Trial Outcomes & Findings for Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy) (NCT NCT02989857)

Last Updated: 2024-08-20

Results Overview

PFS is defined as the time from date of randomization to the date of first documented disease progression as assessed by the IRC using Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.1, or date of death due to any cause, whichever occurred first. Disease progression was defined as greater than or equal to (≥)20 percent (%) increase in sum of the diameter of target lesions, taking as reference the smallest sum diameter recorded since the treatment started. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm) or the appearance of 1 or more new lesions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

187 participants

Primary outcome timeframe

From the date of randomization to the date of first documentation of disease progression or death due to any cause (Up to approximately 2 years)

Results posted on

2024-08-20

Participant Flow

Participants took part in the study at 49 study sites in France, Italy, Spain, South Korea, the United States, and the United Kingdom from 20 February 2017 to 17 May 2021.

The final analysis of progression-free survival (PFS) occurred once 131 PFS events had been determined by Investigator assessment. Two participants were randomized in the study after the data cutoff date (31 January 2019) for the final analysis of PFS.

Participant milestones

Participant milestones
Measure	AG-120 Participants received AG-120 500 mg, tablet, orally, once daily (QD) in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Randomization Phase STARTED	126	61	0
Randomization Phase COMPLETED	123	59	0
Randomization Phase NOT COMPLETED	3	2	0
Cross Over Phase STARTED	0	0	43
Cross Over Phase COMPLETED	0	0	43
Cross Over Phase NOT COMPLETED	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	AG-120 Participants received AG-120 500 mg, tablet, orally, once daily (QD) in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Randomization Phase Not Treated	3	2	0

Baseline Characteristics

Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	AG-120 n=126 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=61 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	Total n=187 Participants Total of all reporting groups
Age, Continuous	60.3 years STANDARD_DEVIATION 10.97 • n=5 Participants	62.9 years STANDARD_DEVIATION 10.38 • n=7 Participants	61.1 years STANDARD_DEVIATION 10.82 • n=5 Participants
Sex: Female, Male Female	82 Participants n=5 Participants	37 Participants n=7 Participants	119 Participants n=5 Participants
Sex: Female, Male Male	44 Participants n=5 Participants	24 Participants n=7 Participants	68 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Hispanic or Latino	7 Participants n=5 Participants	2 Participants n=7 Participants	9 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Not Hispanic or Latino	84 Participants n=5 Participants	40 Participants n=7 Participants	124 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Not Reported	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Missing	35 Participants n=5 Participants	17 Participants n=7 Participants	52 Participants n=5 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	15 Participants n=5 Participants	8 Participants n=7 Participants	23 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	71 Participants n=5 Participants	35 Participants n=7 Participants	106 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Missing	35 Participants n=5 Participants	17 Participants n=7 Participants	52 Participants n=5 Participants

PRIMARY outcome

Timeframe: From the date of randomization to the date of first documentation of disease progression or death due to any cause (Up to approximately 2 years)

Population: ITT set included all participants who were randomized, with the treatment group designated according to the randomization. Number analyzed is the number of participants with data available for analyses at the specified time point. Two participants were excluded from the analysis as they were randomized in the study after the data cutoff date (31 January 2019) for the analysis of PFS.

Outcome measures

Outcome measures
Measure	AG-120 n=124 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=61 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC)	2.7 months Interval 1.6 to 4.2	1.4 months Interval 1.4 to 1.6	—

SECONDARY outcome

Timeframe: From first dose of study drug up to 28 days after last dose for each intervention (Up to approximately 4 Years)

Population: Safety Analysis Set (SAS) included all participants who received at least one dose of study drug (AG-120 or Placebo).

An AE is any untoward medical occurrence associated with the use of a drug in participants, whether or not considered drug related. An AE or suspected adverse reaction is considered serious (an SAE) if it is fatal, life-threatening, causes in-patient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect in a neonate/infant born to a mother or father exposed to study treatment or is an important medical event. Treatment-emergent adverse events are reported.

