed in participants who achieved objective response. | Baseline and end of treatment (up to 1 year after the last participant begins study drug treatment) | 
| Duration of Response (DR) | Duration of response was defined as the duration from the first documentation of objective response to the first documented disease progression. | Baseline and end of treatment (up to 1 year after the last participant begins study drug treatment | 
| Time to Disease Progression (TDP) | Time to disease progression was measured from the start of treatment with moxetumomab pasudotox until the documentation of disease progression. Number of progressions were reported here. | Baseline and end of treatment (up to 1 year after the last participant begins study drug treatment | 
| Progression-Free Survival (PFS) | Progression-free survival was measured from the start of treatment with moxetumomab pasudotox until the documentation of disease progression or death due to any cause, whichever occurs first. Number of progressions/deaths were reported here. | Baseline and end of treatment (up to 1 year after the last participant begins study drug treatment) | 
| Overall Survival (OS) | Overall survival was determined as the time from the start of treatment with Moxetumomab Pasudotox until death. Number of deaths were reported here. | Baseline and end of treatment (up to 1 year after the last participant begins study drug treatment) | 
| Maximum Observed Serum Concentration (Cmax) for Moxetumomab Pasudotox | The Cmax is the maximum observed plasma concentration of Moxetumomab Pasudotox. | Cycles 1, 2 and every 4th cycle: pre-dose, end of infusion (EOI), 1, 1.5, 2.5, 4 and 8 hours post-dose of Dose 1; pre-dose and end of infusion after Dose 6 | 
| Area Under the Serum Concentration Time Curve From Time Zero to Infinity (AUC [0 to Infinity]) for Moxetumomab Pasudotox | The AUC (0 to infinity) is the area under the plasma concentration-time curve from time zero to infinity hours. | Cycles 1, 2 and every 4th cycle: pre-dose, end of infusion (EOI), 1, 1.5, 2.5, 4 and 8 hours post-dose of Dose 1; pre-dose and end of infusion after Dose 6 | 
| Systemic Clearance (CL) for Moxetumomab Pasudotox | The 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 zone to infinite time (AUC[0-infinity]). | Cycles 1, 2 and every 4th cycle: pre-dose, end of infusion (EOI), 1, 1.5, 2.5, 4 and 8 hours post-dose of Dose 1; pre-dose and end of infusion after Dose 6 | 
| Terminal Phase Elimination Half Life (t1/2) for Moxetumomab Pasudotox | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Cycles 1, 2 and every 4th cycle: pre-dose, end of infusion (EOI), 1, 1.5, 2.5, 4 and 8 hours post-dose of Dose 1; pre-dose and end of infusion after Dose 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibody | Participants tested for immunogenicity to CAT-8015 (moxetumomab pasudotox) prior to enrollment, before each cycle and at end of study. The neutralization assay measures the capacity of participant's plasma (antibodies) to inhibit the binding of moxetumomab pasudotox to its target, cluster of differentiation 22 (CD22), coated onto enzyme linked immunosorbent assay (ELISA) plates. It was used as a direct surrogate for biological activity based on the mechanism of action of this drug. Significant level of neutralizing antibody activity defined as the capacity of test plasma to inhibit greater than (>)50 percentage (%) of the binding of CAT-8015 to CD22 using an ELISA-based method. | Baseline until end of treatment (up to 1 year after the last participant begins study drug treatment) | 
| CD22 Expression Cells in Peripheral Blood by Best Response | Participants malignant cells (peripheral blood) was tested for cluster of differentiation 22 (CD22) expression by fluorescence-activated cell sorter (FACS) analysis. | Baseline until end of treatment (up to 1 year after the last participant begins study drug treatment) | 
| Number of Participants With Potential Biomarkers of Predicting Capillary Leak Syndrome (CLS) | Potential biomarkers include orthostatic blood pressure, albumin levels, weight change, edema and hypoxia were evaluated. | Baseline and end of treatment (up to 1 year after the last participant begins study drug treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moxetumomab pasudotox