A Phase I, Multicenter, Dose Escalation Study of CAT-8015 in Participants With Chronic Leukemia

Study Overview
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Brief Summary
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This was a multicenter, Phase 1, standard 3+3 dose-escalation study to evaluate the safety and anti-neoplastic activity of moxetumomab pasudotox in relapsed or refractory participants with chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL) or Small Lymphocytic Lymphoma (SLL).

Detailed Description
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This was a multicenter, Phase 1, standard 3+3 dose-escalation study to evaluate the safety and anti-neoplastic activity of CAT-8015 in relapsed or refractory participants with CLL, PLL, or SLL. Participants in the initial dose cohort were to receive CAT-8015 at a dose of 5 microgram per kilogram (mcg/kg) CAT-8015, increasing to 10 mcg/kg in the second dose cohort, and then increasing by 10 mcg/kg increments in subsequent cohorts (that is, to doses of 20, 30, 40, 50, 60 mcg/kg, etc) until a maximum tolerated dose (MTD) was identified. Following identification of the MTD, the MTD cohort was to be expanded to 16 participants.

Official Title
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A Phase I, Multicenter, Dose-Escalation Study of CAT-8015 in Patients With Relapsed or Refactory Chronic Lymphocytic Leukemia (CLL) Prolymphocytic Leukemia (PLL), or Small Lymphocytic Leukemia (SLL)

Conditions
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Leukemia, Lymphoma, Chronic Lymphocytic, Leukemia, Prolymphocytic Leukemia, Small, Lymphocytic Lymphoma, Moxetumomab Pasudotox

Intervention / Treatment
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* Drug: CAT-8015 5 mcg/kg
* Drug: CAT-8015 10 mcg/kg
* Drug: CAT-8015 20 mcg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of B-Cell Leukemia [(chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), or Small lymphocytic leukemia (SLL)] Measurable Disease Disease characteristics: Participants with CLL or SLL are eligible if they have failed 2 or more prior courses of standard chemo and/or biologic therapy (example, Rituxan) and PLL will be eligible if they have failed at least one prior standard chemotherapeutic regimen. Medical indications for treatment include progressive disease-related symptoms, progressive cytopenias due to marrow involvement, progressive or painful splenomegaly or adenopathy, rapidly increasing lymphocytosis, autoimmune hemolytic anemia or thrombocytopenia and increased frequency of infections. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Participants with other cancers who meet eligibility criteria and have had less than 5 years of disease-free survival will be considered on a case-by-case basis Life expectancy of greater than 6 months, as assessed by the principal investigator Must be able to understand and sign the informed consent Must be at least 18 years old Female and Male participants agree to use an approved method of contraception during the study Exclusion Criteria: History of allogeneic bone marrow transplant. Documented and ongoing central nervous system involvement with their malignant disease [history of central nervous system (CNS) involvement is not an exclusion criterion] Pregnant or breast-feeding females Participants who plasma contains either a significant level of antibody to CAT-8015 as measured by ELISA, or antibody that neutralizes the binding of CAT-8015 to CD22 as measured by a competition ELISA. HIV positive serology (due to increased risk of severe infection and unknown interaction of CAT-8015 with antiretroviral drugs) Hepatitis B surface antigen positive Uncontrolled, symptomatic, intercurrent illness including but not limited to: infections requiring systemic antibiotics, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements. Hepatic function: Serum transaminases [either alanine aminotransferase (ALT) or aspartate aminotransferase (AST)] or direct bilirubin greater than or equal to Grade 2, unless bilirubin is due to Gilbert's disease Renal function: Serum creatinine clearance is less than or equal to 60 millilitre per minute (mL/min) as estimated by Cockcroft-Gault formula Hematologic function: The ANC less than 1000/cubic millimeter (cmm), or platelet count less than 50,000/cmm, if these cytopenias are not judged by the investigator to be due to underlying disease (that is, potentially reversible with anti-neoplastic therapy). A participant will not be excluded because of pancytopenia greater than or equal to Grade 3, or erythropoietin dependence, if it is due to disease, based on the results of bone marrow studies. Baseline coagulopathy greater than or equal to grade 3 unless due to anticoagulant therapy Pulmonary function: - Participants with less than 50 percent (%) of predicted forced expiratory volume (FEV-1) or less than 50% of predicted diffusing capacity for carbon monoxide (DLCO) corrected for hemoglobin concentration and alveolar volume. Note: Participants with no prior history of pulmonary illness are not required to have pulmonary function test (PFTs). FEV1 will be assessed after bronchodilator therapy. Recent prior therapy: Cytotoxic chemotherapy, corticosteroids (except stable doses of prednisone), whole body electron beam radiation therapy, hormonal, biologic or other standard or any investigational therapy of the malignancy for 3 weeks prior to entry into the trial. Less than or equal to 1 month prior monoclonal antibody therapy (that is, rituximab) Participants who are receiving or have received radiation therapy less than 3 weeks prior to study entry will not be excluded providing the volume of the bone marrow treated is less than 10% and also the participant has measurable disease outside the radiation report. Any history of prior pseudomonas - exotoxin immunotoxin administrator

