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| ID | Type | Description | Link |
|---|---|---|---|
| NCI-2021-08786 | Other Identifier | CTRP | |
| KPT-9274 | Other Identifier | Karyopharm Theraeutics Inc. |
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| Name | Class |
|---|---|
| Karyopharm Therapeutics Inc | INDUSTRY |
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This study will evaluate the safety and tolerability of oral KPT-9274 for the treatment of patients with relapsed or refractory acute myeloid leukemia.
KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| De-escalation Cohort; 20mg | Active Comparator | For the purposes of dose escalation decisions, a standard 3+3 dose escalation design will be used.The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. If the MTD is exceeded at cohort 1, de-escalation to cohort 0 (20 mg) will occur. If the MTD is not exceeded in cohort 1, dose escalation will continue based on a standard 3+3 design at the dose levels. |
|
| Cohort 1; 30 mg | Active Comparator | The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. |
|
| Cohort 2; 40mg | Active Comparator | Dose escalation to 40 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. |
|
| Cohort 3; 60mg | Active Comparator | Dose escalation to 60 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| KPT-9274 | Drug | KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Dose escalation will continue until the MTD is determined. The MTD is defined as the highest dose at which ≤1 patient experiences a DLT in Cycle 1. Count of participants who did not experience a DLT are listed in outcome measure data table. | 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| Count of Participants Who Did Not Experience a DLT Are Listed in the Outcome Measure Data Table | A RP2D equal to or less than the MTD will be declared after the MTD is determined and will be used for the Dose Expansion Phase, if conducted. After the RP2D is determined, a dose expansion phase, of up to 10 additional patients, might be conducted, in which a preliminary determination of efficacy will be conducted, using the ELN criteria. |
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Inclusion Criteria:
Written informed consent obtained prior to any study related procedures required solely for this research study.
Age ≥18 years.
Patients with WHO-confirmed non-APL AML who have not responded to or relapsed after at least one prior therapy and for whom no standard therapy that may provide clinical benefit is available.
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
Adequate hepatic function:
Adequate renal function: estimated creatinine clearance of ≥ 60 mL/min, calculated using CKD-EPI Creatinine Equation (2021). https://www.kidney.org/content/ckd-epi-creatinine-equation-2021
Female patients of child-bearing potential must agree to use dual methods of contraception (including one highly effective and one effective method of contraception) and have a negative serum pregnancy test at Screening. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose.
8. Male patients must use 2 highly effective methods of contraception if sexually active with a female of child-bearing potential, during treatment with KPT-9724, during a period of 2 weeks (5 half-lives) after the last dose of KPT-9724 plus a period of 3 months. (for 3.5 months after their last dose of KPT-9724). Fertile male patients must agree to refrain from sperm donation from first dose until at least 3.5 months following the last dose of KPT-9724.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Daniel Pollyea, MD | University of Colorado, Denver | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado Hospital | Aurora | Colorado | 80045 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32822582 | Result | Jones CL, Stevens BM, Pollyea DA, Culp-Hill R, Reisz JA, Nemkov T, Gehrke S, Gamboni F, Krug A, Winters A, Pei S, Gustafson A, Ye H, Inguva A, Amaya M, Minhajuddin M, Abbott D, Becker MW, DeGregori J, Smith CA, D'Alessandro A, Jordan CT. Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells. Cell Stem Cell. 2020 Nov 5;27(5):748-764.e4. doi: 10.1016/j.stem.2020.07.021. Epub 2020 Aug 20. |
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| ID | Title | Description |
|---|---|---|
| FG000 | De-escalation Cohort; 20mg | For the purposes of dose escalation decisions, a standard 3+3 dose escalation design will be used.The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. If the MTD is exceeded at cohort 1, de-escalation to cohort 0 (20 mg) will occur. If the MTD is not exceeded in cohort 1, dose escalation will continue based on a standard 3+3 design at the dose levels. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| FG001 | Cohort 1; 30 mg | The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| FG002 | Cohort 2; 40mg | Dose escalation to 40 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| FG003 | Cohort 3; 60mg | Dose escalation to 60 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| FG004 | Cohort 4; 80mg | Dose escalation to 80 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| FG005 | Cohort 5; 100mg | Dose escalation to 100 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
No patients de-escalated lower than cohort 1 dose. Due to DLTs, no patients treated at cohort 4 or 5 dose level.
