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| ID | Type | Description | Link |
|---|---|---|---|
| MM-121 |
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| Name | Class |
|---|---|
| Sanofi | INDUSTRY |
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This study was a Phase 1 and pharmacologic open-labeled dose-escalation trial using a "3+3" design to determine maximum tolerated dose/recommended Phase 2 dose.
Successive cohorts of three or more patients were treated at escalating doses until a maximum tolerated dose/recommended phase 2 dose was identified. The study initially explored a dosing schedule every 7-days, which may have been modified to longer intervals under certain circumstances but did not expand to more than weekly. When the maximum tolerated dose/recommended Phase 2 dose was identified, an Expansion Cohort was enrolled at that dose to further characterize safety and to explore pharmacodynamic endpoints. There were 3 sites that participated.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dose Escalation | Experimental | Cohorts of escalating doses of MM-121 administered IV QW to determine MTD or RP2D + expansion cohort at MTD/RP2D |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MM-121 | Drug | Dose escalation Frequency - once weekly |
|
| Measure | Description | Time Frame |
|---|---|---|
| Objective Response Rate and Duration | To determine the number of patients reporting an objective response using RECIST v 1.1 where a Partial Response is defined as a >20% decrease in tumor burden from baseline and a Complete Response is defined as complete disappearance of tumor burden from baseline. Duration of response is defined as the length of time in weeks from observation of response until progression. NOTE: because no patients experienced an objective response as shown below, duration of response is not presented. No duration of response could be measured. | Time from first dose to date of progression, with a median of 7.1 weeks |
| Determine the Maximum Tolerated Dose Dependent on Reports of Dose-limiting Toxicities | Using a 3+3 dose escalation model, the maximum tolerated dose was determined by assessing dose-limiting toxicities in each cohort from cohort 1-6. Cohort 1 began at 3.2 mg/kg IV QW and the dose escalated in separate cohorts from 6 mg/kg IV QW, 10 mg/kg IV QW, 15 mg/kg IV QW, 20 mg/kg IV QW, to the highest scheduled testing dose at 40 mg/kg one-time loading dose on cycle 1, week 1 followed by 20 mg/kg IV QW maintenance doses. If 3 patients were treated and passed the observation window, escalation to the next cohort was initiated. If a DLT was reported, 3-4 additional patients were enrolled and observed. If a DLT was observed in the expanded cohort, this dose was considered to be the maximum tolerated dose. The maximum tolerated dose was defined at the cohort in which two dose-limiting toxicities were observed, or as the highest target dose tested in the absence of DLTs. The determined MTD was considered the Recommended Phase 2 Dose and was used to open the expansion cohort. | From date of first dose to 30 days after termination, the longest 47 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| To Describe the Dose-limiting Toxicity of MM-121 as a Monotherapy | To establish the safety of escalating doses of MM-121 administered as a monotherapy in order to determine the recommended phase 2 dose. Dose-escalation conducted using standard 3+3 model to determine maximum tolerated dose. Reports of Dose-Limiting Toxicities (DLTs) were assessed to determine the MTD to be used for the expansion cohort. DLTs were not measured in the Expansion Cohort. |
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Inclusion Criteria:
Patients must have histologically or cytologically confirmed advanced solid tumors that have recurred or progressed following standard therapy, or that have not responded to standard therapy, or for which there is no standard therapy, or who are not candidates for standard therapy
Patients must be > 18 years of age
Patients or their legal representatives must be able to understand and sign an informed consent form
Patients must have evaluable or measurable tumor(s)
In addition, patients to be enrolled the Expansion Cohort must have/be:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Crystal Denlinger, MD | Fox Chase Cancer Center | Principal Investigator |
| Kwok Kin Wong, MD | Dana-Farber Cancer Institute | Principal Investigator |
| Keedy L Vicki, MD | Vanderbilt University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dana-Farber Cancer Institute | Boston | Massachusetts | 02115-6084 | United States | ||
| Fox Chase Cancer Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34250553 | Derived | Denlinger CS, Keedy VL, Moyo V, MacBeath G, Shapiro GI. Phase 1 dose escalation study of seribantumab (MM-121), an anti-HER3 monoclonal antibody, in patients with advanced solid tumors. Invest New Drugs. 2021 Dec;39(6):1604-1612. doi: 10.1007/s10637-021-01145-y. Epub 2021 Jul 11. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Dose Escalation: Cohort 1 | MM-121: 3.2 mg/kg IV QW |