Outcome measures

Outcome measures
Measure	AG-120 n=123 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=59 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 n=43 Participants Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	97.6 percentage of participants	96.6 percentage of participants	95.3 percentage of participants
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	35.0 percentage of participants	23.7 percentage of participants	27.9 percentage of participants

SECONDARY outcome

Timeframe: From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years)

Population: SAS included all participants who received at least one dose of study drug (AG-120 or Placebo).

The laboratory parameters evaluated by the investigator included hematology and chemistry. Laboratory abnormalities reported in this endpoint are Grade 3 or higher adverse events. Grading categories were determined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.

Outcome measures

Outcome measures
Measure	AG-120 n=123 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=59 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 n=43 Participants Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Platelet Count Decreased	2.4 percentage of participants	0.0 percentage of participants	2.3 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Neutrophil Count Decreased	1.6 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events White Blood Cell Count Decreased	1.6 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Lymphocyte Count Decreased	0.8 percentage of participants	3.4 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Hyponatraemia	5.7 percentage of participants	10.2 percentage of participants	2.3 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Aspartate Aminotransferase Increased	4.9 percentage of participants	1.7 percentage of participants	4.7 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Anaemia	7.3 percentage of participants	0.0 percentage of participants	9.3 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Thrombocytopenia	0.8 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Blood Loss Anaemia	0.8 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Blood Bilirubin Increased	5.7 percentage of participants	1.7 percentage of participants	7.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Hypophosphataemia	3.3 percentage of participants	5.1 percentage of participants	4.7 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Hyperbilirubinaemia	3.3 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Hyperkalaemia	2.4 percentage of participants	3.4 percentage of participants	2.3 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Blood Alkaline Phosphatase Increased	2.4 percentage of participants	5.1 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Alanine Aminotransferase Increased	1.6 percentage of participants	0.0 percentage of participants	2.3 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Hypoalbuminaemia	1.6 percentage of participants	1.7 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Gamma-glutamyltransferase Increased	0.8 percentage of participants	1.7 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Hypercalcaemia	0.8 percentage of participants	1.7 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Hyperuricaemia	0.8 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Hypokalaemia	0.8 percentage of participants	1.7 percentage of participants	2.3 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Transaminases Increased	0.8 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events Blood Uric Acid Increased	0.0 percentage of participants	1.7 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years)

Population: SAS included all participants who received at least one dose of study drug (AG-120 or Placebo).

Clinically significant vital signs were recorded as adverse events; there were some vital signs reported as Grade 3 or higher adverse events. Grading categories were determined by NCI CTCAE, version 4.03.

Outcome measures

Outcome measures
Measure	AG-120 n=123 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=59 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 n=43 Participants Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs Pyrexia	0.8 percentage of participants	0.0 percentage of participants	2.3 percentage of participants
Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs Weight Decreased	0.8 percentage of participants	1.7 percentage of participants	0.0 percentage of participants
Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs Hypertension	1.6 percentage of participants	1.7 percentage of participants	7.0 percentage of participants
Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs Hypotension	1.6 percentage of participants	1.7 percentage of participants	2.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline

Population: ITT population included all participants who were randomized, with the treatment group designated according to the randomization.

The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score classified participants according to their functional impairment, with scores ranging from 0 to 4. ECOG PS: 0 = fully active, able to carry on all pre-disease performance without restriction; 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work; 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3 = capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = completely disabled, cannot carry on any self-care, totally confined to bed or chair. A higher score means a worse functional status.

Outcome measures

Outcome measures
Measure	AG-120 n=126 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=61 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status 0	39.7 percentage of participants	31.1 percentage of participants	—
Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status 1	59.5 percentage of participants	67.2 percentage of participants	—
Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status 2	0.0 percentage of participants	1.6 percentage of participants	—
Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status 3	0.8 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status 4	0.0 percentage of participants	0.0 percentage of participants	—

SECONDARY outcome

Timeframe: From first dose of study drug up to 28 days after last dose (Up to approximately 4 Years)

Population: SAS included all participants who received at least one dose of study drug (AG-120 or Placebo).

