Clinical Trial Results:
Pivotal Multicenter Trial of Moxetumomab Pasudotox in Relapsed/Refractory Hairy Cell Leukemia
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Summary
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EudraCT number |
2014-003233-26 |
Trial protocol |
GB ES BE IE DE CZ PL GR IT |
Global end of trial date |
20 Sep 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Apr 2020
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First version publication date |
12 Apr 2020
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CD-ON-CAT-8015-1053
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01829711 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
MedImmune, LLC
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Sponsor organisation address |
One MedImmune Way, Gaithersburg, United States,
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Public contact |
Priti Patel, MedImmune, LLC, +1 650-264-9079, information.center@astrazeneca.com
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Scientific contact |
Priti Patel, MedImmune, LLC, +1 650-264-9079, information.center@astrazeneca.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 Sep 2019
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Sep 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To determine the rate of durable complete response (CR) in multiply relapsed hairy cell leukemia (HCL) with moxetumomab pasudotox.
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Protection of trial subjects |
The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Apr 2013
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy | ||
Long term follow-up duration |
2 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 3
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Country: Number of subjects enrolled |
Canada: 2
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Country: Number of subjects enrolled |
Czech Republic: 1
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Country: Number of subjects enrolled |
France: 8
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Ireland: 1
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Country: Number of subjects enrolled |
Israel: 1
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Country: Number of subjects enrolled |
Italy: 8
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Country: Number of subjects enrolled |
Norway: 1
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Country: Number of subjects enrolled |
Poland: 3
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Country: Number of subjects enrolled |
Serbia: 2
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
United Kingdom: 6
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Country: Number of subjects enrolled |
United States: 35
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Worldwide total number of subjects |
80
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EEA total number of subjects |
40
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
49
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From 65 to 84 years |
31
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85 years and over |
0
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Recruitment
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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). | ||||||||||||||||||||||
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Pre-assignment
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Screening details |
Total 89 participants were screened. Out of 89 participants, 80 participants received the study treatment. | ||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||
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Arms
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Arm title
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Moxetumomab pasudotox 40 µg/kg | ||||||||||||||||||||||
Arm description |
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. | ||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||
Investigational medicinal product name |
Moxetumomab pasudotox
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Moxetumomab pasudotox 40 μg/kg was administered by IV infusion over 30 (± 10) minutes on Days 1, 3 and 5 of each 28-days cycle.
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Baseline characteristics reporting groups
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Reporting group title |
Moxetumomab pasudotox 40 µg/kg
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Moxetumomab pasudotox 40 µg/kg
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Reporting group description |
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. | ||
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End point title |
Percentage of Participants with Durable Complete Response (CR) Assessed by Blinded Independent Central Review [1] | ||||||||
End point description |
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. The Intent to treat (ITT) population was analysed for this endpoint, which included all participants who entered into the study and treated with moxetumomab pasudotox.
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End point type |
Primary
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End point timeframe |
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)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with Durable CR by Investigator's Assessment [2] | ||||||||
End point description |
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. The ITT population was analysed for this endpoint, which included all participants who entered into the study and treated with moxetumomab pasudotox.