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| ID | Title | Description |
|---|---|---|
| BG000 | De-escalation Cohort; 20mg | For the purposes of dose escalation decisions, a standard 3+3 dose escalation design will be used.The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. If the MTD is exceeded at cohort 1, de-escalation to cohort 0 (20 mg) will occur. If the MTD is not exceeded in cohort 1, dose escalation will continue based on a standard 3+3 design at the dose levels. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | 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 | Maximum Tolerated Dose (MTD) | Dose escalation will continue until the MTD is determined. The MTD is defined as the highest dose at which ≤1 patient experiences a DLT in Cycle 1. Count of participants who did not experience a DLT are listed in outcome measure data table. | No descalation cohort less than cohort 1 dose was needed. Due to DLTs, no patients enrolled to cohort 4 or 5. | Posted | Number | participants | 28 days |
|
Adverse Events will be reported and recorded in the eCRF from the time of the first dose of study drug through 30 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurs first. This is patient-dependent based on the # of cycles they complete, with an average of 1 cycle completed or approximately 58 days to report Adverse Events.
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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 | De-escalation Cohort; 20mg | For the purposes of dose escalation decisions, a standard 3+3 dose escalation design will be used.The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. If the MTD is exceeded at cohort 1, de-escalation to cohort 0 (20 mg) will occur. If the MTD is not exceeded in cohort 1, dose escalation will continue based on a standard 3+3 design at the dose levels. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Alkaline phosphatase increased | Investigations | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Daniel Pollyea | University of Colorado | (303) 724-9562 | DANIEL.POLLYEA@CUANSCHUTZ.EDU |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 29, 2025 | Oct 21, 2025 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jun 4, 2025 | Oct 21, 2025 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| C000622300 | KPT-9274 |
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During dose escalation, patients will receive oral KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28-day cycle, and the first dose cohort will be 30 mg. Subsequent dose escalation cohorts, as well as a de-escalation cohort, will be administered. Dose escalation will continue until the MTD is determined. The MTD is defined as the highest dose at which ≤1 patient experiences a DLT in Cycle 1. A RP2D equal to or less than the MTD will be declared and used for the Dose Expansion Phase, if conducted.
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| Cohort 4; 80mg |
| Active Comparator |
Dose escalation to 80 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. |
|
| Cohort 5; 100mg | Active Comparator | Dose escalation to 100 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. |
|
|
| 28 days |
| BG001 | Cohort 1; 30 mg | The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| BG002 | Cohort 2; 40mg | Dose escalation to 40 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| BG003 | Cohort 3; 60mg | Dose escalation to 60 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| BG004 | Cohort 4; 80mg | Dose escalation to 80 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| BG005 | Cohort 5; 100mg | Dose escalation to 100 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| BG006 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| OG001 | Cohort 1; 30 mg | The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| OG002 | Cohort 2; 40mg | Dose escalation to 40 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| OG003 | Cohort 3; 60mg | Dose escalation to 60 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| OG004 | Cohort 4; 80mg | Dose escalation to 80 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
| OG005 | Cohort 5; 100mg | Dose escalation to 100 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. |
|
|
|
| Secondary | Count of Participants Who Did Not Experience a DLT Are Listed in the Outcome Measure Data Table | A RP2D equal to or less than the MTD will be declared after the MTD is determined and will be used for the Dose Expansion Phase, if conducted. After the RP2D is determined, a dose expansion phase, of up to 10 additional patients, might be conducted, in which a preliminary determination of efficacy will be conducted, using the ELN criteria. | No descalation cohort less than cohort 1 dose was needed. Due to DLTs, no patients enrolled to cohort 4 or 5. | Posted | Count of Participants | Participants | 28 days |
|
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|
|
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| EG001 | Cohort 1; 30 mg | The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. | 5 | 5 | 2 | 5 | 5 | 5 |
| EG002 | Cohort 2; 40mg | Dose escalation to 40 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. | 6 | 7 | 3 | 7 | 7 | 7 |
