Trial Outcomes & Findings for Azacitidine, Venetoclax, and Trametinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome (NCT NCT04487106)

Last Updated: 2025-04-22

Results Overview

Overall response is defined as the number of participants achieving Complete Remission (CR) or Complete Remission without recovery of counts (CRi) CR is Normalization of the peripheral blood and bone marrow with \</= to 5 % blasts with a granulocyte count of 1 x 10\^9/L or greater and a platelet count of 100 x 10\^9/L and complete resolution of all extramedullary disease. CRi is Peripheral blood and marrow results as for CR, but with incomplete recover of counts (platelets \< 100 x 10\^9/L or neutrophils \< 1 x 10\^9/L).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

21 participants

Primary outcome timeframe

Up to 2.5 years

Results posted on

2025-04-22

Participant Flow

Participant milestones

Participant milestones
Measure	Cohort A (Newly Diagnosed AML Patients) INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO
Overall Study STARTED	5	16
Overall Study COMPLETED	5	16
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Azacitidine, Venetoclax, and Trametinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort A (Newly Diagnosed AML Patients) n=5 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) n=16 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Total n=21 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=99 Participants	7 Participants n=107 Participants	8 Participants n=206 Participants
Age, Categorical >=65 years	4 Participants n=99 Participants	9 Participants n=107 Participants	13 Participants n=206 Participants
Age, Continuous	75 years n=99 Participants	67 years n=107 Participants	69 years n=206 Participants
Sex: Female, Male Female	1 Participants n=99 Participants	5 Participants n=107 Participants	6 Participants n=206 Participants
Sex: Female, Male Male	4 Participants n=99 Participants	11 Participants n=107 Participants	15 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race (NIH/OMB) White	4 Participants n=99 Participants	13 Participants n=107 Participants	17 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	3 Participants n=107 Participants	3 Participants n=206 Participants
Region of Enrollment United States	5 participants n=99 Participants	16 participants n=107 Participants	21 participants n=206 Participants

PRIMARY outcome

Timeframe: Up to 2.5 years

Population: Of the five participants registered on Cohort A, three were evaluable. Of the sixteen participants registered on Cohort B, thirteen were evaluable.

Outcome measures

Outcome measures
Measure	Cohort A (Newly Diagnosed AML Patients) n=3 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) n=13 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO
Participants With a Response	2 Participants	2 Participants

SECONDARY outcome

Timeframe: Up to time of relapse, assessed up to 2.5 years

Population: Of the five participants in Cohort A, three were evaluable for response. Of the 16 participants in Cohort B, 13 were evaluable for response.

Will be assessed by flow cytometry and estimated along with 95% credible intervals.

Outcome measures

Outcome measures
Measure	Cohort A (Newly Diagnosed AML Patients) n=3 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) n=13 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO
Minimal Residual Disease Negativity	1 Participants	1 Participants

SECONDARY outcome

Timeframe: From documented CR/CRi until relapse or death, assessed until study completion

Relapse-free survival is the time from documented CR/CRi until relapse or death.

Outcome measures

Outcome measures
Measure	Cohort A (Newly Diagnosed AML Patients) n=3 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) n=13 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO
Relapse-free Survival	19 Months Interval 5.6 to 32.3	NA Months Interval 31.0 to 34.6 Within the study's follow-up period, less than half of the patients have experienced relapse, so a median RFS hasn't been statistically determined

SECONDARY outcome

Timeframe: From the first day of treatment until any treatment failure (lack of response within 6 cycles of treatment, relapse, or death), assessed until study completion

Event-free survival is the time from the first day of treatment until any treatment failure (lack of response within 6 cycles of treatment, relapse, or death).

Outcome measures

Outcome measures
Measure	Cohort A (Newly Diagnosed AML Patients) n=3 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) n=13 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO
Event-free Survival	1.8 Months Interval 0.5 to 36.4	2.1 Months Interval 0.2 to 35.9

SECONDARY outcome

Timeframe: From the first day of treatment to time of death from any cause, assessed until study completion

Overall survival is defined as the time from the first day of treatment to time of death from any cause.