Ages Eligible for Study
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Minimum 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAT-8015 5 microgram per kilogram (mcg/kg)<br>Participants received a single intravenous infusion of 5 mcg/kg moxetumomab pasudotox (CAT-8015) on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until progressive disease (PD) or until otherwise they become ineligible. | Drug: CAT-8015 5 mcg/kg<br>* Participants received a single intravenous infusion of 5 mcg/kg moxetumomab pasudotox (CAT-8015) on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until progressive disease (PD) or until otherwise they become ineligible.<br>|
| Experimental: CAT-8015 10 mcg/kg<br>Participants received a single intravenous infusion of 10 mcg/kg moxetumomab pasudotox (CAT-8015) on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until progressive disease (PD) or until otherwise they become ineligible. | Drug: CAT-8015 10 mcg/kg<br>* Participants received a single intravenous infusion of 10 mcg/kg moxetumomab pasudotox (CAT-8015) on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until progressive disease (PD) or until otherwise they become ineligible.<br>|
| Experimental: CAT-8015 20 mcg/kg<br>Participants received a single intravenous infusion of 20 mcg/kg moxetumomab pasudotox (CAT-8015) on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until progressive disease (PD) or until otherwise they become ineligible. | Drug: CAT-8015 20 mcg/kg<br>* Participants received a single intravenous infusion of 20 mcg/kg moxetumomab pasudotox (CAT-8015) on Days 1, 3, and 5 of every 28-day cycle and continued cycles of therapy until progressive disease (PD) or until otherwise they become ineligible.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) 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, for the period extending to 30 days after the last dose of study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening situation (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received moxetumomab pasudotox. Treatment-emergent were events between administration of investigational product and Day 28 that were absent before treatment or that worsened relative to pretreatment 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) | The vital sign abnormalities which require an action or intervention by the investigator, or a finding judged by the investigator were reported as an adverse event. 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 Relevant Electrocardiogram (ECG) Abnormalities Recorded as Adverse Events (AEs) | AEs observed in participants with clinically significant ECG abnormalities were assessed. | 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 for laboratory abnormalities were reported as clinically relevant laboratory changes. | From start of study drug administration until 30 days after the last dose of study drug | 
| Number of Participants With Objective Response Rate (ORR): Complete Response (CR) or Partial Response (PR) | Objective response rate defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria. | Up to 2 years of post-treatment follow-up | 
| Best Overall Objective Tumor Response | Antitumor activity was assessed by best overall objective tumor response. | Up to 2 years of post-treatment follow-up | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox | The Tmax is the time to reach maximum observed plasma concentration of Moxetumomab Pasudotox. | Predose, 0.25 (During Infusion), 0.5 (End of Infusion), 1, 1.5, 2, 4, 8 and 12 hours postdose on Day 1 and 5; Predose and End of Infusion on Day 3 | 
| Maximum Observed Serum Concentration (Cmax) for Moxetumomab Pasudotox | The Cmax is the maximum observed plasma concentration of Moxetumomab Pasudotox. | Predose, 0.25 (During Infusion), 0.5 (End of Infusion), 1, 1.5, 2, 4, 8 and 12 hours postdose on Day 1 and 5; Predose and End of Infusion on Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Positive Neutralizing Antibodies | Participants tested for immunogenicity to 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. | Up to end of treatment (4-6 weeks after the last dose) | 
| Percentage Change From Baseline in Cluster of Differentiation 22 (CD22) Expression | Participants demonstrated CD22 expression on malignant cells at Screening and CD22 is a regulatory molecule that prevents the over activation of the immune system and the development of autoimmune diseases. | End of treatment (4-6 weeks after the last dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Small Lymphocytic Lymphoma, Moxetumomab pasudotox