Clinical trial NCT02989857: Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Advanced Cholangiocarcinoma
Metastatic Cholangiocarcinoma
Keywords: IDH1
Lead sponsor: Servier
Sponsor class: INDUSTRY
First posted: 2016-12-12
Enrollment: 187
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients randomized in a 2:1 allocation (AG-120 vs Placebo)
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC)
timeFrame: From the date of randomization to the date of first documentation of disease progression or death due to any cause (Up to approximately 2 years)
Secondary outcomes:
measure: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study drug up to 28 days after last dose for each intervention (Up to approximately 4 Years)
measure: Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events
timeFrame: From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years)
measure: Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs
timeFrame: From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years)
measure: Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status
timeFrame: Baseline
measure: Percentage of Participants Who Required At Least One Concomitant Medications During the Treatment
timeFrame: 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
timeFrame: Pre-dose C1D1, C2D1; Post-dose C1D1, C1D15, C2D1 and Day 1 of C3D1 and all cycles thereafter up to last dose plus 28 days (Up to approximately 4 years)
measure: Overall Survival (OS)
timeFrame: From date of randomization until the date of death due to any cause (Up to approximately 2 years)
measure: Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1
timeFrame: From the date of randomization up to confirmed CR or PR (Up to approximately 2 years)
measure: ORR as Assessed by the IRC Per RECIST v1.1
timeFrame: From the date of randomization up to confirmed CR or PR (Up to approximately 2 years)
measure: Duration of Response (DOR) as Assessed by the Investigator
timeFrame: From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years)
measure: DOR as Assessed by the IRC Per RECIST v1.1
timeFrame: From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years)
measure: Time to Response (TTR) as Assessed by the Investigator
timeFrame: From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years)
measure: TTR as Assessed by the IRC Per RECIST v1.1
timeFrame: From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years)
measure: PFS as Determined by Investigator
timeFrame: From the date of randomization to the date of first documentation of disease progression or death due to any cause (Up to approximately 2 years)
measure: 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
timeFrame: Cycle 2 Day 1 and Cycle 3 Day 1
measure: Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21)
timeFrame: Cycle 2 Day 1 and Cycle 3 Day 1
measure: Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C)
timeFrame: Cycle 2 Day 1 and Cycle 3 Day 1
measure: Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S)
timeFrame: Cycle 2 Day 1 and Cycle 3 Day 1
measure: Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response
timeFrame: Cycle 3 Day 1
measure: Change From Baseline in EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) Score
timeFrame: Cycle 3 Day 1
measure: Maximum Observed Plasma Concentration (Cmax) of AG-120
timeFrame: Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
measure: Time to Reach Maximal Plasma Concentration (Tmax) of AG-120
timeFrame: Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
measure: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24)
timeFrame: Post-dose of Cycle 2 Day 1 (each cycle = 28 days)
measure: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4)
timeFrame: Post-dose of Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
measure: Accumulation Ratio Based on AUC0-4 (Racc AUC0-4)
timeFrame: Post-dose Cycle 2 Day 1 (each cycle = 28 days)
measure: Accumulation Ratio Based on Cmax (Racc Cmax)
timeFrame: Post-dose Cycle 2 Day 1 (each cycle = 28 days)
measure: Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: B (Baseline Effect Value)
timeFrame: Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
measure: Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: AUEC0-4
timeFrame: Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
measure: Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4
timeFrame: Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
measure: Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: Rtrough
timeFrame: Post-dose Cycle 2 Day 1 (each cycle = 28 days)
measure: Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BRtrough
timeFrame: Post-dose Cycle 2 Day 1 (each cycle = 28 days)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Cancer Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope Cancer Center
state: California
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Jacksonville
country: United States
facility: Mayo Cancer Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Cancer Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Spartanburg
country: United States
facility: Gibbs Cancer Center
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas, SouthWestern
state: Texas
city: Houston
country: United States
facility: UT MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Madison
country: United States
facility: University of Wisconsin, Carbone Cancer Center
state: Wisconsin
city: Besançon
country: France
facility: Universite de Franche-Comte
city: Bordeaux
country: France
facility: Centre de Lutte Contre le Cancer (CLCC) - Institut Bergonie
city: Rennes
country: France
facility: Centre Eugene Marquis Centre Regional de Lutte Contre Le Cancer
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS Candiolo)
city: Milano
country: Italy
facility: Istituto Scientifico Universitario San Raffaele
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul, St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: National Cancer Center
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebrón
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Leeds
country: United Kingdom
facility: St. James University Hospital
city: Liverpool
country: United Kingdom
facility: Liverpool Cancer Center
city: London
country: United Kingdom
facility: University College London Hospitals
city: London
country: United Kingdom
facility: The Royal Free Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust, the Christie Hospital
Study officials:
affiliation: Servier Pharmaceuticals, LLC
name: Medical Affairs Servier Pharmaceuticals LLC
role: STUDY_CHAIR
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.
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.