Concomitant medications were medications that were ongoing or initiated after the first dose of the study drug but before the last dose plus 28 days. Percentage of participants who required at least one concomitant medications during the study along with their prescribed study drug (AG-120 or placebo) were reported.

Outcome measures

Outcome measures
Measure	AG-120 n=123 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=59 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 n=43 Participants Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Percentage of Participants Who Required At Least One Concomitant Medications During the Treatment	99.2 percentage of participants	98.3 percentage of participants	95.3 percentage of participants

SECONDARY outcome

Timeframe: Pre-dose C1D1, C2D1; Post-dose C1D1, C1D15, C2D1 and Day 1 of C3D1 and all cycles thereafter up to last dose plus 28 days (Up to approximately 4 years)

Population: SAS included all participants who received at least one dose of study drug (AG-120 or Placebo).

Outcome measures

Outcome measures
Measure	AG-120 n=123 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=59 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 n=43 Participants Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events Electrocardiogram QT Prolonged	9.8 percentage of participants	3.4 percentage of participants	2.3 percentage of participants
Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events Electrocardiogram Abnormal	0.8 percentage of participants	0.0 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: From date of randomization until the date of death due to any cause (Up to approximately 2 years)

Population: ITT population included all participants who were randomized, with the treatment group designated according to the randomization.

Overall survival was defined as the time in months from date of randomization to the date of death due to any cause. Participants without documentation of death at the time of the final collection were censored at the date the participant was last known to be alive, or the final collection date, whichever is earlier.

Outcome measures

Outcome measures
Measure	AG-120 n=126 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=61 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Overall Survival (OS)	10.3 months Interval 7.8 to 12.4	7.5 months Interval 4.8 to 11.1	—

SECONDARY outcome

Timeframe: From the date of randomization up to confirmed CR or PR (Up to approximately 2 years)

Population: ITT population included all participants who were randomized, with the treatment group designated according to the randomization. Number analyzed is the number of participants with data available for analyses at the specified time point. Two participants were excluded from the analysis as they were randomized in the study after the data cutoff date (31 January 2019) for the analysis of tumor response.

ORR as assessed by the investigator was defined as the percentage of participants with a best overall response (BOR) defined as complete response (CR) or partial response (PR) per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis \<10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline.

Outcome measures

Outcome measures
Measure	AG-120 n=124 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=61 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1	3.2 percentage of participants Interval 0.9 to 8.1	1.6 percentage of participants Interval 0.0 to 8.8	—

SECONDARY outcome

Timeframe: From the date of randomization up to confirmed CR or PR (Up to approximately 2 years)

ORR as assessed by the IRC was defined as the percentage of participants with a best overall response (BOR) defined as complete response (CR) or partial response (PR) per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis \<10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline.

Outcome measures

Outcome measures
Measure	AG-120 n=124 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=61 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
ORR as Assessed by the IRC Per RECIST v1.1	2.4 percentage of participants Interval 0.5 to 6.9	0 percentage of participants Interval 0.0 to 5.9	—

SECONDARY outcome

Timeframe: From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years)

Population: Participants with CR or PR per investigator assessment by the data cutoff date (31 January 2019) for the analysis of tumor response.

DOR was defined as the time in months from date of first documented CR or PR to date of first documented disease progression or death due to any cause, whichever is earlier, as assessed by the Investigator per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis \<10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline. Participants with response and without progression were censored at the last observation.

Outcome measures

Outcome measures
Measure	AG-120 n=4 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=1 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Duration of Response (DOR) as Assessed by the Investigator	NA months Median, lower limit and upper limit were not available due to the insufficient number of participants with events.	NA months Median, lower limit and upper limit were not available due to the insufficient number of participants with events.	—

SECONDARY outcome

Timeframe: From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years)

Population: Participants with CR or PR per investigator assessment by the data cutoff date (31 January 2019) for the analysis of tumor response.

DOR was defined as the time in months from date of first documented CR or PR to date of first documented disease progression or death due to any cause, whichever is earlier, as assessed by the IRC per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis \<10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline. Participants with response and without progression were censored at the last observation.