| FG001 | Dose Escalation: Cohort 2 | MM-121: 6 mg/kg IV QW |
| FG002 | Dose Escalation: Cohort 3 | MM-121: 10 mg/kg IV QW |
| FG003 | Dose Escalation: Cohort 4 | MM-121: 15 mg/kg IV QW |
| FG004 | Dose Escalation: Cohort 5 | MM-121: 20 mg/kg IV QW |
| FG005 | Dose Escalation: Cohort 6 | MM-121: 40 mg/kg IV loading dose on C1W1 followed by weekly maintenance doses of 20 mg/kg IV QW |
| FG006 | Expansion Cohort | (Highest tested dose in absence of reaching maximum tolerated dose) 40 mg/kg IV loading dose on C1W1 followed by weekly maintenance doses of 20 mg/kg IV QW |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | MM-121 Dose Escalation | MM-121: Dose escalation Frequency - once weekly IV |
| BG001 | MM-121 Expansion Cohort | Expansion cohort at recommended phase 2 dose |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Objective Response Rate and Duration | To determine the number of patients reporting an objective response using RECIST v 1.1 where a Partial Response is defined as a >20% decrease in tumor burden from baseline and a Complete Response is defined as complete disappearance of tumor burden from baseline. Duration of response is defined as the length of time in weeks from observation of response until progression. NOTE: because no patients experienced an objective response as shown below, duration of response is not presented. No duration of response could be measured. | Posted | Number | participants with objective response | Time from first dose to date of progression, with a median of 7.1 weeks |
|
AEs were collected from a patient's first dose until 30 days after treatment termination. SAEs were collected from time of informed consent until 30 days after termination. If related, events could be reported at any time after termination.
All related AEs ongoing at the time of treatment discontinuation were followed until resolution. Investigators were to report any AEs/SAEs assumed to be related any time, even if occurring more than 30 days after last dose. Though different for each patient, on average, patients could be followed for related AEs/SAEs for ~1 year after termination.
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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 | All Participatants | Dose Escalation cohort participants + Expansion cohort participants |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Disease Progression | General disorders | MedDRA (13.1) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Trial Manager | Merrimack Pharmaceuticals, Inc. | 617-441-1000 | smathews@merrimack.com |
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| ID | Term |
|---|---|
| D009369 | Neoplasms |
| C564369 | Lethal Congenital Contracture Syndrome 2 |
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| ID | Term |
|---|---|
| C000589319 | seribantumab |
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| From date of first dose to 30 days after termination, the longest 47 weeks |
| To Determine the Pharmacokinetic and Immunogenicity Parameters of MM-121 | Pharmacokinetic (PK) evaluation was performed on plasma samples obtained weekly for the first cycle of the study and then on day 1 of each additional cycle to assess pre-treatment trough concentrations of MM-121. The maximum observed concentration (Cmax) is presented and was calculated usig Non-compartmental analysis (NCA). Serum levels of MM-121 were measured at a central lab using an enzyme-linked immunosorbent assay (ELISA). Data is presented per dose level of MM-121 (3.2 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 40/20 mg/kg). Immunogenicity data is not available. | At Cycle 1, Week 1 pre-treatment, at the end of the infusion, and 2, 4, 8, 24, 48 and 72 hours after starting the infusion; pre-dose collections on Cycle 1, Week 2 and Cycle 2, Week 1 for all patients |
| To Determine the Pharmacokinetic Parameters of MM-121 | Pharmacokinetic (PK) evaluation was performed on plasma samples obtained weekly for the first cycle of the study and then on day 1 of each additional cycle to assess pre-treatment trough concentrations of MM-121. The AUC is presented and was calculated usig Non-compartmental analysis (NCA). Serum levels of MM-121 were measured at a central lab using an enzyme-linked immunosorbent assay (ELISA). Data is presented per dose level of MM-121 (3.2 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 40/20 mg/kg). | At Cycle 1, Week 1 pre-treatment, at the end of the infusion, and 2, 4, 8, 24, 48 and 72 hours after starting the infusion; pre-dose collections on Cycle 1, Week 2 and Cycle 2, Week 1 for all patients |
| Philadelphia |
| Pennsylvania |
| 19111 |
| United States |
