Leukemia, Hairy Cell
Conditions
Keywords
Moxetumomab Pasudotox, CAT-8015, Anti-cd22 recombinant immunotoxin, Biologic Therapy, Monoclonal Antibody, Pseudomonas Exotoxin, Targeted Therapy
Brief summary
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
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.
Interventions
DRUGIV Bag Protectant for Moxetumomab pasudotox
Sponsors
MedImmune LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Durable Complete Response (CR) Assessed by Blinded Independent Central Review | 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) | 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. |
| Percentage of Participants With Durable CR by Investigator's Assessment | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to CR Assessed by Blinded Independent Central Review | 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 CR was defined as the time from the start of moxetumomab pasudotox administration to the first documentation of CR. |
| Duration of CR Assessed by Blinded Independent Central Review | 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 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. |
| Duration of Hematologic Remission | 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 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. |
| Time to Hematologic Remission | 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 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. |
| Percentage of Participants With Objective Response (OR) Assessed by Blinded Independent Central Review | 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) | 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. |
| Percentage of Participants With Objective Response by Investigator's Assessment | 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) | 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. |
| Time to Objective Response Assessed by Blinded Independent Central Review | 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 OR was defined as the time from the start of moxetumomab pasudotox administration to the first documentation of OR (CR or PR). |
| Duration of Objective Response Assessed by Blinded Independent Central Review | 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 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. |
| Progression-free Survival (PFS) Assessed by Blinded Independent Central Review | 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) | 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. |
| Time to Treatment Failure (TTF) Assessed by Blinded Independent Central Review | 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) | 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. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months) | 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. |
| Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months) | 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). |
| Percentage of Participants With Minimal Residual Disease (MRD) Positive or MRD Negative CR Assessed by Blinded Independent Central Review | 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) | 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. |
| Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months) | 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). |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox | 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) | The Tmax of moxetumomab pasudotox is reported. |
| Maximum Observed Plasma Concentration (Cmax) of Moxetumomab Pasudotox | 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) | The Cmax of moxetumomab pasudotox is reported. |
| Time of Last (Tlast) Measurable Concentration of Moxetumomab Pasudotox | 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) | The Tlast of moxetumomab pasudotox is reported. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-last) of Moxetumomab Pasudotox | 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) | The AUC0-last of moxetumomab pasudotox is reported. |
| Area Under the Plasma Concentration-time Curve From Time Zero to 3 Hours (AUC0-3hr) Post End of Moxetumomab Pasudotox | 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) | The AUC0-3hr of moxetumomab pasudotox is reported. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Moxetumomab Pasudotox | 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) | The AUC0-inf of moxetumomab pasudotox is reported. |
| Area Under the Plasma Concentration-time Curve Extrapolated (AUCExt) of Moxetumomab Pasudotox | 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) | The AUCExt of moxetumomab pasudotox is reported. |
| Systemic Clearance (CL) of Moxetumomab Pasudotox | 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) | The CL of moxetumomab pasudotox is reported. |
| Terminal Half Life (t1/2) of Moxetumomab Pasudotox | 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) | The t1/2 of moxetumomab pasudotox is reported. |
| Percentage of Participants With Positive Anti-drug Antibodies (ADA), Neutralizing Anti-drug Antibodies (nAb) and Specificity (CD22 and PE38) Positive to Moxetumomab Pasudotox | 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) | 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. |
| Number of Participants With Abnormal Vital Signs Reported as TEAEs | From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months) | 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). |
| Percentage of Participants With MRD Positive or MRD Negative CR by Investigator's Assessment | 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) | 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. |
Countries
Belgium, Canada, Czechia, France, Germany, Ireland, Israel, Italy, Norway, Poland, Serbia, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted across 14 countries (the USA, France, Italy, Germany, Belgium, Canada, Czech Republic, Ireland, Israel, Norway, Poland, Serbia, Spain, and United Kingdom).
