Advanced Cholangiocarcinoma, Metastatic Cholangiocarcinoma
Conditions
Keywords
IDH1
Brief summary
Study AG120-C-005 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of orally administered AG-120. Participants, all personnel involved in the evaluation of participants' response to treatment (e.g., Investigators, study coordinators, study pharmacists), and designated Sponsor team members will be blinded to study treatment. Participants are required to have a histologically-confirmed diagnosis of isocitrate dehydrogenase-1 (IDH1) gene-mutated cholangiocarcinoma that is not eligible for curative resection, transplantation, or ablative therapies prior to enrollment. IDH1 mutation testing will be performed at participating investigative sites. Participants must have progression of disease and have received at least 1 but not more than 2 prior treatment regimens for advanced disease (nonresectable or metastatic). All participants must have received either a gemcitabine or a 5 fluorouracil (5-FU) based chemotherapy regimen.
Interventions
DRUGAG-120
Tablet administered orally
DRUGPlacebo
Tablet administered orally
Sponsors
Institut de Recherches Internationales Servier
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Patients randomized in a 2:1 allocation (AG-120 vs Placebo)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Be ≥18 years of age. 2. Have a histopathological diagnosis (fresh or banked tumor biopsy sample, preferably collected within the last 3 years) of nonresectable or metastatic cholangiocarcinoma and are not eligible for curative resection, transplantation, or ablative therapies. 3. Have documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most recent banked tumor tissue available) based on central laboratory testing (R132C/L/G/H/S mutation variants tested). 4. Have an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 5. Have an expected survival of ≥3 months. 6. Have at least one evaluable and measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Participants who have received prior local therapy (including but not limited to embolization, chemoembolization, radiofrequency ablation, or radiation therapy) are eligible provided measurable disease falls outside of the treatment field or within the field and has shown ≥20% growth in size since post-treatment assessment. 7. Have documented disease progression following at least 1 and no more than 2 prior systemic regimens for advanced disease (nonresectable or metastatic). Participants must have received at least 1 gemcitabine- or 5-FU-containing regimen for advanced cholangiocarcinoma. Participants who have received systemic adjuvant chemotherapy will be permitted provided there is documented disease progression during or within 6 months of completing the therapy.
Exclusion criteria
1. Received a prior IDH inhibitor. 2. Received systemic anticancer therapy or an investigational agent \<2 weeks prior to Day 1 (washout from prior immune based anticancer therapy is 4 weeks). In addition, the first dose of study treatment should not occur before a period ≥5 half-lives of the investigational agent has elapsed. 3. Received radiotherapy to metastatic sites of disease \<2 weeks prior to Day 1. 4. Underwent hepatic radiation, chemoembolization, and radiofrequency ablation \<4 weeks prior to Day 1. 5. Have known symptomatic brain metastases requiring steroids. Participants with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and have radiographically stable disease for at least 3 months prior to study entry. Note: up to 10 mg per day of prednisone equivalent will be allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC) | 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 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years) | 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. |
| Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years) | 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. |
| Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline | 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. |
| Percentage of Participants Who Required At Least One Concomitant Medications During the Treatment | From first dose of study drug up to 28 days after last dose (Up to approximately 4 Years) | 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. |
| Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events | 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) | — |
| Overall Survival (OS) | From date of randomization until the date of death due to any cause (Up to approximately 2 years) | 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. |
| Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1 | From the date of randomization up to confirmed CR or PR (Up to approximately 2 years) | 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. |
| ORR as Assessed by the IRC Per RECIST v1.1 | 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. |
| Duration of Response (DOR) as Assessed by the Investigator | From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years) | 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. |
| DOR as Assessed by the IRC Per RECIST v1.1 | From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years) | 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. |
| Time to Response (TTR) as Assessed by the Investigator | From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years) | 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. |
| TTR as Assessed by the IRC Per RECIST v1.1 | From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years) | 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. |
| PFS as Determined by Investigator | 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. |
| 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 and Cycle 3 Day 1 | 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. |
| Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21) | 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). |
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose of study drug up to 28 days after last dose for each intervention (Up to approximately 4 Years) | 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. |
| Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | 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. |
| Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | 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. |
| Change From Baseline in EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) Score | 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). |
