Phase 1/2 Study of the ERK1/2 Inhibitor BVD-523 in Patien... | NCT02296242

NCT02296242

ID	Type	Description	Link
BVD-523-02	Other Identifier	BioMed Valley Discoveries, Inc.

Status Module

Sponsor/Collaborators Module

Oversight Module

No data available

No data is available for this block.

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Label	Type	Description	Intervention Names
BVD-523	Experimental		Drug: BVD-523

Name	Type	Description	Arm Group Labels	Other Names
BVD-523	Drug	Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle	BVD-523

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Patients With Dose Limiting Toxicities	DLT defined using CTCAE v.4.03. All toxicities were considered to be related to BVD523 if not definitively explained by underlying disease, intercurrent illness, or con meds.	In the first 21 days of treatment
Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours	The PK population consisted of patients who received at least one dose of BVD-523 and had evaluable PK data in plasma.	Samples will be collected on or about Day 22 of the protocol

Secondary Outcomes

Measure	Description	Time Frame
Clinical Evidence of Cancer Response in Bone Marrow Biopsies	Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Bone marrow assessments (aspiration or biopsy, cytogenetics) were collected prior to therapy on Day 1 and Day 22, every 2 cycles thereafter, as well as at the final study visit if discontinuation was not due to disease progression. Some patients were unable to have bone marrow assessments taken at any or all of the time points. Shown is best response across all time points. Less than partial remission/response (\

Other Outcomes

Measure	Description	Time Frame
Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses.	Multiple biomarkers intended to demonstrate inhibition of the molecular target, and mechanism of action were investigated from blood and/or bone marrow aspirate samples. Phosphorylation of ERK enzyme substrate proteins (e.g. RSK1 and RSK2 genes) were measured. Additional biomarkers, including PBMCs and/or DNA sequence analysis, were identified and measured as appropriate. Measurements were by ELISA. The pharmacodynamics (PD) population was defined as all patients who received at least one dose of study drug and had sufficient, valid PD samples to estimate key parameters for at least one of the days of sampling.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Have either of the following diagnoses:
1. Morphologically confirmed acute myeloid leukemia (AML), except acute promyelocytic leukemia (APL), including leukemia secondary to prior therapy or antecedent hematologic disorder (e.g., MDS or myeloproliferative disorders), who have failed to achieve CR or who have relapsed after prior therapy and are not candidates for potentially curative therapy
2. Intermediate-2 or High-grade risk MDS (including chronic myelomonocytic leukemia (CMML))
Have received at least one prior therapy. Patients who are over age 65 and have not received therapy for AML are also eligible, if they are not candidates for induction chemotherapy
ECOG performance status of 0 to 2
Predicted life expectancy of ≥ 3 months
Adequate liver, renal and cardiac function

For Group 1 in Part 2 of the Study ONLY:

• Positive for RAS mutation at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory prior to study entry

Exclusion Criteria:

Concomitant malignancies except carcinoma in situ, basal or squamous cell skin carcinoma; low grade prostate cancer treated with prostatectomy more than 10 years ago; early stage melanoma treated with complete surgical excision more than 5 years ago; carcinoma in situ of cervix treated with cone procedure more than 8 years ago
Gastrointestinal condition which could impair absorption of study medication
Uncontrolled or severe intercurrent medical condition
Patients with rapidly increasing peripheral blood blast counts
Known uncontrolled central nervous system involvement
Any cancer-directed therapy within 28 days or 5 half-lives, whichever is shorter
Any concurrent or prior use of an investigational drug (including MEK inhibitors) within previous 28 days or 5 half-lives, whichever is shorter
Received chemotherapy regimens with delayed toxicity within the last four weeks (six weeks for prior nitrosourea or mitomycin C). Received chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last two weeks.
Ongoing anticoagulant therapy that cannot be held if necessary to permit bone marrow sampling.
Major surgery within 4 weeks prior to first dose
Pregnant or breast-feeding women
Any evidence of serious active infections
Any important medical illness or abnormal laboratory finding that would increase the risk of participating in this study
A history or current evidence/risk of retinal vein occlusion or central serous retinopathy
Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6, and CYP3A4, or strong inducers of CYP3A4