| EG003 | Cohort 3; 60mg | Dose escalation to 60 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. | 4 | 4 | 3 | 4 | 4 | 4 |
| EG004 | Cohort 4; 80mg | Dose escalation to 80 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG005 | Cohort 5; 100mg | Dose escalation to 100 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions. KPT-9274: KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML. | 0 | 0 | 0 | 0 | 0 | 0 |
| Arthralgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Infections and infestations - Other, specify | Infections and infestations | Systematic Assessment | Covid-19 Infection |
|
| Infections and infestations - Other, specify | Infections and infestations | Systematic Assessment | C. diff infection |
|
| Lung infection | Infections and infestations | Systematic Assessment |
|
| Multi-organ failure | General disorders | Systematic Assessment |
|
| Sepsis | Infections and infestations | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Anorexia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Bacteremia | Infections and infestations | Systematic Assessment |
|
| Blood and lymphatic system disorders - Other, specify | Blood and lymphatic system disorders | Systematic Assessment | Haptoglobin Increase |
|
| Blood and lymphatic system disorders - Other, specify | Blood and lymphatic system disorders | Systematic Assessment | Protein Total Serum Decreased |
|
| Blood and lymphatic system disorders - Other, specify | Blood and lymphatic system disorders | Systematic Assessment | Uric Acid Decreased |
|
| Blood and lymphatic system disorders - Other, specify | Blood and lymphatic system disorders | Systematic Assessment | White Blood Cell Increased |
|
| Blood and lymphatic system disorders - Other, specify | Blood and lymphatic system disorders | Systematic Assessment | Chloride Serum Increased |
|
| Blood and lymphatic system disorders - Other, specify | Blood and lymphatic system disorders | Systematic Assessment | Monocytes Decreased |
|
| Blood and lymphatic system disorders - Other, specify | Blood and lymphatic system disorders | Systematic Assessment | Increased Cardiac Troponin I |
|
| Blood bicarbonate decreased | Investigations | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | Systematic Assessment |
|
| Blood lactate dehydrogenase increased | Investigations | Systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Bruising | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Cardiac arrest | Cardiac disorders | Systematic Assessment |
|
| Cardiac disorders - Other, specify | Cardiac disorders | Systematic Assessment | CPK Decrease |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Cough | General disorders | Systematic Assessment |
|
| Cystitis noninfective | Renal and urinary disorders | Systematic Assessment |
|
| Depression | Psychiatric disorders | Systematic Assessment |
|
| Device related infection | Infections and infestations | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Dizziness | Immune system disorders | Systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Eczema | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Edema limbs | General disorders | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Erythema multiforme | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Eye disorders - Other, specify | Eye disorders | Systematic Assessment | scleral icterus |
|
| Eye disorders - Other, specify | Eye disorders | Systematic Assessment | Posterior Vitreus Detachment |
|
| Fall | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Gastrointestinal disorders - Other, specify | Gastrointestinal disorders | Systematic Assessment | blackening gums |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | Appetite change |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | mild nasal swelling |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | toenail fungus |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | carbon dioxide decrease |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | bleeding gums |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | activity change |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | forgetfulness |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | Intermittent decreased total protein |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | left leg edeuma |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | lightheadedness |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | Arthralgia |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | decreased protein |
|
| General disorders and administration site conditions - Other, specify | General disorders | Systematic Assessment | increased chlorine |
|
| Generalized edema | General disorders | Systematic Assessment |
|