| The Vanderbilt-Ingram Cancer Center | Nashville | Tennessee | 37232 | United States |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
|
MM-121 6 mg/kg IV QW |
| OG002 | Dose Escalation: Cohort 3 | MM-121 10 mg/kg IV QW |
| OG003 | Dose Escalation: Cohort 4 | MM-121 15 mg/kg IV QW |
| OG004 | Dose Escalation: Cohort 5 | MM-121 20 mg/kg IV QW |
| OG005 | Dose Escalation: Cohort 6 | MM-121 40 mg/kg IV loading dose on Cycle 1, Week 1 followed by 20 mg/kg IV weekly maintenance doses |
| OG006 | MM-121 Expansion Cohort | Expansion cohort at recommended phase 2 dose |
|
|
| Primary | Determine the Maximum Tolerated Dose Dependent on Reports of Dose-limiting Toxicities | Using a 3+3 dose escalation model, the maximum tolerated dose was determined by assessing dose-limiting toxicities in each cohort from cohort 1-6. Cohort 1 began at 3.2 mg/kg IV QW and the dose escalated in separate cohorts from 6 mg/kg IV QW, 10 mg/kg IV QW, 15 mg/kg IV QW, 20 mg/kg IV QW, to the highest scheduled testing dose at 40 mg/kg one-time loading dose on cycle 1, week 1 followed by 20 mg/kg IV QW maintenance doses. If 3 patients were treated and passed the observation window, escalation to the next cohort was initiated. If a DLT was reported, 3-4 additional patients were enrolled and observed. If a DLT was observed in the expanded cohort, this dose was considered to be the maximum tolerated dose. The maximum tolerated dose was defined at the cohort in which two dose-limiting toxicities were observed, or as the highest target dose tested in the absence of DLTs. The determined MTD was considered the Recommended Phase 2 Dose and was used to open the expansion cohort. | All participants in the 6 cohorts of dose escalation | Posted | Number | mg/kg | From date of first dose to 30 days after termination, the longest 47 weeks |
|
|
|
| Secondary | To Describe the Dose-limiting Toxicity of MM-121 as a Monotherapy | To establish the safety of escalating doses of MM-121 administered as a monotherapy in order to determine the recommended phase 2 dose. Dose-escalation conducted using standard 3+3 model to determine maximum tolerated dose. Reports of Dose-Limiting Toxicities (DLTs) were assessed to determine the MTD to be used for the expansion cohort. DLTs were not measured in the Expansion Cohort. | Posted | Number | participants reporting DLTs | From date of first dose to 30 days after termination, the longest 47 weeks |
|
|
|
| Secondary | To Determine the Pharmacokinetic and Immunogenicity Parameters of MM-121 | Pharmacokinetic (PK) evaluation was performed on plasma samples obtained weekly for the first cycle of the study and then on day 1 of each additional cycle to assess pre-treatment trough concentrations of MM-121. The maximum observed concentration (Cmax) is presented and was calculated usig Non-compartmental analysis (NCA). Serum levels of MM-121 were measured at a central lab using an enzyme-linked immunosorbent assay (ELISA). Data is presented per dose level of MM-121 (3.2 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 40/20 mg/kg). Immunogenicity data is not available. | All patients. NOTE: There are 22 patients included in the final cohort (4 patients in dose escalation portion Cohort 6 + 18 patients in Expansion Cohort), as PK analysis was performed per dose level and not per cohort. Cohort 6 and the Expansion Cohort were administered the same dose, and therefore the analysis reflects all 22 patients. | Posted | Geometric Mean | Geometric Coefficient of Variation | ug/mL | At Cycle 1, Week 1 pre-treatment, at the end of the infusion, and 2, 4, 8, 24, 48 and 72 hours after starting the infusion; pre-dose collections on Cycle 1, Week 2 and Cycle 2, Week 1 for all patients |
|
|
|
| Secondary | To Determine the Pharmacokinetic Parameters of MM-121 | Pharmacokinetic (PK) evaluation was performed on plasma samples obtained weekly for the first cycle of the study and then on day 1 of each additional cycle to assess pre-treatment trough concentrations of MM-121. The AUC is presented and was calculated usig Non-compartmental analysis (NCA). Serum levels of MM-121 were measured at a central lab using an enzyme-linked immunosorbent assay (ELISA). Data is presented per dose level of MM-121 (3.2 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 40/20 mg/kg). | All patients. NOTE: There are 22 patients included in the final cohort (4 patients in dose escalation portion Cohort 6 + 18 patients in Expansion Cohort), as PK analysis was performed per dose level and not per cohort. Cohort 6 and the Expansion Cohort were administered the same dose, and therefore the analysis reflects all 22 patients. | Posted | Geometric Mean | Geometric Coefficient of Variation | hr* ug/mL | At Cycle 1, Week 1 pre-treatment, at the end of the infusion, and 2, 4, 8, 24, 48 and 72 hours after starting the infusion; pre-dose collections on Cycle 1, Week 2 and Cycle 2, Week 1 for all patients |
|
|
|
| 14 |
| 43 |