Contacts/Locations Module

Facility	Status	City	State	ZIP	Country	Contacts
UCLA Medical Center		Los Angeles	California	90024	United States
Winship Cancer Institute of Emory University

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
28939558	Derived	Germann UA, Furey BF, Markland W, Hoover RR, Aronov AM, Roix JJ, Hale M, Boucher DM, Sorrell DA, Martinez-Botella G, Fitzgibbon M, Shapiro P, Wick MJ, Samadani R, Meshaw K, Groover A, DeCrescenzo G, Namchuk M, Emery CM, Saha S, Welsch DJ. Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib). Mol Cancer Ther. 2017 Nov;16(11):2351-2363. doi: 10.1158/1535-7163.MCT-17-0456. Epub 2017 Sep 22.

IPD Sharing Statement Module

No data available

No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Dose-escalation 300mg b.i.d. Cohort	Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Nov 18, 2015	Jun 27, 2018

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	Dose-escalation 300mg b.i.d. Cohort	Patients received 300mg oral doses of BVD-523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
BG001	Dose-escalation 600mg b.i.d. Cohort	Patients received 600mg oral doses of BVD-523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
BG002	Dose-escalation 750mg b.i.d. Cohort	Patients received 750mg oral doses of BVD-523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
BG003	Cohort-expansion RAS(+) Group	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
BG004	Cohort-expansion RAS(-) Group	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
BG005	Total	Total of all reporting groups

Units	Counts
Participants	BG0005 BG0016 BG0027 BG00314 BG00421 BG00553

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00071.6± 9.21 BG00158.7± 19.18 BG00265.6± 18.11 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG0002 BG0011 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG0000 BG0010 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Region of Enrollment

Number

participants

Title

Denominators

Categories

United States

Title	Measurements
	BG0005 BG0016 BG002

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

Number of Patients With Dose Limiting Toxicities

DLT defined using CTCAE v.4.03. All toxicities were considered to be related to BVD523 if not definitively explained by underlying disease, intercurrent illness, or con meds.

Posted

Count of Participants

Participants

In the first 21 days of treatment

ID	Title	Description
OG000	Dose-escalation 300mg b.i.d. Cohort	Patients received 300mg oral doses of BVD-523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
OG001	Dose-escalation 600mg b.i.d. Cohort	Patients received 600mg oral doses of BVD-523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
OG002	Dose-escalation 750mg b.i.d. Cohort	Patients received 750mg oral doses of BVD-523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
OG003	Cohort-expansion RAS(+) Group	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
OG004	Cohort-expansion RAS(-) Group	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.

Units	Counts
Participants	OG0005 OG0016 OG0027 OG003

Title

Denominators

Categories

Any BVD-523-related DLTs?

Title	Measurements
Yes	OG0000 OG0010 OG0022 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001 OG002	In Part 1, 2 patients experienced DLTs in the 750 mg b.i.d. treatment group (2/7; 29%). There were no dose-limiting toxicities in the 600 mg b.i.d. group or 300 mg b.i.d. group. Therefore, based on these results, 600 mg b.i.d. was selected as the MTD dose (and RP2D dose) which was used as the treatment dose in Part 2 of the study.					Highest dose (mg) with no DLTs.	600			2-Sided								Other

Primary

Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours

The PK population consisted of patients who received at least one dose of BVD-523 and had evaluable PK data in plasma.

The cohort-expansion patients were not separated by RAS status for the purposes of this assessment. Two patients in the cohort expansion had to have their dose reduced to 300mg BID and were analyzed separately (Cmax 1000 & 1340 ng/mL on Day 22). 00 = not calculated (only 1 evaluable patient).

Posted

Mean

Standard Deviation

ng/mL

Samples will be collected on or about Day 22 of the protocol

ID	Title	Description
OG000	Dose-escalation 300mg b.i.d. Cohort	Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
OG001	Dose-escalation 600mg b.i.d. Cohort	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).

