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| ID | Type | Description | Link |
|---|---|---|---|
| NCI-2014-02341 | Registry Identifier | CTRP (Clinical Trial Reporting Program) | |
| HEMMPD0021 | Other Identifier | OnCore | |
| P30CA124435 | U.S. NIH Grant/Contract | View source |
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Slow accrual
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| Name | Class |
|---|---|
| National Cancer Institute (NCI) | NIH |
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This phase 2 trial studies ibrutinib to see how well it works in treating patients with systemic (affecting the entire body) mastocytosis that has spread to other parts of the body and usually cannot be cured or controlled with treatment (advanced). Systemic mastocytosis is a disease in which too many mast cells (a type of immune system cell) are found throughout the body. Mast cells give off chemicals such as histamine that can cause flushing (a hot, red face), itching, abdominal cramps, muscle pain, nausea, vomiting, diarrhea, low blood pressure, and shock. Ibrutinib may stop the growth of mast cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVE:
Evaluate the response rate to ibrutinib in patients with advanced systemic mastocytosis (SM) (aggressive systemic mastocytosis [ASM] or mast cell leukemia [MCL], or SM-associated hematologic non-mast cell disorder [AHNMD]) by the end of 6 cycles (6 months).
SECONDARY OBJECTIVES:
OUTLINE:
Patients receive ibrutinib orally (PO) once daily (QD) on days 1 to 28. Treatment repeats every 28 days for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients achieving an unconfirmed or confirmed clinical improvement (CI), partial response (PR), or complete response (CR) by the end of course 6 will be permitted to continue maintenance courses of ibrutinib on an ongoing basis until loss of response/progressive disease, or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days and then every 6 months thereafter.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ibrutinib 420 mg/day | Experimental | Participants receive ibrutinib daily on days 1 to 28, at 420 mg/day in 28-day cycles |
|
| Ibrutinib 560 mg/day | Experimental | Participants receive ibrutinib daily on days 1 to 28, at 560 mg/day in 28-day cycles |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ibrutinib | Drug | Given orally in 28-day cycles |
|
| Measure | Description | Time Frame |
|---|---|---|
| Overall Response Rate (ORR) | Overall response rate (ORR) is reported as the sum of the rates of participants achieving complete remission (CR), partial remission (PR), & clinical improvement (CI). A clinical response is a response with duration of ≥ 12 weeks. CR is defined as all 4 criteria:
PR is defined as all 3 criteria with response duration ≥12 weeks, that is not CR or progressive disease:
CI is defined as any improvement in any of the above measures. | Up to 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Adverse Events | Adverse events will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, and reported as the number and percentage of participants having any adverse event; by each grade of adverse event; and by affected body systems. | 30 days |
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INCLUSION CRITERIA
EXCLUSION CRITERIA
Received any investigational agent, chemotherapy, interferon-alpha, or 2-chlorodeoxyadenosine (2-CdA, cladribine) within 30 days prior to day 1; or monoclonal antibody ≤ 6 weeks prior to first administration of study treatment (patients with an AHNMD with progressive leukocytosis who require control of their counts are permitted to receive hydroxyurea)
Diagnosis of AHNMD requiring immediate cytoreductive therapy or targeted drugs (eg, acute myeloid leukemia [AML])
History of other malignancies, except:
Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration [> 14 days] of > 10 mg/day of prednisone) within 28 days of the first dose of study drug
Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
Systemic treatment for infection completed ≤ 14 days before the first dose of study drug
Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
Known bleeding disorders (eg, severe von Willebrand's disease) or severe hemophilia
History of stroke or intracranial hemorrhage within 6 months prior to enrollment
Known history of human immunodeficiency virus (HIV) or
Active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
Major surgery within 4 weeks of first dose of study drug
Any life-threatening illness, medical condition, or organ system dysfunction that could compromise the subject's safety or put the study outcomes at undue risk
Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
Unable to swallow capsules or malabsorption syndrome
Disease significantly affecting gastrointestinal function
Resection of the stomach or small bowel
Symptomatic inflammatory bowel disease
Ulcerative colitis
Partial or complete bowel obstruction
Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
Lactating or pregnant
Unwilling or unable to participate in all required study evaluations and procedures
Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
Known hypersensitivity to any excipient contained in the drug
Received hematopoietic growth factor support within 14 days of day 1 of ibrutinib (Jehovah's witnesses may be given an erythropoiesis-stimulating agent before and during the trial in lieu of red blood cell transfusions but anemia and/or red blood cell (RBC) transfusion dependence cannot be used for response assessment in these patients)