| Maximum Observed Plasma Concentration (Cmax) of AG-120 | Post-dose 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. |
| Time to Reach Maximal Plasma Concentration (Tmax) of AG-120 | Post-dose 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. |
| Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) | 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. |
| Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) | 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. |
| Accumulation Ratio Based on AUC0-4 (Racc AUC0-4) | Post-dose Cycle 2 Day 1 (each cycle = 28 days) | Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint. |
| Accumulation Ratio Based on Cmax (Racc Cmax) | Post-dose Cycle 2 Day 1 (each cycle = 28 days) | Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint. |
| Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: B (Baseline Effect Value) | Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days) | 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. |
| Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: AUEC0-4 | Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days) | 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. |
| Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4 | 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. |
| Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: Rtrough | 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. |
| Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BRtrough | 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. |
| Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Cycle 2 Day 1 and Cycle 3 Day 1 | 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. |
Countries
France, Italy, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| AG-120 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. | 126 |
| 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. | 61 |
| Total | 187 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Randomization Phase | Not Treated | 3 | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | AG-120 |
|---|---|---|---|
| Age, Continuous | 62.9 years STANDARD_DEVIATION 10.38 | 61.1 years STANDARD_DEVIATION 10.82 | 60.3 years STANDARD_DEVIATION 10.97 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 2 Participants | 9 Participants | 7 Participants |
| Race/Ethnicity, Customized Ethnicity Missing | 17 Participants | 52 Participants | 35 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 40 Participants | 124 Participants | 84 Participants |
| Race/Ethnicity, Customized Ethnicity Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 8 Participants | 23 Participants | 15 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Missing | 17 Participants | 52 Participants | 35 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 35 Participants | 106 Participants | 71 Participants |
| Sex: Female, Male Female | 37 Participants | 119 Participants | 82 Participants |
| Sex: Female, Male Male | 24 Participants | 68 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 99 / 126 | 14 / 61 | 34 / 43 |
| other Total, other adverse events | 118 / 123 | 56 / 59 | 36 / 43 |
| serious Total, serious adverse events | 43 / 123 | 14 / 59 | 12 / 43 |
Outcome results
Primary
Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC)
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AG-120 | Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC) | 2.7 months |
| Placebo | Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC) | 1.4 months |
p-value: <0.000195% CI: [0.25, 0.54]Log Rank
Secondary
Accumulation Ratio Based on AUC0-4 (Racc AUC0-4)
Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint.
Time frame: Post-dose 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-120 | Accumulation Ratio Based on AUC0-4 (Racc AUC0-4) | 1.6881 ratio | Standard Deviation 0.83303 |
Secondary
Accumulation Ratio Based on Cmax (Racc Cmax)
Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint.
Time frame: Post-dose 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-120 | Accumulation Ratio Based on Cmax (Racc Cmax) | 1.2369 ratio | Standard Deviation 0.50798 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24)
Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint.
Time frame: Post-dose of 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-120 | 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
Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4)
Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint.
Time frame: Post-dose of 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-120 | 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 |
| AG-120 | 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
Change From Baseline in EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) Score
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).
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-120 | 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 |
| Placebo | Change From Baseline in EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) Score | -2.8 score on a scale | Standard Deviation 7.76 |
Secondary
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
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.
Time frame: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 2.6 |
| AG-120 | 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 |
| AG-120 | 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 |
| Placebo | 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 | 3.2 score on a scale | Standard Error 6.4 |
| Placebo | 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 | -13.3 score on a scale | Standard Error 2.95 |
| Placebo | 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 | 12.5 score on a scale | Standard Error 4.35 |
| Placebo | 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 | 4.3 score on a scale | Standard Error 4.55 |
| Placebo | 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 | -12.6 score on a scale | Standard Error 3.88 |
| Placebo | 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 | -5.3 score on a scale | Standard Error 5.96 |
Comparison: Cycle 2 Day 1: Physical Functioning95% CI: [4.23, 17.73]
Comparison: Cycle 2 Day 1: Pain95% CI: [-20.18, -0.52]
Comparison: Cycle 2 Day 1: Appetite Loss95% CI: [-6.65, 13.91]
Comparison: Cycle 3 Day 1: Physical Functioning95% CI: [3.85, 20.78]
Comparison: Cycle 3 Day 1: Pain95% CI: [-8.74, 17.04]
Comparison: Cycle 3 Day 1: Appetite Loss95% CI: [-17.46, 10.11]
Secondary
Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21)
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).