Secondary

Clinical Evidence of Cancer Response in Bone Marrow Biopsies

Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Bone marrow assessments (aspiration or biopsy, cytogenetics) were collected prior to therapy on Day 1 and Day 22, every 2 cycles thereafter, as well as at the final study visit if discontinuation was not due to disease progression. Some patients were unable to have bone marrow assessments taken at any or all of the time points. Shown is best response across all time points. Less than partial remission/response (\

Posted

Count of Units

Response(s)

Until patient discontinuation; ~24 months on average

Response(s)

ID	Title	Description
OG000	Dose-escalation	Patients received 300-750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
OG001	Cohort-expansion	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.

Secondary

Duration of Disease Control in Patients That Respond

Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Progression-free survival (PFS) and duration of response (DOR) of AML or MDS patients was assessed in patients treated with BVD-523 that achieved complete remission/response (CR) or complete remission/response with incomplete platelet recovery (CRp). \

Part 1: \

Posted

Number

Days

Until patient discontinuation; ~24 months on average

ID	Title	Description
OG000	Cohort-expansion RAS(+) Group	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
OG001	Cohort-expansion RAS(-) Group	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.

Other Pre-specified

Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses.

Multiple biomarkers intended to demonstrate inhibition of the molecular target, and mechanism of action were investigated from blood and/or bone marrow aspirate samples. Phosphorylation of ERK enzyme substrate proteins (e.g. RSK1 and RSK2 genes) were measured. Additional biomarkers, including PBMCs and/or DNA sequence analysis, were identified and measured as appropriate. Measurements were by ELISA. The pharmacodynamics (PD) population was defined as all patients who received at least one dose of study drug and had sufficient, valid PD samples to estimate key parameters for at least one of the days of sampling.

Data was not collected/reported for patient at time point or patient did not start a second cycle.

Posted

Mean

Standard Deviation

Percent (%) Inhibition

Patients will be evaluated at baseline and on or about Day 22 of the protocol

ID	Title	Description
OG000	Dose-escalation	Patients received 300-750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
OG001

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Dose-escalation 300mg b.i.d. Cohort	Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).	4	5	5	5	2	5
EG001	Dose-escalation 600mg b.i.d. Cohort	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).	2	6	4	6	1	6
EG002	Dose-escalation 750mg b.i.d. Cohort	Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).	4	7	6	7	6	7
EG003	Cohort-expansion RAS(+) Group	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.	2	14	10	14	9	14
EG004	Cohort-expansion RAS(-) Group	Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.	4	21	18	21	11	21

