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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-controlled Study of AG-120 in Previously-treated Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation

Conditions
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Advanced Cholangiocarcinoma, Metastatic Cholangiocarcinoma

Intervention / Treatment
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* Drug: AG-120
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be ≥18 years of age. 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. 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). Have an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 Have an expected survival of ≥3 months. 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. 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: Received a prior IDH inhibitor. 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. Received radiotherapy to metastatic sites of disease <2 weeks prior to Day 1. Underwent hepatic radiation, chemoembolization, and radiofrequency ablation <4 weeks prior to Day 1. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients randomized in a 2:1 allocation (AG-120 vs Placebo)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AG-120<br>Participants received AG-120 500 mg, tablet, orally, once a day (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. | Drug: AG-120<br>* Tablet administered orally<br>* Other names: Ivosidenib;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* Tablet administered orally<br>|
| Experimental: After Cross over to AG-120<br>Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months. | Drug: AG-120<br>* Tablet administered orally<br>* Other names: Ivosidenib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From first dose of study drug up to 28 days after last dose for each intervention (Up to approximately 4 Years) | 
| 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. | From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years) | 
| 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. | From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years) | 
| 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. | Baseline | 
| 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. | From first dose of study drug up to 28 days after last dose (Up to approximately 4 Years) | 
| 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) | 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. | From date of randomization until the date of death due to any cause (Up to approximately 2 years) | 
| 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. | From the date of randomization up to confirmed CR or PR (Up to approximately 2 years) | 
| 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. | From the date of randomization up to confirmed CR or PR (Up to approximately 2 years) | 
| 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. | From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years) | 
| 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. | From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years) | 
| 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. | From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years) | 
| 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. | From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years) | 
| 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. | 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) | 
| 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. | Cycle 2 Day 1 and Cycle 3 Day 1 | 
| 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). | Cycle 2 Day 1 and Cycle 3 Day 1 | 
| 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. | Cycle 2 Day 1 and Cycle 3 Day 1 | 
| 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. | Cycle 2 Day 1 and Cycle 3 Day 1 | 
| 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. | Cycle 3 Day 1 | 
| 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). | Cycle 3 Day 1 | 
| 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. | Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days) | 
| 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. | Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days) | 
| 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. | Post-dose of Cycle 2 Day 1 (each cycle = 28 days) | 
| 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. | Post-dose of Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days) | 
| Accumulation Ratio Based on AUC0-4 (Racc AUC0-4) | Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint. | Post-dose Cycle 2 Day 1 (each cycle = 28 days) | 
| Accumulation Ratio Based on Cmax (Racc Cmax) | Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint. | Post-dose Cycle 2 Day 1 (each cycle = 28 days) | 
| 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. | Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days) | 
| 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. | Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days) | 
| 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. | Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days) | 
| 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. | Post-dose Cycle 2 Day 1 (each cycle = 28 days) | 
| 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. | Post-dose Cycle 2 Day 1 (each cycle = 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IDH1