| Hallucinations | Psychiatric disorders | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperkalemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypermagnesemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperphosphatemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperuricemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypoalbuminemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypocalcemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypoglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypokalemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypomagnesemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypophosphatemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypotension | Vascular disorders | Systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Ileus | Gastrointestinal disorders | Systematic Assessment |
|
| Investigations - Other, specify | Investigations | Systematic Assessment | BUN Increased |
|
| Investigations - Other, specify | Investigations | Systematic Assessment | activity change |
|
| Investigations - Other, specify | Investigations | Systematic Assessment | Appetite change (Poor appetite) |
|
| Investigations - Other, specify | Investigations | Systematic Assessment | aspartate aminotransferase decrease |
|
| Investigations - Other, specify | Investigations | Systematic Assessment | hyperbilirubinemia |
|
| Investigations - Other, specify | Infections and infestations | Systematic Assessment | joint swelling |
|
| Investigations - Other, specify | Investigations | Systematic Assessment | mouth sores |
|
| Investigations - Other, specify | Investigations | Systematic Assessment | pneumonia |
|
| Investigations - Other, specify | Investigations | Systematic Assessment | post arrest mixed shock |
|
| Investigations - Other, specify | Investigations | Systematic Assessment | subarachinoid hemorrhage |
|
| Lung infection | Infections and infestations | Systematic Assessment |
|
| Metabolism and nutrition disorders - Other, specify | Metabolism and nutrition disorders | Systematic Assessment | Creatinine Decrease (Intermittent) |
|
| Metabolism and nutrition disorders - Other, specify | Metabolism and nutrition disorders | Systematic Assessment | increased chloride |
|
| Myalgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Musculoskeletal and connective tissue disorder - Other, specify | Musculoskeletal and connective tissue disorders | Systematic Assessment | Right Sided Hip Pain |
|
| Musculoskeletal and connective tissue disorder - Other, specify | Musculoskeletal and connective tissue disorders | Systematic Assessment | Bilateral Wrist Edema |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Nervous system disorders - Other, specify | Nervous system disorders | Systematic Assessment | lightheadedness |
|
| Neutrophil count decreased | Investigations | Systematic Assessment |
|
| Oral hemorrhage | Gastrointestinal disorders | Systematic Assessment |
|
| Peripheral sensory neuropathy | Nervous system disorders | Systematic Assessment |
|
| Platelet Count Decrease | Investigations | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pulmonary edema | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pulmonary hypertension | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Respiratory, thoracic and mediastinal disorders - Other, specify | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Intermittent Tachypnea |
|
| Respiratory, thoracic and mediastinal disorders - Other, specify | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | interstitial lung disease |
|
| Respiratory, thoracic and mediastinal disorders - Other, specify | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | acute respiratory failure |
|
| Respiratory, thoracic and mediastinal disorders - Other, specify | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | right sided pleural effusion |
|
| Respiratory, thoracic and mediastinal disorders - Other, specify | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Covid-19 Infection |
|
| Respiratory, thoracic and mediastinal disorders - Other, specify | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Epistaxis |
|
| Respiratory, thoracic and mediastinal disorders - Other, specify | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Rales |
|
| Rhinorrhea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Sepsis | Infections and infestations | Systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | Systematic Assessment |
|
| Skin and subcutaneous tissue disorders - Other, specify | Skin and subcutaneous tissue disorders | Systematic Assessment | 0.5 cm nodule (right anterior thigh) |
|
| Skin infection | Infections and infestations | Systematic Assessment |
|
| Sore throat | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Stomach pain | Gastrointestinal disorders | Systematic Assessment |
|
| Thromboembolic event | Vascular disorders | Systematic Assessment |
|
| Thrush | Infections and infestations | Systematic Assessment |
|
| Thyroid stimulating hormone increased | Investigations | Systematic Assessment |
|
| Tooth infection | Infections and infestations | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | Systematic Assessment |
|
| Urine output decreased | Investigations | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Weight loss | Investigations | Systematic Assessment |
|
| White blood cell decreased | Investigations | Systematic Assessment |
|
Not provided
Not provided
| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
|
| Male |
|