Outcome measures

Outcome measures
Measure	Cohort A (Newly Diagnosed AML Patients) n=3 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) n=13 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO
Overall Survival	2.5 Months Interval 0.5 to 36.4	2.4 Months Interval 0.5 to 38.6

SECONDARY outcome

Timeframe: Up to 2.5 years

Will be totaled based on the number of participants who continue with hematopoietic stem cell transplantation post treatment.

Outcome measures

Outcome measures
Measure	Cohort A (Newly Diagnosed AML Patients) n=3 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) n=13 Participants INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO
Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation	0 Participants	1 Participants

Adverse Events

Cohort A (Newly Diagnosed AML Patients)

Serious events: 2 serious events

Other events: 3 other events

Deaths: 1 deaths

Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients)

Serious events: 4 serious events

Other events: 15 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Cohort A (Newly Diagnosed AML Patients) n=5 participants at risk INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) n=16 participants at risk INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO
Infections and infestations Catheter related infection	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Cardiac disorders Heart failure	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Musculoskeletal and connective tissue disorders Hip pain	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Nervous system disorders Intracranial hemorrhage	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	0.00% 0/16 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Infections and infestations Lung infection	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Gastrointestinal disorders Oral ulcers	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Infections and infestations Sepsis	20.0% 1/5 • Number of events 3 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	0.00% 0/16 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Infections and infestations Skin infection	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
General disorders Subdural Hemorrhage	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	12.5% 2/16 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Infections and infestations Upper Respiratory Infection	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Infections and infestations Urinary tract infection	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	0.00% 0/16 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years

Other adverse events

Additional Information

Nichols Short MD/Associate Professor

The University of Texas MD Anderson Cancer Center

Phone: 713-563-4485

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Cohort A (Newly Diagnosed AML Patients) n=5 participants at risk INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO	Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) n=16 participants at risk INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV or SC Trametinib: Given PO Venetoclax: Given PO
Investigations alanine aminotransferase increased	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Gastrointestinal disorders Anorexia	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	12.5% 2/16 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Cardiac disorders Cardiac-General Other	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Psychiatric disorders Confusion	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Gastrointestinal disorders Constipation	40.0% 2/5 • Number of events 3 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Investigations Creatinine Increased	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Gastrointestinal disorders Diarrhea	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	75.0% 12/16 • Number of events 12 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Respiratory, thoracic and mediastinal disorders Dyspnea (shortness of breath)	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
General disorders Edema limb	40.0% 2/5 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	12.5% 2/16 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
General disorders Fatigue (asthenia, lethargy, malaise)	40.0% 2/5 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	62.5% 10/16 • Number of events 10 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Blood and lymphatic system disorders Febrile neutropenia	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	18.8% 3/16 • Number of events 3 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Gastrointestinal disorders Hemorrhoids	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Vascular disorders Hypertension	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
General disorders Hypothermia	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	0.00% 0/16 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Infections and infestations Infection-Other	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Gastrointestinal disorders Mucositis/stomatitis	20.0% 1/5 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	31.2% 5/16 • Number of events 5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Musculoskeletal and connective tissue disorders Muscle weakness, generalized or specific area	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Gastrointestinal disorders Nausea	40.0% 2/5 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	50.0% 8/16 • Number of events 8 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
General disorders Pain	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	12.5% 2/16 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Skin and subcutaneous tissue disorders Rash/desquamation	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	12.5% 2/16 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Eye disorders Retinopathy	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Skin and subcutaneous tissue disorders Skin ulceration	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Cardiac disorders Tachycardia	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	6.2% 1/16 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Skin and subcutaneous tissue disorders Ulceration	0.00% 0/5 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	12.5% 2/16 • Number of events 2 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years
Gastrointestinal disorders Vomiting	20.0% 1/5 • Number of events 1 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years	25.0% 4/16 • Number of events 4 • All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years