Time frame: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| Placebo | Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21) | Cycle 3 Day 1: Appetite Loss | 4.1 score on a scale | Standard Error 4.24 |
| Placebo | Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21) | Cycle 2 Day 1: Pain | 10.1 score on a scale | Standard Error 3.49 |
| Placebo | Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21) | Cycle 3 Day 1: Pain | -2.1 score on a scale | Standard Error 4.7 |
| Placebo | Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21) | Cycle 2 Day 1: Appetite Loss | 3.6 score on a scale | Standard Error 3.19 |
Comparison: Cycle 2 Day 1: Pain95% CI: [-12.93, 2.8]
Comparison: Cycle 2 Day 1: Appetite Loss95% CI: [-6.56, 7.88]
Comparison: Cycle 3 Day 1: Pain95% CI: [-5.82, 14.55]
Comparison: Cycle 3 Day 1: Appetite Loss95% CI: [-15.34, 3.12]
Secondary
DOR as Assessed by the IRC Per RECIST v1.1
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AG-120 | DOR as Assessed by the IRC Per RECIST v1.1 | NA months |
Secondary
Duration of Response (DOR) as Assessed by the Investigator
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AG-120 | Duration of Response (DOR) as Assessed by the Investigator | NA months |
| Placebo | Duration of Response (DOR) as Assessed by the Investigator | NA months |
Secondary
Maximum Observed Plasma Concentration (Cmax) of AG-120
Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-120 | Maximum Observed Plasma Concentration (Cmax) of AG-120 | Cycle 1 Day 1 | 4424.0 ng/mL | Standard Deviation 1808.07 |
| AG-120 | Maximum Observed Plasma Concentration (Cmax) of AG-120 | Cycle 2 Day 1 | 5050.5 ng/mL | Standard Deviation 1666.07 |
Secondary
Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AG-120 | Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1 | 3.2 percentage of participants |
| Placebo | Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1 | 1.6 percentage of participants |
p-value: 0.466Fisher Exact
Secondary
ORR as Assessed by the IRC Per RECIST v1.1
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AG-120 | ORR as Assessed by the IRC Per RECIST v1.1 | 2.4 percentage of participants |
| Placebo | ORR as Assessed by the IRC Per RECIST v1.1 | 0 percentage of participants |
p-value: 0.299Fisher Exact
Secondary
Overall Survival (OS)
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AG-120 | Overall Survival (OS) | 10.3 months |
| Placebo | Overall Survival (OS) | 7.5 months |
p-value: 0.09395% CI: [0.56, 1.12]Log Rank
Secondary
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events
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.