Outcome measures

Outcome measures
Measure	AG-120 n=3 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
DOR as Assessed by the IRC Per RECIST v1.1	NA months Median, lower limit and upper limit were not available due to the insufficient number of participants with events.	—	—

SECONDARY outcome

Timeframe: From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years)

Population: Participants with CR or PR per investigator assessment by the data cutoff date (31 January 2019) were analyzed for tumor response.

TTR was defined as the time from date of randomization to date of first documented CR or PR for responders, as assessed by the Investigator per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis \<10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline. Only responders were analyzed for this outcome measure.

Outcome measures

Outcome measures
Measure	AG-120 n=4 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=1 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Time to Response (TTR) as Assessed by the Investigator	NA months Median, upper and lower limit were not available due to the insufficient number of participants with events.	NA months Median, upper and lower limit were not available due to the insufficient number of participants with events.	—

SECONDARY outcome

Timeframe: From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years)

Population: Participants with CR or PR per investigator assessment by the data cutoff date (31 January 2019) were analyzed for tumor response.

TTR was defined as the time from date of randomization to date of first documented CR or PR for responders, as assessed by the IRC per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis \<10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline. Only responders were analyzed for this outcome measure.

Outcome measures

Outcome measures
Measure	AG-120 n=3 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
TTR as Assessed by the IRC Per RECIST v1.1	NA months Median, upper and lower limit were not available due to the insufficient number of participants with events.	—	—

SECONDARY outcome

Timeframe: From the date of randomization to the date of first documentation of disease progression or death due to any cause (Up to approximately 2 years)

PFS was defined as the time from date of randomization to the date of first documented disease progression as assessed by the investigator using RECIST v1.1, or date of death due to any cause, whichever occurred first. Disease progression was defined as ≥20% increase in sum of the diameter of target lesions, taking as reference the smallest sum diameter recorded since the treatment started. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm or the appearance of 1 or more new lesions. No progression or death by data cutoff date was censored at the last adequate assessment date.

Outcome measures

Outcome measures
Measure	AG-120 n=124 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=61 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
PFS as Determined by Investigator	2.7 months Interval 1.6 to 3.6	1.4 months Interval 1.4 to 2.5	—

SECONDARY outcome

Timeframe: Cycle 2 Day 1 and Cycle 3 Day 1

Population: ITT population included all randomized participants, with treatment group designated according to the randomization. Overall Number of Participants Analyzed is the number of participants with data available for analyses at baseline and the given post-baseline timepoints. Number Analyzed at a particular timepoint is the number of participants with data available for analyses at baseline and given timepoint.

EORTC-QLQ-C30 is the European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire - Core Questionnaire. For EORTC QLQ-C30, subscales of physical functioning, pain, and appetite loss were assessed. These had 4 response levels (not at all, a little, quite a bit, and very much). For functional scales, higher scores=better QOL (positive change from Baseline=improvement). For symptom scales, lower scores=better QOL (negative change from Baseline=improvement). Using linear transformation, raw scores were standardized, so that scores ranged from 0 to 100.

Outcome measures

Outcome measures
Measure	AG-120 n=73 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=23 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Change From Baseline in Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Subscales Scores Cycle 2 Day 1: Appetite Loss	7.9 score on a scale Standard Error 2.60	4.3 score on a scale Standard Error 4.55	—
Change From Baseline in Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Subscales Scores Cycle 3 Day 1: Pain	-1.2 score on a scale Standard Error 2.73	-5.3 score on a scale Standard Error 5.96	—
Change From Baseline in Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Subscales Scores Cycle 2 Day 1: Physical Functioning	-2.4 score on a scale Standard Error 1.75	-13.3 score on a scale Standard Error 2.95	—
Change From Baseline in Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Subscales Scores Cycle 2 Day 1: Pain	2.2 score on a scale Standard Error 2.48	12.5 score on a scale Standard Error 4.35	—
Change From Baseline in Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Subscales Scores Cycle 3 Day 1: Physical Functioning	-0.2 score on a scale Standard Error 1.89	-12.6 score on a scale Standard Error 3.88	—
Change From Baseline in Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Subscales Scores Cycle 3 Day 1: Appetite Loss	-0.5 score on a scale Standard Error 2.89	3.2 score on a scale Standard Error 6.40	—

