Moxetumomab Pasudotox for Advanced Hairy Cell Leukemia

Study Overview
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Brief Summary
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Background: - Moxetumomab pasudotox is an experimental non-chemotherapy cancer treatment drug. It targets CD22, a molecule on the surface of essentially all hairy cell leukemia cells. Moxetumomab pasudotox binds to CD22, goes into the cell, and releases a toxin which kills the cell. In a phase I trial it had activity in relapsed/refractory hairy cell leukemia with safety profile supporting further clinical study (http://ncbi.nlm.nih.gov/pubmed/22355053). This is a phase III multicenter trial designed to confirm these results.

Detailed Description
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Background: Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias, or approximately 900 of the 44,000 new cases of leukemia/year in the US Over the last two decades, immunotoxin research has accumulated to support a role for CD22-targeted therapy in the treatment of HCL. Moxetumomab pasudotox is a recombinant immunotoxin containing an Fv fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin. Moxetumomab pasudotox has demonstrated a high complete response (CR) rate in patients with chemoresistant HCL and has shown activity in pediatric acute lymphoblastic leukemia as well. Modification of the structure of moxetumomab pasudotox has greatly improved binding and cytotoxicity toward CD22 expressing malignant cells compared to the precursor molecule. Preclinical and clinical studies have demonstrated that this increase in binding affinity results in improved antitumor activity and tolerability Currently there are no approved agents with significant efficacy for HCL patients after failure of standard therapy Design: This is a multicenter, single-arm study of moxetumomab pasudotox in patients with relapsed/refractory hairy cell leukemia. 77 patients will be enrolled to receive moxetumomab pasudotox intravenously (IV) on days 1, 3 and 5 of each 28 day cycle for a maximum of 6 cycles or until disease progression, unacceptable toxicity occurs, the subject begins alternate therapy, or documented CR (for subjects who have no assessable minimal residual disease and not to exceed 6 cycles). If less than or equal to 2 of the first 25 patients do not achieve durable CR, no additional patients will be accrued. The overall IRB accrual ceiling is currently set at 80 to allow for a small number of patients that cannot be assessed for response.

Official Title
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A Pivotal Multicenter Trial of Moxetumomab Pasudotox in Relapsed/ Refractory Hairy Cell Leukemia

Conditions
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Leukemia, Hairy Cell

Intervention / Treatment
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* Drug: Moxetumomab pasudotox
* Drug: IV Bag Protectant for Moxetumomab pasudotox


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have histologically confirmed hairy cell leukemia or hairy cell leukemia variant .with a need for therapy Patients must be Pseudomonas-immunotoxin naive Patients must have had at least 2 prior purine analogs, or at least 1 course of purine analog and 1 of either rituximab or BRAF inhibitor. Men or women age greater than or equal to 18 years. ECOG performance status less than or equal to 2. Patients must have adequate organ function EXCLUSION CRITERIA Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to entering the study. Patients who are receiving any other investigational agents. Patients with known brain metastases should be excluded from this clinical trial Patients with clinically significant ophthalmologic findings during screening Pregnant or breastfeeding females. Positive for Hepatitis B core antibody or surface antigen unless the patient is on Lamivudine or Entecavir and Hepatitis B Viral DNA load is less than 2000 IU/mL. Active second malignancy requiring treatment other than minor resection of indolent cancers like basal cell and squamous skin cancers HIV-positive patients unless taking appropriate anti-HIV medications with a CD4 count of greater than 200. History of allogeneic bone marrow transplant. Patients with history of both thromboembolism and known congenital hypercoagulable conditions. Uncontrolled pulmonary infection, pulmonary edema. Adequate oxygen saturation Radioimmunotherapy within 2 years prior to enrollment in study. Adequate hematologic function Adequate lung function Patients with history of thrombotic microangiopathy or thrombotic microangiopathy / hemolytic uremic syndrome Patients with QTc interval (Friderica) elevation > 500 msec based on at least 2 separate 12-lead ECGs Patient on high dose estrogen Patients with clinical evidence of disseminated intravascular coagulation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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 µg/kg<br>Patients will receive Moxetumomab Pasudotox intravenously (IV) over 30 minutes on days 1, 3, 5 of each 28 day cycle for a maximum of 6 