Time frame: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyperbilirubinaemia | 3.3 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Uric Acid Increased | 0.0 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Anaemia | 7.3 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Platelet Count Decreased | 2.4 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Neutrophil Count Decreased | 1.6 percentage of participants |
| AG-120 | 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 |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Lymphocyte Count Decreased | 0.8 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Thrombocytopenia | 0.8 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Loss Anaemia | 0.8 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Bilirubin Increased | 5.7 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyponatraemia | 5.7 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Aspartate Aminotransferase Increased | 4.9 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypophosphataemia | 3.3 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyperkalaemia | 2.4 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Alkaline Phosphatase Increased | 2.4 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Alanine Aminotransferase Increased | 1.6 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypoalbuminaemia | 1.6 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Gamma-glutamyltransferase Increased | 0.8 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypercalcaemia | 0.8 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyperuricaemia | 0.8 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypokalaemia | 0.8 percentage of participants |
| AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Transaminases Increased | 0.8 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypokalaemia | 1.7 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyperbilirubinaemia | 0.0 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypercalcaemia | 1.7 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Alanine Aminotransferase Increased | 0.0 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyperuricaemia | 0.0 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Anaemia | 0.0 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypophosphataemia | 5.1 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyponatraemia | 10.2 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Platelet Count Decreased | 0.0 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Bilirubin Increased | 1.7 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypoalbuminaemia | 1.7 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Neutrophil Count Decreased | 0.0 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Loss Anaemia | 0.0 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyperkalaemia | 3.4 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | White Blood Cell Count Decreased | 0.0 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Aspartate Aminotransferase Increased | 1.7 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Uric Acid Increased | 1.7 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Lymphocyte Count Decreased | 3.4 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Alkaline Phosphatase Increased | 5.1 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Gamma-glutamyltransferase Increased | 1.7 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Thrombocytopenia | 0.0 percentage of participants |
| Placebo | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Transaminases Increased | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Thrombocytopenia | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Loss Anaemia | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Bilirubin Increased | 7.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypercalcaemia | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyponatraemia | 2.3 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Transaminases Increased | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Aspartate Aminotransferase Increased | 4.7 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypophosphataemia | 4.7 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyperbilirubinaemia | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyperuricaemia | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hyperkalaemia | 2.3 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Alkaline Phosphatase Increased | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Alanine Aminotransferase Increased | 2.3 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Anaemia | 9.3 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypokalaemia | 2.3 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Platelet Count Decreased | 2.3 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Neutrophil Count Decreased | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Hypoalbuminaemia | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | White Blood Cell Count Decreased | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Blood Uric Acid Increased | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Lymphocyte Count Decreased | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events | Gamma-glutamyltransferase Increased | 0.0 percentage of participants |
Secondary
Percentage of Participants Who Required At Least One Concomitant Medications During the Treatment
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.
Time frame: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AG-120 | Percentage of Participants Who Required At Least One Concomitant Medications During the Treatment | 99.2 percentage of participants |
| Placebo | Percentage of Participants Who Required At Least One Concomitant Medications During the Treatment | 98.3 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants Who Required At Least One Concomitant Medications During the Treatment | 95.3 percentage of participants |
Secondary
Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events
Time frame: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-120 | Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events | Electrocardiogram Abnormal | 0.8 percentage of participants |
| AG-120 | Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events | Electrocardiogram QT Prolonged | 9.8 percentage of participants |
| Placebo | Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events | Electrocardiogram QT Prolonged | 3.4 percentage of participants |
| Placebo | Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events | Electrocardiogram Abnormal | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events | Electrocardiogram QT Prolonged | 2.3 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events | Electrocardiogram Abnormal | 0.0 percentage of participants |
Secondary
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-120 | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 97.6 percentage of participants |
| AG-120 | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 35.0 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 96.6 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 23.7 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 95.3 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 27.9 percentage of participants |
Secondary
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C)
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 2 Day 1: No Change | 54.5 percentage of participants |
| Placebo | 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 |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 2 Day 1: Very Much Worse | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 3 Day 1: A Little Better | 8.3 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 2 Day 1: Moderately Worse | 13.6 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 3 Day 1: Moderately Worse | 8.3 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 2 Day 1: A Little Worse | 9.1 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 2 Day 1: A Little Better | 18.2 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 2 Day 1: No Change | 27.3 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 3 Day 1: A Little Worse | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 2 Day 1: A Little Better | 36.4 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 3 Day 1: A Little Worse | 8.3 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 2 Day 1: Moderately Better | 9.1 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 3 Day 1: No Change | 50.0 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 2 Day 1: Very Much Better | 4.5 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 3 Day 1: Very Much Worse | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 2 Day 1: Moderately Better | 4.5 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 3 Day 1: Moderately Worse | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 3 Day 1: A Little Better | 25.0 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 3 Day 1: A Little Worse | 8.3 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 3 Day 1: Very Much Better | 8.3 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 3 Day 1: No Change | 58.3 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 3 Day 1: Moderately Better | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 3 Day 1: A Little Better | 16.7 percentage of participants |
| Placebo | 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 |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 3 Day 1: Moderately Better | 16.7 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 3 Day 1: Very Much Better | 16.7 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Physical Change: Cycle 3 Day 1: Very Much Better | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 3 Day 1: No Change | 66.7 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 2 Day 1: Very Much Worse | 0.0 percentage of participants |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 2 Day 1: A Little Worse | 18.2 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 2 Day 1: Moderately Worse | 13.6 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 2 Day 1: No Change | 45.5 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 3 Day 1: Moderately Better | 8.3 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 2 Day 1: A Little Better | 13.6 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 2 Day 1: A Little Worse | 9.1 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 2 Day 1: Moderately Better | 9.1 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Pain Change: Cycle 3 Day 1: Moderately Worse | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C) | Appetite Change: Cycle 2 Day 1: Very Much Better | 9.1 percentage of participants |
Secondary
Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs
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.