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End point type |
Primary
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End point timeframe |
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)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with Minimal Residual Disease (MRD) Positive or MRD Negative CR Assessed by Blinded Independent Central Review | ||||||||||||
End point description |
The MRD status by blinded independent review refers specifically to results of central pathologist read of bone marrow biopsy by immunohistochemistry. CR with Positive or Negative MRD 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. 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, 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. The ITT population was analysed for this endpoint.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Participants with MRD Positive or MRD Negative CR by Investigator’s Assessment | ||||||||||||
End point description |
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. The ITT population was analysed for this endpoint.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to CR Assessed by Blinded Independent Central Review | ||||||||
End point description |
Time to CR was defined as the time from the start of moxetumomab pasudotox administration to the first documentation of CR. The ITT population was analysed for this endpoint, which included all 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.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of CR Assessed by Blinded Independent Central Review | ||||||||
End point description |
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. The ITT population was analysed for this endpoint, which included all 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.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Hematologic Remission | ||||||||
End point description |
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. The ITT population was analysed for this endpoint, which included all participants who entered into the study and treated with moxetumomab pasudotox. Duration of HR was evaluated for participants who achieved HR.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Hematologic Remission | ||||||||
End point description |
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. The ITT population was analysed for this endpoint, which included all 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.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Objective Response (OR) Assessed by Blinded Independent Central Review | ||||||||
End point description |
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 lymphadenopathy by CT or MRI (maximum diameter of spleen should be either <17 cm or have decreased by >25% from its baseline); normal CBC 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. The ITT population was analysed for this endpoint.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Objective Response by Investigator’s Assessment | ||||||||
End point description |
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 lymphadenopathy by CT or MRI (maximum diameter of spleen should be either <17 cm or have decreased by >25% from its baseline); normal CBC 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. The ITT population was analysed for this endpoint.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Objective Response Assessed by Blinded Independent Central Review | ||||||||
End point description |
Time to OR was defined as the time from the start of moxetumomab pasudotox administration to the first documentation of OR (CR or PR). The ITT population was analysed for this endpoint, which included all 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.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Objective Response Assessed by Blinded Independent Central Review | ||||||||
End point description |
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. The ITT population was analysed for this endpoint, which included all 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.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression-free Survival (PFS) Assessed by Blinded Independent Central Review | ||||||||
End point description |
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. The ITT population was analysed for this endpoint, which included all participants who entered into the study and treated with moxetumomab pasudotox.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Treatment Failure (TTF) Assessed by Blinded Independent Central Review | ||||||||
End point description |
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. The ITT population was analysed for this endpoint, which included all participants who entered into the study and treated with moxetumomab pasudotox.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | ||||||||||
End point description |
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. The safety population was analysed for this endpoint, which included all participants who received at least 1 dose of moxetumomab pasudotox.
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End point type |
Secondary
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End point timeframe |
From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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). The safety population was analysed for this endpoint, which included all participants who received at least 1 dose of moxetumomab pasudotox.
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Number of Participants With Abnormal Vital Signs Reported as TEAEs | ||||||||||||||||
End point description |
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). The safety population was analysed for this endpoint, which included all participants who received at least 1 dose of moxetumomab pasudotox.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Number of Participants with Abnormal Electrocardiogram (ECG) Reported as TEAEs | ||||||||||||||||||||||||||||||
End point description |
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). The safety population was analysed for this endpoint, which included all participants who received at least 1 dose of moxetumomab pasudotox.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||
End point title |
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox | ||||||||||||||
End point description |
The Tmax of moxetumomab pasudotox is reported. The pharmacokinetic (PK) population was analysed for this endpoint, which 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.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
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)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Maximum Observed Plasma Concentration (Cmax) of Moxetumomab Pasudotox | ||||||||||||||
End point description |
The Cmax of moxetumomab pasudotox is reported. The PK population was analysed for this endpoint, which 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.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
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)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Time of Last (Tlast) Measurable Concentration of Moxetumomab Pasudotox | ||||||||||||||
End point description |
The Tlast of moxetumomab pasudotox is reported. The PK population was analysed for this endpoint, which 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.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
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)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-last) of Moxetumomab Pasudotox | ||||||||||||||
End point description |
The AUC0-last of moxetumomab pasudotox is reported. The PK population was analysed for this endpoint, which 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.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
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)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Area Under the Plasma Concentration-time Curve From Time Zero to 3 hours (AUC0-3hr) post end of moxetumomab pasudotox | ||||||||||||||
End point description |
The AUC0-3hr of moxetumomab pasudotox is reported. The PK population was analysed for this endpoint, which 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.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
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)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Moxetumomab Pasudotox | ||||||||||||||
End point description |
The AUC0-inf of moxetumomab pasudotox is reported. The PK population was analysed for this endpoint, which 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. Here, the arbitrary number "999" signifies that 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).
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
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)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Area Under the Plasma Concentration-time Curve Extrapolated (AUCExt) of Moxetumomab Pasudotox | ||||||||||||||
End point description |
The AUCExt of moxetumomab pasudotox is reported. The PK population was analysed for this endpoint, which 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.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
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)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Systemic Clearance (CL) of Moxetumomab Pasudotox | ||||||||||||||
End point description |
The CL of moxetumomab pasudotox is reported. The PK population was analysed for this endpoint, which 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. Here, the arbitrary number "999" signifies that 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).
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
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)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Terminal Half life (t1/2) of Moxetumomab Pasudotox | ||||||||||||||
End point description |
The t1/2 of moxetumomab pasudotox is reported. The PK population was analysed for this endpoint, which 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. Here, the arbitrary number "999" signifies that 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).
