TriangleNCT02989857 · CITED IN SOURCE DOCUMENTS
Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy)
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE3
- Status at capture
- COMPLETED
- Registry last update
- 2024-08-20
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.
Open the original ClinicalTrials.gov record → · Download preserved record
What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC)
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events
Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs
Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status
Percentage of Participants Who Required At Least One Concomitant Medications During the Treatment
Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events
Overall Survival (OS)
Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1
ORR as Assessed by the IRC Per RECIST v1.1
Duration of Response (DOR) as Assessed by the Investigator
DOR as Assessed by the IRC Per RECIST v1.1
Time to Response (TTR) as Assessed by the Investigator
TTR as Assessed by the IRC Per RECIST v1.1
PFS as Determined by Investigator
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
Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21)
Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C)
Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S)
Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response
Change From Baseline in EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) Score
Maximum Observed Plasma Concentration (Cmax) of AG-120
Time to Reach Maximal Plasma Concentration (Tmax) of AG-120
Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24)
Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4)
Accumulation Ratio Based on AUC0-4 (Racc AUC0-4)
Accumulation Ratio Based on Cmax (Racc Cmax)
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: B (Baseline Effect Value)
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: AUEC0-4
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: Rtrough
Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BRtrough
Adverse events
Limitations, agreements, and source contact
Who could take part
- eligibility Criteria
- 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.
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- 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.
- intervention Names
- Drug: AG-120
- label
- AG-120
- type
- ACTIVE_COMPARATOR
- description
- 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.
- intervention Names
- Drug: Placebo
- label
- Placebo
- type
- PLACEBO_COMPARATOR
- description
- 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.
- intervention Names
- Drug: AG-120
- label
- After Cross over to AG-120
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- AG-120
- After Cross over to AG-120
- description
- Tablet administered orally
- name
- AG-120
- other Names
- Ivosidenib
- type
- DRUG
- arm Group Labels
- Placebo
- description
- Tablet administered orally
- name
- Placebo
- type
- DRUG
Study design
- allocation
- RANDOMIZED
- intervention Model
- PARALLEL
- intervention Model Description
- Patients randomized in a 2:1 allocation (AG-120 vs Placebo)
- masking Info
- masking
- DOUBLE
- who Masked
- PARTICIPANT
- INVESTIGATOR
- primary Purpose
- TREATMENT
Enrollment
- count
- 187
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- 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.
- measure
- Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC)
- 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)
- secondary Outcomes
- description
- 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.
- measure
- Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
- time Frame
- From first dose of study drug up to 28 days after last dose for each intervention (Up to approximately 4 Years)
- description
- 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.
- measure
- Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events
- time Frame
- From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years)
- description
- 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.
- measure
- Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs
- time Frame
- From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years)
- description
- 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.
- measure
- Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status
- time Frame
- Baseline
- description
- 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.
- measure
- Percentage of Participants Who Required At Least One Concomitant Medications During the Treatment
- time Frame
- From first dose of study drug up to 28 days after last dose (Up to approximately 4 Years)
- measure
- 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)
- description
- 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.
- measure
- Overall Survival (OS)
- time Frame
- From date of randomization until the date of death due to any cause (Up to approximately 2 years)
- description
- 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.
- measure
- Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1
- time Frame
- From the date of randomization up to confirmed CR or PR (Up to approximately 2 years)
- description
- 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.
- measure
- ORR as Assessed by the IRC Per RECIST v1.1
- time Frame
- From the date of randomization up to confirmed CR or PR (Up to approximately 2 years)
- description
- 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.
- measure
- Duration of Response (DOR) as Assessed by the Investigator
- time Frame
- From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years)
- description
- 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.
- measure
- DOR as Assessed by the IRC Per RECIST v1.1
- time Frame
- From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years)
- description
- 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.
- measure
- Time to Response (TTR) as Assessed by the Investigator
- time Frame
- From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years)
Full study description
- 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.
Source references
- avail Ipds
- type
- Individual Participant Data Set
- type
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- type
- Statistical Analysis Plan
- type
- Informed Consent Form
- type
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- references
- citation
- Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, Catenacci DV, Borad MJ, Bridgewater J, Harris WP, Murphy AG, Oh DY, Whisenant J, Lowery MA, Goyal L, Shroff RT, El-Khoueiry AB, Fan B, Wu B, Chamberlain CX, Jiang L, Gliser C, Pandya SS, Valle JW, Zhu AX. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Jun;21(6):796-807. doi: 10.1016/S1470-2045(20)30157-1. Epub 2020 May 13.
- pmid
- 32416072
- type
- BACKGROUND
- citation
- Valle JW, Abou-Alfa GK, Kelley RK, Lowery MA, Shroff RT, Bian Y, Saint-Hilary G, Liu H, Teng Z, Hua Z, Gliser C, Vogel A, Javle MM. Quantitative benefit-risk assessment of data from the phase III ClarIDHy study of ivosidenib versus placebo in patients with mIDH1 cholangiocarcinoma. ESMO Gastrointest Oncol. 2025 Apr 3;8:100159. doi: 10.1016/j.esmogo.2025.100159. eCollection 2025 Jun.
- pmid
- 41646284
- type
- DERIVED
- citation
- Fan B, Abou-Alfa GK, Zhu AX, Pandya SS, Jia H, Yin F, Gliser C, Hua Z, Hossain M, Yang H. Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study. Cancer Chemother Pharmacol. 2024 May;93(5):471-479. doi: 10.1007/s00280-023-04633-5. Epub 2024 Jan 27.
- pmid
- 38278871
- type
- DERIVED
- citation
- Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, Catenacci DVT, Borad MJ, Bridgewater JA, Harris WP, Murphy AG, Oh DY, Whisenant JR, Lowery MA, Goyal L, Shroff RT, El-Khoueiry AB, Chamberlain CX, Aguado-Fraile E, Choe S, Wu B, Liu H, Gliser C, Pandya SS, Valle JW, Abou-Alfa GK. Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial. JAMA Oncol. 2021 Nov 1;7(11):1669-1677. doi: 10.1001/jamaoncol.2021.3836.
- pmid
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- DERIVED
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Discovery and provenance
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- holangiocarcinoma The efficacy of TIBSOVO was evaluated in a randomized (2:1), multicenter, double-blind, placebo-controlled clinical trial (Study AG120-C-005, NCT02989857) of 185 adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation whose disease had progressed following at least 1 but not m
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- <p id="_586" tabindex="-1">Evidence (IDH1 inhibitors):</p> <div class="pdq-content-list"><ol id="_587"><li>The phase III <a href="/clinicaltrials/NCT02989857">ClarIDHy</a> trial (NCT02989857) included 187 patients with cholangiocarcinoma and <em class="gene-name">IDH1</em> variants. Patients had disease that had pro
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- idence (IDH1 inhibitors):</p> <div class="pdq-content-list"><ol id="_587"><li>The phase III <a href="/clinicaltrials/NCT02989857">ClarIDHy</a> trial (NCT02989857) included 187 patients with cholangiocarcinoma and <em class="gene-name">IDH1</em> variants. Patients had disease that had progressed during previous systemic
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Preserved source evidence · Not medical advice