Presence of the factor interacting with poly(A) polymerase alpha (PAPOLA) and cleavage and polyadenylation specific factor 1 (CPSF1) (FIP1L1)-platelet-derived growth factor receptor, alpha polypeptide (PDGFRalpha) fusion even with resistance to imatinib (such patients are no longer defined as systemic mastocytosis by the WHO)
Received any treatment with ibrutinib prior to study entry
The concomitant use of warfarin or other vitamin K antagonists unless felt to be of significant clinical need; low molecular weight heparin or other anticoagulants may be used instead if anticoagulation is required
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| Name | Affiliation | Role |
|---|---|---|
| Jason Gotlib | Stanford University Hospitals and Clinics | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University Hospitals and Clinics | Stanford | California | 94305 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Ibrutinib 420 mg/Day | Participants receive ibrutinib daily on days 1 to 28, at 420 mg/day in 28-day cycles Ibrutinib: Given orally |
| FG001 | Ibrutinib 560 mg/Day | Participants receive ibrutinib daily on days 1 to 28, at 560 mg/day in 28-day cycles Ibrutinib: Given orally |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Ibrutinib 420 mg/Day | Participants receive ibrutinib daily on days 1 to 28, at 420 mg/day in 28-day cycles Ibrutinib: Given orally |
| BG001 | Ibrutinib 560 mg/Day | Participants receive ibrutinib daily on days 1 to 28, at 560 mg/day in 28-day cycles Ibrutinib: Given orally |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Overall Response Rate (ORR) | Overall response rate (ORR) is reported as the sum of the rates of participants achieving complete remission (CR), partial remission (PR), & clinical improvement (CI). A clinical response is a response with duration of ≥ 12 weeks. CR is defined as all 4 criteria:
PR is defined as all 3 criteria with response duration ≥12 weeks, that is not CR or progressive disease:
CI is defined as any improvement in any of the above measures. | Posted | Count of Participants | Participants | Up to 6 months |
|
26 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ibrutinib 420 mg/Day | Participants receive ibrutinib daily on days 1 to 28, at 420 mg/day in 28-day cycles Ibrutinib: Given orally |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Increased Aspartate aminotransferase (AST) | Investigations | CTCAE (4.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jason Robert Gotlib, MD; Professor of Medicine (Hematology) | Stanford University Medical Center | 650-498-6000 | C.Langford@stanford.edu |
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| ID | Term |
|---|---|
| D034721 | Mastocytosis, Systemic |
| D007946 | Leukemia, Mast-Cell |
| ID | Term |
|---|---|
| D008415 | Mastocytosis |
| D009372 | Neoplasms, Connective Tissue |
| D018204 | Neoplasms, Connective and Soft Tissue |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| C551803 | ibrutinib |
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| Ibrutinib Pharmacokinetics (PK) | Plasma concentration-time profiles for each subject and mean plasma concentration-time profiles for each dose level will be plotted, plasma concentration data for ibrutinib at each time point will be summarized by descriptive statistics, and PK parameters such as maximum concentration (Cmax), minimum concentration, time at which the Cmax is reached, and area under the curve will be summarized with mean, geometric mean, medium, minimum, maximum, standard deviation, and coefficient of variation. | 28 days |
| Change of Mast Cell Burden | The change in the number of neoplastic mast cells in tissues (blood and/or bone marrow), ie, a measure of mast cell burden, will be assessed by immunophenotyping and/or immunohistochemistry (depending on patient and disease specifics) using mast cell markers, eg, CD25, CD30, CD117, tryptase, reticulin, Wright-Giemsa staining, and/or hematoxylin-eosin staining, in peripheral blood smears or bone marrow samples. For each participant, the data are used to collectively determine a single assessment for the number of mast cells present at baseline and after treatment. The outcome is reported as the median change in that level of mast cells, with full range, from baseline up to 2 years. | 2 years |
| Serum Tryptase Levels | Serum tryptase level is a surrogate marker for the desired histopathologic response, ie, reduction in mast cell burden. Serum tryptase levels are reported as the median of the percent reduction, with full range, from baseline up to 2 years. | 2 years |
| Total Symptom Score (TSS) | The totality of systemic mastocytosis was assessed by the total symptom score as measured by a Myeloproliferative Neoplasm Symptom Assessment Form modified for mast cell disorders [MPN-SAF (MCD)], and reported as the change in median score with standard deviation at baseline and 30 days. The MPN-SAF is a single, 27-question questionnaire that scores the following general measures on a scale of 0 (best) to 10 (worst): fatigue levels, effects of fatigue, satiety, pain, activity, concentration, dizziness, sleep, mood, anxiety, sexual function, itching, flushing, fever, weight loss, respiratory functions, diarrhea, lesions, and allergic reactions (some of these general terms may describe more than 1 assessment). The score on the MPN-SAF is the sum total of all 27 scores, and the range of scores is from a minimum of 0 (best; symptoms for all assessment absent) to a maximum of 270 (worst; score of 10 on all assessments). | 30 days |