SECONDARY outcome

Timeframe: Cycle 2 Day 1 and Cycle 3 Day 1

For HRQOL based on QLQ-BIL21, subscales of eating symptoms and pain symptoms were assessed. Each item is a 4-point Likert scale. There are 4 response levels (not at all, a little, quite a bit, and very much). Raw scores are converted into scale scores ranging from 0 to 100. For symptom scales, lower scores=better QOL (negative change from Baseline=improvement).

Outcome measures

Outcome measures
Measure	AG-120 n=70 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=22 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21) Cycle 2 Day 1: Appetite Loss	4.3 score on a scale Standard Error 1.84	3.6 score on a scale Standard Error 3.19	—
Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21) Cycle 3 Day 1: Pain	2.3 score on a scale Standard Error 2.16	-2.1 score on a scale Standard Error 4.70	—
Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21) Cycle 3 Day 1: Appetite Loss	-2.0 score on a scale Standard Error 2.02	4.1 score on a scale Standard Error 4.24	—
Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21) Cycle 2 Day 1: Pain	5.1 score on a scale Standard Error 1.94	10.1 score on a scale Standard Error 3.49	—

SECONDARY outcome

Timeframe: Cycle 2 Day 1 and Cycle 3 Day 1

Population: ITT population included all participants who were randomized, with the treatment group designated according to the randomization. Overall number analyzed is the number of participants available for analysis. Number analyzed is the number of participants available for analysis at the given timepoint.

The PGI-C is a self-rated evaluative instrument for assessment across 3 domains (physical function, appetite loss, and pain). The PGI-C is measured using a 7-point Likert scale, with 6= very much better, 5= moderately better, 4= a little better, 3= no change, 2= a little worse, 1= moderately worse, and 0= very much worse. A lower score indicates a worse outcome. Percentages are rounded off to whole number at the nearest decimal.

Outcome measures

Outcome measures
Measure	AG-120 n=67 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=22 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 2 Day 1: Moderately Worse	4.5 percentage of participants	13.6 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 2 Day 1: A Little Worse	22.4 percentage of participants	9.1 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 2 Day 1: No Change	38.8 percentage of participants	27.3 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 2 Day 1: A Little Better	22.4 percentage of participants	36.4 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 3 Day 1: Moderately Worse	5.9 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 3 Day 1: A Little Better	29.4 percentage of participants	16.7 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 3 Day 1: Moderately Better	15.7 percentage of participants	16.7 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 3 Day 1: Very Much Better	2.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 2 Day 1: Very Much Worse	1.5 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 2 Day 1: Moderately Worse	4.5 percentage of participants	4.5 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 2 Day 1: A Little Worse	20.9 percentage of participants	18.2 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 3 Day 1: Moderately Worse	5.9 percentage of participants	8.3 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 3 Day 1: Moderately Better	7.8 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 3 Day 1: Very Much Better	3.9 percentage of participants	16.7 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 2 Day 1: A Little Worse	9.0 percentage of participants	9.1 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 2 Day 1: No Change	64.2 percentage of participants	54.5 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 2 Day 1: A Little Better	7.5 percentage of participants	18.2 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 2 Day 1: Moderately Better	10.4 percentage of participants	4.5 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 3 Day 1: Very Much Worse	0.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 3 Day 1: Moderately Worse	3.9 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 2 Day 1: Very Much Worse	1.5 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 2 Day 1: Moderately Better	9.0 percentage of participants	9.1 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 2 Day 1: Very Much Better	1.5 percentage of participants	4.5 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 3 Day 1: Very Much Worse	2.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 3 Day 1: A Little Worse	3.9 percentage of participants	8.3 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Physical Change: Cycle 3 Day 1: No Change	41.2 percentage of participants	58.3 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 2 Day 1: No Change	50.7 percentage of participants	45.5 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 2 Day 1: A Little Better	13.4 percentage of participants	13.6 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 2 Day 1: Moderately Better	7.5 percentage of participants	9.1 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 2 Day 1: Very Much Better	1.5 percentage of participants	9.1 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 3 Day 1: Very Much Worse	0.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 3 Day 1: A Little Worse	5.9 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 3 Day 1: No Change	64.7 percentage of participants	50.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Appetite Change: Cycle 3 Day 1: A Little Better	11.8 percentage of participants	25.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 2 Day 1: Very Much Worse	0.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 2 Day 1: Moderately Worse	9.0 percentage of participants	13.6 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 2 Day 1: Very Much Better	0.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 3 Day 1: A Little Worse	11.8 percentage of participants	8.3 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 3 Day 1: No Change	60.8 percentage of participants	66.7 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 3 Day 1: A Little Better	7.8 percentage of participants	8.3 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 3 Day 1: Moderately Better	11.8 percentage of participants	8.3 percentage of participants	—
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) Pain Change: Cycle 3 Day 1: Very Much Better	3.9 percentage of participants	8.3 percentage of participants	—