Participants by arm
| Arm | Count |
|---|---|
| Moxetumomab Pasudotox 40 µg/kg Participants received intravenous infusion of moxetumomab pasudotox 40 µg/kg on Days 1, 3, and 5 of each 28-day cycle for up to 6 cycles, until documentation of complete response, progressive disease, initiation of alternate therapy, or unacceptable toxicity. | 80 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Death | 4 |
| Overall Study | Due to lack of response | 1 |
| Overall Study | Due to progression of disease | 13 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Started new therapies | 17 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Moxetumomab Pasudotox 40 µg/kg |
|---|---|
| Age, Continuous | 60.3 Years STANDARD_DEVIATION 11.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) White | 70 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 80 |
| other Total, other adverse events | 77 / 80 |
| serious Total, serious adverse events | 28 / 80 |
Outcome results
Primary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With Durable Complete Response (CR) Assessed by Blinded Independent Central Review | 36.3 Percentage of participants |
Primary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With Durable CR by Investigator's Assessment | 48.8 Percentage of participants |
Secondary
Area Under the Plasma Concentration-time Curve Extrapolated (AUCExt) of Moxetumomab Pasudotox
The AUCExt of moxetumomab pasudotox is reported.
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve Extrapolated (AUCExt) of Moxetumomab Pasudotox | Cycle 1 Day 1 | 13.2 ng*hr/mL | Standard Deviation 3.04 |
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve Extrapolated (AUCExt) of Moxetumomab Pasudotox | Cycle 1 Day 5 | 14.3 ng*hr/mL | Standard Deviation 5.72 |
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve Extrapolated (AUCExt) of Moxetumomab Pasudotox | Cycle 2 Day 1 | 20.2 ng*hr/mL | Standard Deviation 7.62 |
Secondary
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.
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve From Time Zero to 3 Hours (AUC0-3hr) Post End of Moxetumomab Pasudotox | Cycle 1 Day 1 | 869 ng*hr/mL | Standard Deviation 200 |
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve From Time Zero to 3 Hours (AUC0-3hr) Post End of Moxetumomab Pasudotox | Cycle 1 Day 5 | 856 ng*hr/mL | Standard Deviation 370 |
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve From Time Zero to 3 Hours (AUC0-3hr) Post End of Moxetumomab Pasudotox | Cycle 2 Day 1 | 1030 ng*hr/mL | Standard Deviation 333 |
Secondary
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.
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point. Data for Cycle 1 Day 1 was not reported as no evaluable participants for the calculation of the concerned parameters (ie., data were not sufficient).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Moxetumomab Pasudotox | Cycle 1 Day 5 | 1300 ng*hr/mL | Standard Deviation 742 |
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Moxetumomab Pasudotox | Cycle 2 Day 1 | 1470 ng*hr/mL | Standard Deviation 541 |
| Unknown | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Moxetumomab Pasudotox | Cycle 1 Day 1 | — ng*hr/mL | — |
Secondary
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.
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-last) of Moxetumomab Pasudotox | Cycle 1 Day 1 | 120 ng*hr/mL | Standard Deviation 261 |
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-last) of Moxetumomab Pasudotox | Cycle 1 Day 5 | 820 ng*hr/mL | Standard Deviation 721 |
| Moxetumomab Pasudotox 40 µg/kg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-last) of Moxetumomab Pasudotox | Cycle 2 Day 1 | 626 ng*hr/mL | Standard Deviation 610 |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Duration of CR was evaluated for participants who achieved CR per independent central review.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Duration of CR Assessed by Blinded Independent Central Review | 62.8 Months |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Duration of HR was evaluated for participants who achieved HR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Duration of Hematologic Remission | 45.8 Months |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Duration of OR was evaluated for participants who achieved OR per independent central review.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Duration of Objective Response Assessed by Blinded Independent Central Review | 66.7 Months |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Moxetumomab Pasudotox
The Cmax of moxetumomab pasudotox is reported.
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Maximum Observed Plasma Concentration (Cmax) of Moxetumomab Pasudotox | Cycle 1 Day 5 | 435 ng/mL | Standard Deviation 233 |
| Moxetumomab Pasudotox 40 µg/kg | Maximum Observed Plasma Concentration (Cmax) of Moxetumomab Pasudotox | Cycle 1 Day 1 | 192 ng/mL | Standard Deviation 162 |
| Moxetumomab Pasudotox 40 µg/kg | Maximum Observed Plasma Concentration (Cmax) of Moxetumomab Pasudotox | Cycle 2 Day 1 | 379 ng/mL | Standard Deviation 262 |
Secondary
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).