| Change in Quality of Life (QoL) | The quality of life (QoL) component of the Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF) modified for mast cell symptoms, a scale of life quality ranking from 0 (best) to 10 (worst), was assessed at baseline and after 1 cycle of ibrutinib treatment (30 days), and reported as the median change in score with standard deviation. | 30 days |
| Duration of Response (DoR) | Duration of response (DoR) was assessed through 2 years of treatment, and reported as the median with standard deviation, with response duration censored at last response assessment in the event of death or progression not documented. | 2 years |
| Time-to-Response (TTR) | Time-to-response (TTR) was assessed through 2 years of treatment, and reported as the median with standard deviation, censored at last response assessment in the event of death or progression not documented. | 2 years |
| Progression-free Survival (PFS) | Participants were assessed for progression-free survival (PFS) from the start of treatment through 2 years of treatment. The outcome is reported as the number of participants who were alive without disease progression after 2 years of treatment. | 2 years |
| Overall Survival (OS) | Overall survival (OS) was assessed through 2 years of treatment, and recorded as the time from the start of treatment to either progression or death, with values censored at the last response assessment if the participant did not progress or die during that period. OS is reported as reported as the median with standard deviation. | 26 months |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Ibrutinib 420 mg/Day |
Participants receive ibrutinib daily on days 1 to 28, at 420 mg/day in 28-day cycles Ibrutinib: Given orally |
| OG001 | Ibrutinib 560 mg/Day | Participants receive ibrutinib daily on days 1 to 28, at 560 mg/day in 28-day cycles Ibrutinib: Given orally |
|
|
| Secondary | Number of Participants With Adverse Events | Adverse events will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, and reported as the number and percentage of participants having any adverse event; by each grade of adverse event; and by affected body systems. | All study participants are included in this analysis. | Posted | Count of Participants | Participants | 30 days |
|
|
|
| Secondary | Ibrutinib Pharmacokinetics (PK) | Plasma concentration-time profiles for each subject and mean plasma concentration-time profiles for each dose level will be plotted, plasma concentration data for ibrutinib at each time point will be summarized by descriptive statistics, and PK parameters such as maximum concentration (Cmax), minimum concentration, time at which the Cmax is reached, and area under the curve will be summarized with mean, geometric mean, medium, minimum, maximum, standard deviation, and coefficient of variation. | Because this study terminated with low total accrual, the funding sponsor elected not to analyze the samples for ibrutinib levels. There are no pharmacokinetics values on which to conduct the outcome analysis. | Posted | 28 days |
|
|
| Secondary | Change of Mast Cell Burden | The change in the number of neoplastic mast cells in tissues (blood and/or bone marrow), ie, a measure of mast cell burden, will be assessed by immunophenotyping and/or immunohistochemistry (depending on patient and disease specifics) using mast cell markers, eg, CD25, CD30, CD117, tryptase, reticulin, Wright-Giemsa staining, and/or hematoxylin-eosin staining, in peripheral blood smears or bone marrow samples. For each participant, the data are used to collectively determine a single assessment for the number of mast cells present at baseline and after treatment. The outcome is reported as the median change in that level of mast cells, with full range, from baseline up to 2 years. | The result was only calculated for those participants for whom a post-treatment mast cell level could be determined. | Posted | Median | Full Range | Percent reduction of mast cells | 2 years |
|
|
|
| Secondary | Serum Tryptase Levels | Serum tryptase level is a surrogate marker for the desired histopathologic response, ie, reduction in mast cell burden. Serum tryptase levels are reported as the median of the percent reduction, with full range, from baseline up to 2 years. | Results were determined for all participants. | Posted | Median | Full Range | Percent reduction serum tryptase level | 2 years |
|
|
|
| Secondary | Total Symptom Score (TSS) | The totality of systemic mastocytosis was assessed by the total symptom score as measured by a Myeloproliferative Neoplasm Symptom Assessment Form modified for mast cell disorders [MPN-SAF (MCD)], and reported as the change in median score with standard deviation at baseline and 30 days. The MPN-SAF is a single, 27-question questionnaire that scores the following general measures on a scale of 0 (best) to 10 (worst): fatigue levels, effects of fatigue, satiety, pain, activity, concentration, dizziness, sleep, mood, anxiety, sexual function, itching, flushing, fever, weight loss, respiratory functions, diarrhea, lesions, and allergic reactions (some of these general terms may describe more than 1 assessment). The score on the MPN-SAF is the sum total of all 27 scores, and the range of scores is from a minimum of 0 (best; symptoms for all assessment absent) to a maximum of 270 (worst; score of 10 on all assessments). | Results were analyzed for all participants. | Posted | Median | Standard Deviation | score on a scale | 30 days |