Time frame: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-120 | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Hypotension | 1.6 percentage of participants |
| AG-120 | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Weight Decreased | 0.8 percentage of participants |
| AG-120 | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Hypertension | 1.6 percentage of participants |
| AG-120 | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Pyrexia | 0.8 percentage of participants |
| Placebo | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Weight Decreased | 1.7 percentage of participants |
| Placebo | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Pyrexia | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Hypertension | 1.7 percentage of participants |
| Placebo | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Hypotension | 1.7 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Hypertension | 7.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Weight Decreased | 0.0 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Pyrexia | 2.3 percentage of participants |
| After Crossover to AG-120 | Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs | Hypotension | 2.3 percentage of participants |
Secondary
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-120 | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Mobility: No Problems Walking | 52.0 percentage of participants |
| AG-120 | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Mobility: Slight Problems Walking | 28.0 percentage of participants |
| AG-120 | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Mobility: Moderate Problems Walking | 16.0 percentage of participants |
| AG-120 | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Mobility: Severe Problems Walking | 4.0 percentage of participants |
| AG-120 | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Mobility: Unable to Walk | 0.0 percentage of participants |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Usual Activities: Moderate Problems Doing Usual Activities | 25.0 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Mobility: No Problems Walking | 41.7 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Pain/Discomfort: Severe Pain or Discomfort | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Mobility: Slight Problems Walking | 25.0 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Usual Activities: Severe Problems Doing Usual Activities | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Mobility: Moderate Problems Walking | 33.3 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Anxiety/Depression: Slightly Anxious or Depressed | 33.3 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Mobility: Severe Problems Walking | 0.0 percentage of participants |
| Placebo | 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 |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Mobility: Unable to Walk | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Pain/Discomfort: Extreme Pain or Discomfort | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Self-Care: No Problems Washing or Dressing | 83.3 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Pain/Discomfort: No Pain or Discomfort | 41.7 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Self-Care: Slight Problems Washing or Dressing | 16.7 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Anxiety/Depression: Severely Anxious or Depressed | 8.3 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Self-Care: Moderate Problems Washing or Dressing | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Pain/Discomfort: Slight Pain or Discomfort | 33.3 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Self-Care: Severe Problems Washing or Dressing | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Anxiety/Depression: Not Anxious or Depressed | 33.3 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Usual Activities: No Problems Doing Usual Activities | 33.3 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Pain/Discomfort: Moderate Pain or Discomfort | 25.0 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Usual Activities: Slight Problems Doing Usual Activities | 41.7 percentage of participants |
| Placebo | Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response | Anxiety/Depression: Moderately Anxious or Depressed | 25.0 percentage of participants |
Secondary
Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status
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.