cycles or until disease progression, unacceptable toxivity, initiation of alternate therapy or documented CR. | Drug: Moxetumomab pasudotox<br> <br> Drug: IV Bag Protectant for Moxetumomab pasudotox<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Durable Complete Response (CR) Assessed by Blinded Independent Central Review | Durable CR was defined as overall response that meets blood, bone marrow and imaging criteria for CR, followed by a >180 day duration of hematologic remission (HR). CR requires all of the following to be present: No evidence of leukemic cells in peripheral blood and/or by routine H/E staining of bone marrow; Resolution of any hepatomegaly, splenomegaly, and abnormal (>= 2 cm minimum length) lymphadenopathy by CT or MRI (maximum diameter of spleen should be either < 17 cm or have decreased by >25% from its baseline.); HR requires normal complete blood count (CBC) as exhibited by: Neutrophils >= 1.5 x 10^9/L, Platelets >= 100 x 10^9/L, and hemoglobin >= 11.0 g/dL without transfusions or growth factors for at least 4 weeks. | Full disease assessment (CBC, bone marrow and imaging) at end of treatment (EOT; up to 24 weeks) and post EOT Day 181; CBC monthly for 6 months post EOT, every 3 months post Day 181 for first 2 years and every 6 months thereafter (approximately 6 years) | 
| Percentage of Participants With Durable CR by Investigator's Assessment | Durable CR was defined as overall response that meets blood, bone marrow and imaging criteria for CR, followed by a >180 day duration of HR. CR requires all of the following to be present: No evidence of leukemic cells in peripheral blood and/or by routine H/E staining of bone marrow; Resolution of any hepatomegaly, splenomegaly, and abnormal (>= 2 cm minimum length) lymphadenopathy by CT or MRI (maximum diameter of spleen should be either < 17 cm or have decreased by >25% from its baseline.); HR requires normal complete blood count (CBC) as exhibited by: Neutrophils >= 1.5 x 10^9/L, Platelets >= 100 x 10^9/L, and hemoglobin >= 11.0 g/dL without transfusions or growth factors for at least 4 weeks. | Full disease assessment (CBC, bone marrow and imaging) at end of treatment (EOT; up to 24 weeks) and post EOT Day 181; CBC monthly for 6 months post EOT, every 3 months post Day 181 for first 2 years and every 6 months thereafter (approximately 6 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Minimal Residual Disease (MRD) Positive or MRD Negative CR Assessed by Blinded Independent Central Review | The MRD status by blinded independent review refers specifically to results of central pathologist read of bone marrow biopsy by immunohistochemistry. The CR with Positive or Negative MRD requires all of the following to be present: No evidence of leukemic cells in the peripheral blood and/or by routine H/E staining of bone marrow. Minimal Residual Disease: CR with HCL evident in blood or in bone marrow biopsy by immunohistochemistry. Resolution of any hepatomegaly, splenomegaly, and abnormal (>= 2 cm minimum length) lymphadenopathy by CT or MRI. Although a normal spleen size is not defined, the maximum diameter of the spleen should be either < 17 cm or have decreased by >25% from its baseline. Normal CBC as exhibited by: Neutrophils >= 1.5 x 10^9/L, Platelets >= 100 x 10^9/L, and hemoglobin >= 11.0 g/dL without transfusions or growth factors for at least 4 weeks. | Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years) | 
| Percentage of Participants With MRD Positive or MRD Negative CR by Investigator's Assessment | The MRD status by investigator refers to results of investigator assessment of bone marrow biopsy or bone marrow aspirate by immunohistochemistry and/or flow cytometry. The CR with Positive or Negative MRD requires all of the following to be present: No evidence of leukemic cells in the peripheral blood and/or by routine H/E staining of bone marrow. Minimal Residual Disease: CR with HCL evident in blood or marrow by flow cytometry. Resolution of any hepatomegaly, splenomegaly, and abnormal (>= 2 cm minimum length) lymphadenopathy by CT or MRI. Although a normal spleen size is not defined, the maximum diameter of the spleen should be either < 17 cm or have decreased by >25% from its baseline. Normal CBC as exhibited by: Neutrophils >= 1.5 x 10^9/L, Platelets >= 100 x 10^9/L, and hemoglobin >= 11.0 g/dL without transfusions or growth factors for at least 4 weeks. | Prior to each treatment cycle, end of treatment, and at follow-up visits every 3 months for the next 24 months and every 6 months thereafter (Approximately 6 years) | 
| Time to CR Assessed by Blinded Independent Central Review | Time to CR was defined as the time from the start of moxetumomab pasudotox administration to the first documentation of CR. | Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years) | 