|
|
|
| Secondary | Change in Quality of Life (QoL) | The quality of life (QoL) component of the Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF) modified for mast cell symptoms, a scale of life quality ranking from 0 (best) to 10 (worst), was assessed at baseline and after 1 cycle of ibrutinib treatment (30 days), and reported as the median change in score with standard deviation. | Results were analyzed for all participants. | Posted | Median | Standard Deviation | score on a scale | 30 days |
|
|
|
| Secondary | Duration of Response (DoR) | Duration of response (DoR) was assessed through 2 years of treatment, and reported as the median with standard deviation, with response duration censored at last response assessment in the event of death or progression not documented. | No participants achieved clinical response per protocol (minimum of any clinical improvement ≥ 12 weeks). On that basis, the overall duration of that response can not be determined. | Posted | 2 years |
|
|
| Secondary | Time-to-Response (TTR) | Time-to-response (TTR) was assessed through 2 years of treatment, and reported as the median with standard deviation, censored at last response assessment in the event of death or progression not documented. | No participants achieved clinical response per protocol (minimum of any clinical improvement ≥ 12 weeks). On that basis, the time to achieve per-protocol clinical response can not be determined. | Posted | 2 years |
|
|
| Secondary | Progression-free Survival (PFS) | Participants were assessed for progression-free survival (PFS) from the start of treatment through 2 years of treatment. The outcome is reported as the number of participants who were alive without disease progression after 2 years of treatment. | Results were analyzed for all participants. Values were censored at the last assessment if the participant was lost-to-follow-up or otherwise did not have a 2-year assessment. | Posted | Count of Participants | Participants | 2 years |
|
|
|
| Secondary | Overall Survival (OS) | Overall survival (OS) was assessed through 2 years of treatment, and recorded as the time from the start of treatment to either progression or death, with values censored at the last response assessment if the participant did not progress or die during that period. OS is reported as reported as the median with standard deviation. | The single patient receiving ibrutinib 560 mg/day was censored per protocol. | Posted | Mean | 95% Confidence Interval | months | 26 months |
|
|
|
| 1 |
| 3 |
| 1 |
| 3 |
| 3 |
| 3 |
| EG001 | Ibrutinib 560 mg/Day | Participants receive ibrutinib daily on days 1 to 28, at 560 mg/day in 28-day cycles Ibrutinib: Given orally | 0 | 1 | 0 | 1 | 1 | 1 |
| Increased alanine aminotransferase (ALT) | Investigations | CTCAE (4.0) | Systematic Assessment |
|
| Increased total bilirubin | Investigations | CTCAE (4.0) | Systematic Assessment |
|
| Increased alkaline phosphatase | Investigations | CTCAE (4.0) | Systematic Assessment |
|
| Acute hepatitis A infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
|
| Disease progression | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| Cryptococcal pneumonia | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
|
| Death | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Mouth sores | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Tongue sensitivity | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Increased fatigue | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| Cold symptoms | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| Edema, limbs | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| Hypocalcemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
|
| Iron total, decreased | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
|
| Upper respiratory infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
|
| Basal cell carcinoma, scalp | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Erythmateous rash | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Skin changes, fingertips | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Skin lesion, forearm | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Increased flushing | Vascular disorders | CTCAE (4.0) | Systematic Assessment |
|
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| D009369 | Neoplasms |
| D000090362 | Mast Cell Activation Disorders |
| D007154 | Immune System Diseases |
| D007938 | Leukemia |
| D015470 | Leukemia, Myeloid, Acute |
| D007951 | Leukemia, Myeloid |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| Any Grade 2 Adverse Event (moderate) |
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| Any Grade 3 Adverse Event (severe) |
|
| Any Grade 4 Adverse Event (life-threatening) |
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| Any Grade 5 Adverse Event (death) |
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| Any Blood or Lymphatic System Disorder |
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| Any Gastrointestinal Disorder |
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| Any General Disorder |
|
| Any Infection or Infestation |
|
| Any Investigations |
|
| Any Metabolism or Nutrition Disorder |
|
| Any Musculoskeletal or Connective Tissue Disorder |
|
| Any Nervous System Disorder |
|
| Any Skin or Subcutaneous Tissue Disorder |
|
| Any Vascular Disorder |
|