Time frame: From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
Population: Safety population included participants who received at least 1 dose of moxetumomab pasudotox.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Anaemia | 17 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Disseminated intravascular coagulation | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Febrile neutropenia | 5 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Iron deficiency anaemia | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Leukopenia | 2 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Lymphopenia | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Neutropenia | 4 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Thrombocytopenia | 3 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Activated partial thromboplastin time prolonged | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Lymphocyte count decreased | 16 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Lymphocyte count increased | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Neutrophil count decreased | 6 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Platelet count decreased | 9 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | White blood cell count decreased | 8 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Aspartate aminotransferase increased | 15 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Blood albumin decreased | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Blood alkaline phosphatase increased | 4 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Blood bicarbonate decreased | 2 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Blood bilirubin increased | 5 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Blood creatinine increased | 9 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Blood triglycerides increased | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Gamma-glutamyltransferase increased | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Lipase increased | 2 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hyperglycaemia | 8 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hyperkalaemia | 6 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hypermagnesaemia | 3 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hypernatraemia | 4 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hypertriglyceridaemia | 2 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hypoalbuminaemia | 16 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hypocalcaemia | 19 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hypoglycaemia | 2 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hypokalaemia | 13 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hypomagnesaemia | 6 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Hyponatraemia | 9 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Haematuria | 6 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Haemoglobinuria | 2 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | Proteinuria | 1 Participants |
Secondary
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).
Time frame: From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
Population: Safety population included participants who received at least 1 dose of moxetumomab pasudotox.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Angina pectoris | 2 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Atrial fibrillation | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Atrioventricular block first degree | 3 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Bundle branch block left | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Left ventricular dysfunction | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Palpitations | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Pericardial effusion | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Sinus bradycardia | 2 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Sinus tachycardia | 6 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Supraventricular tachycardia | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Tachycardia | 1 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs | Ventricular arrhythmia | 1 Participants |
Secondary
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).
Time frame: From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
Population: Safety population included participants who received at least 1 dose of moxetumomab pasudotox.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Dyspnoea | 9 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Dyspnoea exertional | 3 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypertension | 12 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypotension | 6 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Pyrexia | 25 Participants |
Secondary
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.
Time frame: From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
Population: Safety population included participants who received at least 1 dose of moxetumomab pasudotox.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 79 Participants |
| Moxetumomab Pasudotox 40 µg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 28 Participants |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With Minimal Residual Disease (MRD) Positive or MRD Negative CR Assessed by Blinded Independent Central Review | MRD negative CR | 33.8 Percentage of participants |
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With Minimal Residual Disease (MRD) Positive or MRD Negative CR Assessed by Blinded Independent Central Review | MRD positive CR | 7.5 Percentage of participants |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With MRD Positive or MRD Negative CR by Investigator's Assessment | MRD negative CR | 32.5 Percentage of participants |
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With MRD Positive or MRD Negative CR by Investigator's Assessment | MRD positive CR | 7.5 Percentage of participants |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With Objective Response by Investigator's Assessment | 78.8 Percentage of participants |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With Objective Response (OR) Assessed by Blinded Independent Central Review | 75.0 Percentage of participants |
Secondary
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.
Time frame: 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)
Population: Safety population included participants who received at least 1 dose of moxetumomab pasudotox.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With Positive Anti-drug Antibodies (ADA), Neutralizing Anti-drug Antibodies (nAb) and Specificity (CD22 and PE38) Positive to Moxetumomab Pasudotox | ADA positive | 87.5 Percentage of Participants |
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With Positive Anti-drug Antibodies (ADA), Neutralizing Anti-drug Antibodies (nAb) and Specificity (CD22 and PE38) Positive to Moxetumomab Pasudotox | ADA and NAb positive | 83.8 Percentage of Participants |
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With Positive Anti-drug Antibodies (ADA), Neutralizing Anti-drug Antibodies (nAb) and Specificity (CD22 and PE38) Positive to Moxetumomab Pasudotox | Specificity CD22 positive of ADA+/NAb+ | 55.2 Percentage of Participants |
| Moxetumomab Pasudotox 40 µg/kg | Percentage of Participants With Positive Anti-drug Antibodies (ADA), Neutralizing Anti-drug Antibodies (nAb) and Specificity (CD22 and PE38) Positive to Moxetumomab Pasudotox | Specificity PE38 positive of ADA+/NAb+ | 98.5 Percentage of Participants |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Progression-free Survival (PFS) Assessed by Blinded Independent Central Review | 41.5 Months |
Secondary
Systemic Clearance (CL) of Moxetumomab Pasudotox
The CL of moxetumomab pasudotox is reported.