Time frame: Baseline
Population: ITT population included all participants who were randomized, with the treatment group designated according to the randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-120 | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | 1 | 59.5 percentage of participants |
| AG-120 | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | 3 | 0.8 percentage of participants |
| AG-120 | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | 0 | 39.7 percentage of participants |
| AG-120 | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | 4 | 0.0 percentage of participants |
| AG-120 | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | 2 | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | 4 | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | 0 | 31.1 percentage of participants |
| Placebo | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | 1 | 67.2 percentage of participants |
| Placebo | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | 2 | 1.6 percentage of participants |
| Placebo | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | 3 | 0.0 percentage of participants |
Secondary
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S)
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| AG-120 | 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 |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Appetite Decrease: Cycle 2 Day 1: Very Severe | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Pain Severity: Cycle 2 Day 1: Moderate | 40.9 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Appetite Decrease: Cycle 3 Day 1: None | 58.3 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Physical Decline: Cycle 2 Day 1: None | 31.8 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Pain Severity: Cycle 3 Day 1: Mild | 25.0 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Physical Decline: Cycle 2 Day 1: Mild | 27.3 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Appetite Decrease: Cycle 3 Day 1: Mild | 25.0 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Physical Decline: Cycle 2 Day 1: Moderate | 31.8 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Physical Decline: Cycle 2 Day 1: Severe | 9.1 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Pain Severity: Cycle 2 Day 1: Severe | 9.1 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Physical Decline: Cycle 2 Day 1: Very Severe | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Appetite Decrease: Cycle 3 Day 1: Moderate | 16.7 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Physical Decline: Cycle 3 Day 1: None | 75.0 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Pain Severity: Cycle 3 Day 1: Severe | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Physical Decline: Cycle 3 Day 1: Mild | 16.7 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Appetite Decrease: Cycle 3 Day 1: Severe | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Physical Decline: Cycle 3 Day 1: Moderate | 8.3 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Pain Severity: Cycle 3 Day 1: Moderate | 41.7 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Physical Decline: Cycle 3 Day 1: Severe | 0.0 percentage of participants |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Pain Severity: Cycle 3 Day 1: None | 33.3 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Appetite Decrease: Cycle 2 Day 1: None | 45.5 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Pain Severity: Cycle 2 Day 1: None | 31.8 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Appetite Decrease: Cycle 2 Day 1: Mild | 13.6 percentage of participants |
| Placebo | 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 |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Appetite Decrease: Cycle 2 Day 1: Moderate | 36.4 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Pain Severity: Cycle 2 Day 1: Mild | 13.6 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Appetite Decrease: Cycle 2 Day 1: Severe | 4.5 percentage of participants |
| Placebo | Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S) | Pain Severity: Cycle 2 Day 1: Very Severe | 4.5 percentage of participants |
Secondary
PFS as Determined by Investigator
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AG-120 | PFS as Determined by Investigator | 2.7 months |
| Placebo | PFS as Determined by Investigator | 1.4 months |
p-value: <0.000195% CI: [0.33, 0.68]Log Rank
Secondary
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: AUEC0-4
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-120 | Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: AUEC0-4 | Cycle 1 Day 1 | 3334.3 h*ng/mL | Standard Deviation 4785.48 |
| AG-120 | 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
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4
%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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-120 | Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4 | Cycle 1 Day 1 | 20.22090 percent | Standard Deviation 10.13659 |
| AG-120 | Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4 | Cycle 2 Day 1 | 74.9750 percent | Standard Deviation 22.53852 |
Secondary
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: B (Baseline Effect Value)
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-120 | 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 |
| AG-120 | 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
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BRtrough
%BRtrough is the percent inhibition for Rtrough. Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint.
Time frame: Post-dose 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-120 | Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BRtrough | 73.726 percent | Standard Deviation 23.3113 |
Secondary
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: Rtrough
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.
Time frame: Post-dose 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-120 | Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: Rtrough | 97.66 ng/mL | Standard Deviation 72.838 |
Secondary
Time to Reach Maximal Plasma Concentration (Tmax) of AG-120
Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-120 | Time to Reach Maximal Plasma Concentration (Tmax) of AG-120 | Cycle 1 Day 1 | 2.63 hours (h) |
| AG-120 | Time to Reach Maximal Plasma Concentration (Tmax) of AG-120 | Cycle 2 Day 1 | 2.07 hours (h) |
Secondary
Time to Response (TTR) as Assessed by the Investigator
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AG-120 | Time to Response (TTR) as Assessed by the Investigator | NA months |
| Placebo | Time to Response (TTR) as Assessed by the Investigator | NA months |
Secondary
TTR as Assessed by the IRC Per RECIST v1.1
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AG-120 | TTR as Assessed by the IRC Per RECIST v1.1 | NA months |