| 43 |
| 43 |
| Pyrexia | General disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Abdominal Pain | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Abdominal Pain Lower | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Pancreatitis Acute | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Malignant Neoplasm Progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (13.1) | Non-systematic Assessment |
|
| Tumor Pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (13.1) | Non-systematic Assessment |
|
| Hydronephrosis | Renal and urinary disorders | MedDRA (13.1) | Non-systematic Assessment |
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| Renal Failure | Renal and urinary disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Ureteric Obstruction | Renal and urinary disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Dyspnea Exertional | Respiratory, thoracic and mediastinal disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Pleural Effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Arrhythmia | Cardiac disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Flank Pain | Musculoskeletal and connective tissue disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Confusional State | Psychiatric disorders | MedDRA (13.1) | Non-systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA (13.1) | Non-systematic Assessment |
|
|
| Diarrhea | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Vomiting | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Abdominal Pain | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Constipation | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Decreased Appetite | Metabolism and nutrition disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Hypokalemia | Metabolism and nutrition disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Hyperglycemia | Metabolism and nutrition disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Hypoalbuminemia | Metabolism and nutrition disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Hypomagnesemia | Metabolism and nutrition disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Hypocalcemia | Metabolism and nutrition disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Hyponatremia | Metabolism and nutrition disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Hemoglobin Decreased | Investigations | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Weight Decreased | Investigations | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Blood Alkaline Phosphatase Increased | Investigations | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Aspartate Aminotransferase Increased | Investigations | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Activated Partial Thrombostatin Time Prolonged | Investigations | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Blood Creatinine Increased | Investigations | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Ejection Fraction Decreased | Investigations | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Electrocardiogram Qt Prolonged | Investigations | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Fatigue | General disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Disease Progression | General disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Peripheral Edema | General disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Asthenia | General disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Chills | General disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Back Pain | Musculoskeletal and connective tissue disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Muscle Spasms | Musculoskeletal and connective tissue disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Musculoskeletal Pain | Musculoskeletal and connective tissue disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Flank Pain | Musculoskeletal and connective tissue disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Pain in Extremity | Musculoskeletal and connective tissue disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Dyspnea Exertional | Respiratory, thoracic and mediastinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Rhinitis Allergic | Respiratory, thoracic and mediastinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Wheezing | Respiratory, thoracic and mediastinal disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Dizziness | Nervous system disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Headache | Nervous system disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Anemia | Blood and lymphatic system disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Urinary Tract Infection | Infections and infestations | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
| Hypotension | Vascular disorders | MedDRA (13.1) | Non-systematic Assessment | Any Relationship |
|
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