SECONDARY outcome

Timeframe: Cycle 2 Day 1 and Cycle 3 Day 1

The anchor-based questionnaire PGI-S contains the following 3 items (the severity of the physical functioning decline over the past week, the severity of the appetite decrease over the past week, and the severity of the pain over the past week). The PGI-S was measured using the possible outcomes none, mild, moderate, severe, and very severe. Percentages are rounded off to whole number at the nearest decimal.

Outcome measures

Outcome measures
Measure	AG-120 n=67 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=22 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Physical Decline: Cycle 2 Day 1: None	55.2 percentage of participants	31.8 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Physical Decline: Cycle 2 Day 1: Very Severe	1.5 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Physical Decline: Cycle 3 Day 1: None	70.6 percentage of participants	75.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Physical Decline: Cycle 3 Day 1: Moderate	15.7 percentage of participants	8.3 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Physical Decline: Cycle 3 Day 1: Severe	2.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Appetite Decrease: Cycle 2 Day 1: Mild	32.8 percentage of participants	13.6 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Appetite Decrease: Cycle 2 Day 1: Moderate	10.4 percentage of participants	36.4 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Appetite Decrease: Cycle 2 Day 1: Very Severe	1.5 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Appetite Decrease: Cycle 3 Day 1: None	70.6 percentage of participants	58.3 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Appetite Decrease: Cycle 3 Day 1: Mild	15.7 percentage of participants	25.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Appetite Decrease: Cycle 3 Day 1: Severe	5.9 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Appetite Decrease: Cycle 3 Day 1: Very Severe	0.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Pain Severity: Cycle 2 Day 1: Moderate	23.9 percentage of participants	40.9 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Pain Severity: Cycle 2 Day 1: Severe	4.5 percentage of participants	9.1 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Pain Severity: Cycle 3 Day 1: Mild	35.3 percentage of participants	25.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Pain Severity: Cycle 3 Day 1: Moderate	17.6 percentage of participants	41.7 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Appetite Decrease: Cycle 3 Day 1: Moderate	7.8 percentage of participants	16.7 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Pain Severity: Cycle 2 Day 1: None	32.8 percentage of participants	31.8 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Pain Severity: Cycle 2 Day 1: Mild	38.8 percentage of participants	13.6 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Pain Severity: Cycle 2 Day 1: Very Severe	0.0 percentage of participants	4.5 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Pain Severity: Cycle 3 Day 1: None	39.2 percentage of participants	33.3 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Pain Severity: Cycle 3 Day 1: Severe	7.8 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Pain Severity: Cycle 3 Day 1: Very Severe	0.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Physical Decline: Cycle 2 Day 1: Mild	23.9 percentage of participants	27.3 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Physical Decline: Cycle 2 Day 1: Moderate	16.4 percentage of participants	31.8 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Physical Decline: Cycle 2 Day 1: Severe	3.0 percentage of participants	9.1 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Physical Decline: Cycle 3 Day 1: Mild	11.8 percentage of participants	16.7 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Physical Decline: Cycle 3 Day 1: very Severe	0.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Appetite Decrease: Cycle 2 Day 1: None	53.7 percentage of participants	45.5 percentage of participants	—
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) Appetite Decrease: Cycle 2 Day 1: Severe	1.5 percentage of participants	4.5 percentage of participants	—

SECONDARY outcome

Timeframe: Cycle 3 Day 1

The EQ-5D-5L assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Percentages are rounded off to whole number at the nearest decimal.