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
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)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Participants With Positive Anti-drug Antibodies (ADA), Neutralizing Anti-drug Antibodies (nAb) and Specificity (CD22 and PE38) Positive to Moxetumomab Pasudotox | ||||||||||||||||
End point description |
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. The safety population was analysed for this endpoint, which included all participants who received at least 1 dose of moxetumomab pasudotox.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
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)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
For TEAEs and TESAEs: From Day 1 through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
For all-cause death data: From Day 1 through end of study (approximately 6 years)
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
|
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Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Moxetumomab pasudotox 40 µg/kg
|
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
26 Mar 2013 |
Stopping rules were updated for when participants redevelop Grade 3 or more severity non-hematologic toxicities after withholding study drug and re-challenge. Addition of the exclusion criterion for participants with clinically significant ophthalmologic findings during screening. Added ophthalmologic exam at baseline and follow-up visits. |
||
20 Feb 2014 |
Modified the secondary objectives to replace relapse-free survival with TTF. Malaria infection was added as an excluded intercurrent illness. Added the exclusion criterion for participants with history of both thromboembolism and known congenital hypercoagulable conditions, participants on high dose estrogen, and participants with clinical evidence of disseminated intravascular coagulation. Updated to state that participants who experienced Grade 4 CLS and Grade 3 HUS were to be taken of off treatment instead of off study, and specified that an event of Grade 2 or more severity of hypercalcemia with calcium level corrected for serum albumin required a delay in dosing until resolution to < Grade 2. Updated time points of PK collection. |
||
09 Jun 2014 |
Updated the length of abnormal lymphadenopathy. summarized CR duration as it is added as a secondary endpoint. Modified the eligibility criteria for participants with HCL variant and revised the eligibility criteria for prior systemic therapies. Updated the exclusion criterion regarding high dose estrogen. Revised the timing of procedures for Cycle 1 Days 1 and 5. Updated the immunogenicity evaluation. Updated the treatment plan to indicate guidelines for fluid and antihistamine administration. Added the text related to the use of non-steroidal anti-inflammatory medications. |
||
12 Aug 2014 |
Updated the AE definition for baseline laboratory abnormality. Updated the inclusion criteria for females of childbearing potential and added the inclusion criterion pertaining to non-sterilized males. Modified the inclusion criteria related to prior systemic therapies. Uncontrolled hypertension was added to the list of conditions that are exclusionary for this study. Modified the exclusion criteria for exclusion criterion related to abnormal ECGs. Updated assessments conducted at screening, during treatment cycles, and at follow-up visits. Specified the requirement for HUS resolution. Added a criterion specifying that 6 cycles of therapy are allowed; treatment delay was specified as > 2 weeks. Specified the inclusion of bone marrow examination and cross-sectional imaging as post baseline disease assessments. Modified the statement related to the replacement of enrolled but untreated participants. |
||
02 Oct 2014 |
Added to instructions for use of steroids. Updated the text for dose delays and dose modifications. Added the instruction on collection times of PK samples for participants who develop any grade of HUS. Added new sections to describe how bone aspirate for MRD would analyzed, the collection time points during the study, and where it would processed and analyzed. |
||
22 Jan 2015 |
Revised immunogenicity evaluation time points. Added immunogenicity to be in line with PK evaluation upon both diagnosis and resolution of HUS and > Grade 2 CLS. Added wording regarding HUS-like event and CLS specified in the assessment of safety section. Added section of "Peripheral Blood Disease B-cell Clone Detection". Removed reference to thrombotic microangiopathy/HUS from important potential risks and added it as an identified risk. |
||
23 Apr 2015 |
Updated the inclusion criteria for contraceptive methods. removed prior splenectomy and lymph nodes > 4 cm from the list of exclusion criteria. |
||
06 Jan 2017 |
Updated the text related to CR with or without MRD. This text was updated for the detailed procedure of central review. Updated the text related to the assessments applicable to duration of CR are relevant to duration of hematologic remission. Clarified relapse definition. Modified the text to align with the regulatory definition of PFS. |
||
29 Mar 2017 |
Updated the text reacted to concomitant medications. Modified the table of "Study Calendar for End of Treatment and Follow-up" related to the data collections of blood component transfusions and hematopoietic growth factors. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