| Duration of CR Assessed by Blinded Independent Central Review | Duration of CR was defined as the duration from documentation of CR to the time of relapse from CR. Relapse from CR was defined as any CR criteria (blood counts, imaging or bone marrow) no longer consistent with CR. CR requires all of the following to be present: No evidence of leukemic cells in peripheral blood and/or by routine H/E staining of bone marrow; Resolution of any hepatomegaly, splenomegaly, and abnormal (>= 2 cm minimum length) lymphadenopathy by CT or MRI (maximum diameter of spleen should be either < 17 cm or have decreased by >25% from its baseline); normal CBC as exhibited by: Neutrophils >= 1.5 x 10^9/L, Platelets >= 100 x 10^9/L, and hemoglobin >= 11.0 g/dL without transfusions or growth factors for at least 4 weeks. | Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years) | 
| Duration of Hematologic Remission | Duration of HR was defined as the duration from documentation of HR to the time of relapse. HR was defined as the blood counts required for CR as normal CBC as exhibited by: Neutrophils >= 1.5 x 10^9/L, Platelets >= 100 x 10^9/L, and hemoglobin >= 11.0 g/dL without transfusions or growth factors for at least 4 weeks. Duration of HR was censored on the date of the last hematologic assessment for participants who have no documented relapse based on blood count prior to data cutoff, dropout, or initiation of alternative anticancer therapy. | Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years) | 
| Time to Hematologic Remission | Time to HR was defined as the time from the start of moxetumomab pasudotox administration to the first documentation of HR. HR was defined as the blood counts required for CR as normal CBC as exhibited by: Neutrophils >= 1.5 x 10^9/L, Platelets >= 100 x 10^9/L, and hemoglobin >= 11.0 g/dL without transfusions or growth factors for at least 4 weeks. | Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years) | 
| Percentage of Participants With Objective Response (OR) Assessed by Blinded Independent Central Review | The OR was defined as number of participants with a best response of CR or PR. CR requires all of following to be present: No evidence of leukemic cells in peripheral blood and/or by routine H/E staining of bone marrow; Resolution of any hepatomegaly, splenomegaly, and abnormal (>=2 cm minimum length) lymphadenopathy by CT or MRI (maximum diameter of spleen should be either <17 cm or have decreased by >25% from its baseline); normal CBC (Neutrophils >=1.5 x 10^9/L, Platelets >=100 x 10^9/L, and hemoglobin >=11.0 g/dL) without transfusions or growth factors for at least 4 weeks. PR requires all of following for a period of at least 4 weeks: >=50% decrease or normalization (<5.0 x 10^9/L) in peripheral blood lymphocyte count and >=50% reduction in lymphadenopathy and in abnormal haepatosplenomegaly by CT or MRI from pre-treatment baseline value; normal CBC as mentioned above or 50% improvement in CBC values over baseline without transfusions or growth factors for at least 4 weeks. | Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years) | 
| Percentage of Participants With Objective Response by Investigator's Assessment | The OR was defined as number of participants with a best response of CR or PR. CR requires all of following to be present: No evidence of leukemic cells in peripheral blood and/or by routine H/E staining of bone marrow; Resolution of any hepatomegaly, splenomegaly, and abnormal (>=2 cm minimum length) lymphadenopathy by CT or MRI (maximum diameter of spleen should be either <17 cm or have decreased by >25% from its baseline); normal CBC (Neutrophils >=1.5 x 10^9/L, Platelets >=100 x 10^9/L, and hemoglobin >=11.0 g/dL) without transfusions or growth factors for at least 4 weeks. PR requires all of following for a period of at least 4 weeks: >=50% decrease or normalization (<5.0 x 10^9/L) in peripheral blood lymphocyte count and >=50% reduction in lymphadenopathy and in abnormal haepatosplenomegaly by CT or MRI from pre-treatment baseline value; normal CBC as mentioned above or 50% improvement in CBC values over baseline without transfusions or growth factors for at least 4 weeks. | Prior to each treatment cycle, end of treatment, and at follow-up visits every 3 months for the next 24 months and every 6 months thereafter (Approximately 6 years) | 
| Time to Objective Response Assessed by Blinded Independent Central Review | Time to OR was defined as the time from the start of moxetumomab pasudotox administration to the first documentation of OR (CR or PR). | Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years) | 
| Duration of Objective Response Assessed by Blinded Independent Central Review | Duration of OR was defined as the time from the first documentation of objective response (CR or PR) to the date of relapse. Duration of OR was censored on the date of last disease assessment or hematologic assessment for participants who have no documented relapse prior to data cut-off, dropout, or the initiation of alternative anticancer therapy. | Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years) | 