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG0001 affected5 at risk EG0010 affected6 at risk EG0022 affected7 at risk EG0033 affected14 at risk EG004
Leukocytosis	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG0001 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Diarrhea	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 affected5 at risk EG0012 affected6 at risk EG0020 affected7 at risk EG003
Gastrointestinal hemorrhage	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0001 affected5 at risk EG0012 affected6 at risk EG0021 affected7 at risk EG003
Death	General disorders	MedDRA (17.1)	Systematic Assessment	EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Disease progression	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0001 affected5 at risk EG0011 affected6 at risk EG0021 affected7 at risk EG003
Pyrexia	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Bacteremia	Infections and infestations	MedDRA (17.1)	Systematic Assessment	EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Pneumonia	Infections and infestations	MedDRA (17.1)	Systematic Assessment	EG0003 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Sepsis	Infections and infestations	MedDRA (17.1)	Systematic Assessment	EG0001 affected5 at risk EG0010 affected6 at risk EG0022 affected7 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment	EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Renal failure acute	Renal and urinary disorders	MedDRA (17.1)	Systematic Assessment	EG0001 affected5 at risk EG0010 affected6 at risk EG0022 affected7 at risk EG003
Hypotension	Vascular disorders	MedDRA (17.1)	Systematic Assessment	EG0001 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Vision Blurred	Eye disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG0031 affected14 at risk EG0040 affected21 at risk
Diarrhea	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0022 affected7 at risk EG003
Gastroesophageal Reflux Disease	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment		EG0001 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0023 affected7 at risk EG003
Oral Mucosal Eruption	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0022 affected7 at risk EG003
Fatigue	General disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0022 affected7 at risk EG003
Hypertransaminasaemia	Hepatobiliary disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Sepsis	Infections and infestations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Blood Creatinine Increased	Investigations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Liver Function Test Abnormal	Investigations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Decreased Appetite	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0011 affected6 at risk EG0021 affected7 at risk EG003
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Renal Failure Acute	Renal and urinary disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Eczema	Skin and subcutaneous tissue disorders	MedDRA (17.1)	Systematic Assessment		EG0001 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Erythema Multiforme	Skin and subcutaneous tissue disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Pruritus Generalized	Skin and subcutaneous tissue disorders	MedDRA (17.1)	Systematic Assessment	Also includes 'Pruritus'	EG0000 affected5 at risk EG0010 affected6 at risk EG0022 affected7 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA (17.1)	Systematic Assessment		EG0001 affected5 at risk EG0010 affected6 at risk EG0021 affected7 at risk EG003
Febrile Neutropenia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Leukocytosis	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Lacrimation Increased	Eye disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Abdominal Pain	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Asthenia	General disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Oedema Peripheral	General disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Pyrexia	General disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Hyperbilirubinaemia	Hepatobiliary disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Diverticulitis	Infections and infestations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Upper Respiratory Tract Infection	Infections and infestations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Subdural Hematoma	Injury, poisoning and procedural complications	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Alanine Aminotransferase Increased	Investigations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Aspartate Aminotransferase Increased	Investigations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Electrocardiogram QT Prolonged	Investigations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Neutrophil Count Decreased	Investigations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Platelet Count Decreased	Investigations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Weight Decreased	Investigations	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Dizziness	Nervous system disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Headache	Nervous system disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Presyncope	Nervous system disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Hallucination	Psychiatric disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Acute Prerenal Failure	Renal and urinary disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Hiccups	Respiratory, thoracic and mediastinal disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Dry Skin	Skin and subcutaneous tissue disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Rash Macular	Skin and subcutaneous tissue disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Hypotension	Vascular disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Orthostatic Hypotension	Vascular disorders	MedDRA (17.1)	Systematic Assessment		EG0000 affected5 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003

ID	Term
D015470	Leukemia, Myeloid, Acute
D009190	Myelodysplastic Syndromes

ID	Term
C000618314	ulixertinib

EG0041 affected21 at risk

EG0042 affected21 at risk

EG0041 affected21 at risk

EG0042 affected21 at risk

EG0043 affected21 at risk

EG0044 affected21 at risk

EG0042 affected21 at risk

EG0040 affected21 at risk

EG0042 affected21 at risk

EG0046 affected21 at risk

EG0041 affected21 at risk

EG0045 affected21 at risk

EG0040 affected21 at risk

EG0043 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0042 affected21 at risk

EG0040 affected21 at risk

EG0041 affected21 at risk

EG0042 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0042 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

EG0041 affected21 at risk

EG0040 affected21 at risk

Title	Measurements
	OG000428± 193 OG0011670± 00 OG0022020± 1240 OG0031280± 767

Title	Measurements
	OG000506± 159 OG0011590± 00 OG0022130± 693 OG0031440± 698

Title	Measurements
	OG0001300± 1090 OG0011760± 00 OG0022220± 1500 OG0031790± 776

Title	Measurements
	OG0001150± 555 OG0011520± 00 OG0022670± 1490 OG0031800± 914

Title	Measurements
	OG000728± 435 OG0011510± 00 OG0022360± 1510 OG0031400± 741

Title	Measurements
	OG000480± 301 OG0011100± 00 OG0021870± 1150 OG0031140± 623

Title	Measurements
	OG000528± 364 OG001902± 00 OG0021650± 1070 OG003974± 567

ID	Term
D007951	Leukemia, Myeloid
D007938	Leukemia
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D001855	Bone Marrow Diseases