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point. Data for Cycle 1 Day 1 was not reported as no evaluable participants for the calculation of the concerned parameters (ie., data were not sufficient).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Systemic Clearance (CL) of Moxetumomab Pasudotox | Cycle 1 Day 5 | 44.6 mL/hr/kg | Standard Deviation 30.5 |
| Moxetumomab Pasudotox 40 µg/kg | Systemic Clearance (CL) of Moxetumomab Pasudotox | Cycle 2 Day 1 | 31.8 mL/hr/kg | Standard Deviation 13.7 |
| Unknown | Systemic Clearance (CL) of Moxetumomab Pasudotox | Cycle 1 Day 1 | — mL/hr/kg | — |
Secondary
Terminal Half Life (t1/2) of Moxetumomab Pasudotox
The t1/2 of moxetumomab pasudotox is reported.
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point. Data for Cycle 1 Day 1 was not reported as no evaluable participants for the calculation of the concerned parameters (ie., data were not sufficient).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Terminal Half Life (t1/2) of Moxetumomab Pasudotox | Cycle 1 Day 5 | 1.38 Hours | Standard Deviation 0.632 |
| Moxetumomab Pasudotox 40 µg/kg | Terminal Half Life (t1/2) of Moxetumomab Pasudotox | Cycle 2 Day 1 | 1.39 Hours | Standard Deviation 0.351 |
| Unknown | Terminal Half Life (t1/2) of Moxetumomab Pasudotox | Cycle 1 Day 1 | — Hours | — |
Secondary
Time of Last (Tlast) Measurable Concentration of Moxetumomab Pasudotox
The Tlast of moxetumomab pasudotox is reported.
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Time of Last (Tlast) Measurable Concentration of Moxetumomab Pasudotox | Cycle 1 Day 1 | 0.841 Hours | Standard Deviation 0.866 |
| Moxetumomab Pasudotox 40 µg/kg | Time of Last (Tlast) Measurable Concentration of Moxetumomab Pasudotox | Cycle 1 Day 5 | 3.37 Hours | Standard Deviation 2.38 |
| Moxetumomab Pasudotox 40 µg/kg | Time of Last (Tlast) Measurable Concentration of Moxetumomab Pasudotox | Cycle 2 Day 1 | 2.16 Hours | Standard Deviation 1.43 |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Time to CR was evaluated for participants who achieved CR per independent central review.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Time to CR Assessed by Blinded Independent Central Review | 5.9 Months |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Time to HR was evaluated for participants in the ITT population who achieved HR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Time to Hematologic Remission | 1.1 Months |
Secondary
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).
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Time to OR was evaluated for participants who achieved OR per independent central review.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Time to Objective Response Assessed by Blinded Independent Central Review | 5.7 Months |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox
The Tmax of moxetumomab pasudotox is reported.
Time frame: 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)
Population: Pharmacokinetic (PK) population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox | Cycle 1 Day 1 | 0.567 Hours |
| Moxetumomab Pasudotox 40 µg/kg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox | Cycle 1 Day 5 | 0.550 Hours |
| Moxetumomab Pasudotox 40 µg/kg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox | Cycle 2 Day 1 | 0.583 Hours |
Secondary
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.
Time frame: 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)
Population: The ITT population included participants who entered into the study and treated with moxetumomab pasudotox.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moxetumomab Pasudotox 40 µg/kg | Time to Treatment Failure (TTF) Assessed by Blinded Independent Central Review | 41.5 Months |