| Progression-free Survival (PFS) Assessed by Blinded Independent Central Review | The PFS was defined as the time from the start of moxetumomab pasudotox administration to the earliest date of a disease assessment showing a progressive disease/relapse, earliest date of hematologic relapse or date of death, whichever was earlier. The PFS was censored on the date of last disease assessment or hematologic assessment for participants who are alive with no documented relapse or PD prior to data cut-off, dropout, or the initiation of alternative anticancer therapy. | Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years) | 
| Time to Treatment Failure (TTF) Assessed by Blinded Independent Central Review | The TTF was defined as the time from the start of moxetumomab pasudotox administration to the date of the first of relapse, progressive disease, initiation of alternative anticancer therapy, or death due to disease or disease-related complication. The TTF was censored on the date of last disease assessment or hematologic assessment for participants who are alive with no documented relapse or PD prior to data cut-off, dropout, or the initiation of alternative anticancer therapy and also censored for death not accompanied by relapse. | Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | An Adverse Event (AE) is any unfavourable and unintended sign, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. A serious adverse event (SAE) is an AE that results in death, initial or prolonged inpatient hospitalization, life-threatening, persistent or significant disability/incapacity, congenital anomaly/birth defect, or an important medical event. TEAEs and TESAEs are defined as AEs and SAEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug. | From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months) | 
| Number of Participants With Abnormal Clinical Laboratory Results Reported as 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 AEs. The TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 30 days after the last dose of study drug (approximately 7 months). | From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months) | 
| Number of Participants With Abnormal Vital Signs Reported as TEAEs | An abnormal vital signs that were judged by the investigator to be medically significant were reported as AEs. The TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 30 days after the last dose of study drug (approximately 7 months). | From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months) | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | An abnormal ECG findings that were judged by the investigator to be medically significant were reported as AEs. The TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 30 days after the last dose of study drug (approximately 7 months). | From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox | The Tmax of moxetumomab pasudotox is reported. | Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose) | 
| Maximum Observed Plasma Concentration (Cmax) of Moxetumomab Pasudotox | The Cmax of moxetumomab pasudotox is reported. | Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose) | 
| Time of Last (Tlast) Measurable Concentration of Moxetumomab Pasudotox | The Tlast of moxetumomab pasudotox is reported. | Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose) | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-last) of Moxetumomab Pasudotox | The AUC0-last of moxetumomab pasudotox is reported. | Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose) | 
| Area Under the Plasma Concentration-time Curve From Time Zero to 3 Hours (AUC0-3hr) Post End of Moxetumomab Pasudotox | The AUC0-3hr of moxetumomab pasudotox is reported. | Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, and 3 hr post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose) | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Moxetumomab Pasudotox | The AUC0-inf of moxetumomab pasudotox is reported. | Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose) | 
| Area Under the Plasma Concentration-time Curve Extrapolated (AUCExt) of Moxetumomab Pasudotox | The AUCExt of moxetumomab pasudotox is reported. | Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose) | 
| Systemic Clearance (CL) of Moxetumomab Pasudotox | The CL of moxetumomab pasudotox is reported. | Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose) | 
| Terminal Half Life (t1/2) of Moxetumomab Pasudotox | The t1/2 of moxetumomab pasudotox is reported. | Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose) | 
| Percentage of Participants With Positive Anti-drug Antibodies (ADA), Neutralizing Anti-drug Antibodies (nAb) and Specificity (CD22 and PE38) Positive to Moxetumomab Pasudotox | Participants with ADA positive, nAb positive, cluster of differentiation 22 (CD22) positive of ADA positive/NAb positive, and pseudomonas exotoxin 38 (PE38) positive of ADA positive/NAb positive to moxetumomab pasudotox at any visit are reported. | Pre-infusion on Day 1 of Cycles 1, 2, 3, and 5; at the End of Treatment (4 to 6 weeks after the last dose; approximately 7 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moxetumomab Pasudotox, CAT-8015, Anti-cd22 recombinant immunotoxin, Biologic Therapy, Monoclonal Antibody, Pseudomonas Exotoxin, Targeted Therapy