Outcome measures

Outcome measures
Measure	AG-120 n=50 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=12 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Mobility: Slight Problems Walking	28.0 percentage of participants	25.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Mobility: Moderate Problems Walking	16.0 percentage of participants	33.3 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Mobility: Severe Problems Walking	4.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Mobility: Unable to Walk	0.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Self-Care: Moderate Problems Washing or Dressing	2.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Self-Care: Severe Problems Washing or Dressing	2.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Usual Activities: Moderate Problems Doing Usual Activities	16.0 percentage of participants	25.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Usual Activities: Severe Problems Doing Usual Activities	8.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Usual Activities: Unable to do Usual Activities	0.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Pain/Discomfort: No Pain or Discomfort	40.0 percentage of participants	41.7 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Pain/Discomfort: Slight Pain or Discomfort	42.0 percentage of participants	33.3 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Pain/Discomfort: Moderate Pain or Discomfort	10.0 percentage of participants	25.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Pain/Discomfort: Severe Pain or Discomfort	6.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Anxiety/Depression: Slightly Anxious or Depressed	44.0 percentage of participants	33.3 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Mobility: No Problems Walking	52.0 percentage of participants	41.7 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Self-Care: No Problems Washing or Dressing	88.0 percentage of participants	83.3 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Self-Care: Slight Problems Washing or Dressing	8.0 percentage of participants	16.7 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Usual Activities: No Problems Doing Usual Activities	42.0 percentage of participants	33.3 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Usual Activities: Slight Problems Doing Usual Activities	34.0 percentage of participants	41.7 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Pain/Discomfort: Extreme Pain or Discomfort	2.0 percentage of participants	0.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Anxiety/Depression: Not Anxious or Depressed	50.0 percentage of participants	33.3 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Anxiety/Depression: Moderately Anxious or Depressed	6.0 percentage of participants	25.0 percentage of participants	—
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response Anxiety/Depression: Severely Anxious or Depressed	0.0 percentage of participants	8.3 percentage of participants	—

SECONDARY outcome

Timeframe: Cycle 3 Day 1

The EQ visual analogue scale records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled "The best health you can imagine" and "The worst health you can imagine." Responses are marked on a 0-100 scale with higher scores indicating higher health-related quality of life (i.e., better outcome).

Outcome measures

Outcome measures
Measure	AG-120 n=46 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo n=9 Participants Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Change From Baseline in EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) Score	4.6 score on a scale Standard Deviation 13.48	-2.8 score on a scale Standard Deviation 7.76	—

SECONDARY outcome

Timeframe: Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)

Population: Pharmacokinetic (PK) Analysis Population consisted of all participants who were enrolled and received at least one dose of study medication (AG-120) with sufficient plasma sample data to assess PK parameters. Number analyzed is the number of participants with data available for analyses at the specified time point.

Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=142 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Maximum Observed Plasma Concentration (Cmax) of AG-120 Cycle 1 Day 1	4424.0 ng/mL Standard Deviation 1808.07	—	—
Maximum Observed Plasma Concentration (Cmax) of AG-120 Cycle 2 Day 1	5050.5 ng/mL Standard Deviation 1666.07	—	—

SECONDARY outcome

Timeframe: Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)

Population: PK Analysis Population consisted of all participants who were enrolled and received at least one dose of study medication (AG-120) with sufficient plasma sample data to assess PK parameters. Number analyzed is the number of participants with data available for analyses at the specified time point.

Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=142 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Time to Reach Maximal Plasma Concentration (Tmax) of AG-120 Cycle 1 Day 1	2.63 hours (h) Interval 0.5 to 4.87	—	—
Time to Reach Maximal Plasma Concentration (Tmax) of AG-120 Cycle 2 Day 1	2.07 hours (h) Interval 0.5 to 4.08	—	—

SECONDARY outcome

Timeframe: Post-dose of Cycle 2 Day 1 (each cycle = 28 days)

Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=107 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24)	91219.4 h*ng/mL Standard Deviation 31574.57	—	—

SECONDARY outcome

Timeframe: Post-dose of Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)

Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=141 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) Cycle 1 Day 1	10972.2 h*ng/mL Standard Deviation 5044.1	—	—
Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) Cycle 2 Day 1	16651.7 h*ng/mL Standard Deviation 5269.9	—	—

SECONDARY outcome

Timeframe: Post-dose Cycle 2 Day 1 (each cycle = 28 days)

Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=98 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Accumulation Ratio Based on AUC0-4 (Racc AUC0-4)	1.6881 ratio Standard Deviation 0.83303	—	—

SECONDARY outcome

Timeframe: Post-dose Cycle 2 Day 1 (each cycle = 28 days)

Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=100 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Accumulation Ratio Based on Cmax (Racc Cmax)	1.2369 ratio Standard Deviation 0.50798	—	—

SECONDARY outcome

Timeframe: Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)

Population: Pharmacodynamic (PD) Analysis Population consisted of all participants who were enrolled and received any dose of study medication (AG-120) with sufficient plasma sample data to assess pharmacodynamic parameters. Number analyzed is the number of participants with data available for analyses at the specified time point.

B is the Baseline Effect Value. Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=142 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: B (Baseline Effect Value) Cycle 1 Day 1	1107.70 ng/mL Standard Deviation 1709.919	—	—
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: B (Baseline Effect Value) Cycle 2 Day 1	795.09 ng/mL Standard Deviation 938.677	—	—

SECONDARY outcome

Timeframe: Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)

Population: PD Analysis Population consisted of all participants who were enrolled and received any dose of study medication (AG-120) with sufficient plasma sample data to assess pharmacodynamic parameters. Number analyzed is the number of participants with data available for analyses at the specified time point.

AUEC0-4 is the area of the response curve from time point zero (predose) up to 4 hr postdose. Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=141 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: AUEC0-4 Cycle 1 Day 1	3334.3 h*ng/mL Standard Deviation 4785.48	—	—
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: AUEC0-4 Cycle 2 Day 1	368.4 h*ng/mL Standard Deviation 278.78	—	—

SECONDARY outcome

Timeframe: Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)

%BAUEC0-4 is the percent inhibition for AUEC0-4. Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=141 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4 Cycle 1 Day 1	20.22090 percent Standard Deviation 10.13659	—	—
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4 Cycle 2 Day 1	74.9750 percent Standard Deviation 22.53852	—	—

SECONDARY outcome

Timeframe: Post-dose Cycle 2 Day 1 (each cycle = 28 days)

Rtrough is the observed response value at the end of a dosing interval. Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=108 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: Rtrough	97.66 ng/mL Standard Deviation 72.838	—	—

SECONDARY outcome

Timeframe: Post-dose Cycle 2 Day 1 (each cycle = 28 days)

%BRtrough is the percent inhibition for Rtrough. Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint.

Outcome measures

Outcome measures
Measure	AG-120 n=108 Participants Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.	Placebo Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.	After Crossover to AG-120 Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BRtrough	73.726 percent Standard Deviation 23.3113	—	—

Adverse Events

AG-120

Serious events: 43 serious events

Other events: 118 other events

Deaths: 99 deaths

Placebo

Serious events: 14 serious events

Other events: 56 other events

Deaths: 14 deaths

After Cross Over to AG-120

Serious events: 12 serious events

Other events: 36 other events

Deaths: 34 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Affairs

Servier Pharmaceuticals LLC

Phone: 888-788-1735

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The information obtained from the clinical study will be used towards the development of ivosidenib and may be disclosed to regulatory authority(ies), other Investigators, corporate partners, or consultants as required.
Publication restrictions are in place

Restriction type: OTHER