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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02989857
Recruitment Status : Completed
First Posted : December 12, 2016
Results First Posted : April 13, 2022
Last Update Posted : April 13, 2022
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.

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.

Condition or disease Intervention/treatment Phase
Advanced Cholangiocarcinoma Metastatic Cholangiocarcinoma Drug: AG-120 Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 187 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients randomized in a 2:1 allocation (AG-120 vs Placebo)
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : February 20, 2017
Actual Primary Completion Date : January 31, 2019
Actual Study Completion Date : May 17, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Ivosidenib

Arm Intervention/treatment
Active Comparator: AG-120
Participants received AG-120 500 mg, tablet, orally, once daily (QD) in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 24 months.
Drug: AG-120
Tablet administered orally
Other Name: Ivosidenib

Placebo Comparator: 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 24 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.
Drug: Placebo
Tablet administered orally

Experimental: After Cross over to AG-120
Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 24 months.
Drug: AG-120
Tablet administered orally
Other Name: Ivosidenib




Primary Outcome Measures :
  1. 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) ]
    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 Outcome Measures :
  1. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to approximately 4 years ]
  2. Percentage of Participants With Laboratory Abnormalities [ Time Frame: Up to approximately 4 years ]
  3. Percentage of Participants With Clinically Significant Vital Signs [ Time Frame: Up to approximately 4 years ]
  4. Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: Up to approximately 4 years ]
    The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score classifies 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.

  5. Percentage of Participants With Concomitant Medications [ Time Frame: Up to approximately 4 years ]
  6. Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes [ Time Frame: Up to approximately 4 years ]
  7. Overall Survival (OS) [ Time Frame: Up to 52 weeks ]
  8. Overall Response Rate (ORR) by the Investigator [ 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) ]
  9. ORR as Assessed by the IRC Per RECIST v1.1 [ 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) ]
  10. Duration of Response (DOR) as Assessed by the Investigator [ 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) ]
  11. DOR as Assessed by the IRC Per RECIST v1.1 [ 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) ]
  12. Time to Response (TTR) as Assessed by the Investigator [ 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) ]
  13. TTR as Assessed by the IRC Per RECIST v1.1 [ 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) ]
  14. PFS Per Investigator Assessment [ 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) ]
  15. Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 [ Time Frame: Up to approximately 4 years ]
    The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single-item assessments (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. Most of the 30 items have 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 C30-Overall Health and C30-Quality of Life, higher scores indicate better condition.

  16. HRQOL: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21) [ Time Frame: Up to approximately 4 years ]
    The QLQ-BIL21 contains 21 items in total and each item is a 4-point Likert scale. These 21 items can be grouped into 5 scales (eating symptoms, jaundice symptoms, tiredness, pain symptoms, and anxiety symptoms) and 3 single-item assessments (treatment side-effects, difficulties with drainage bag/tubes, and concerns regarding weight loss). Most of the 21 items have 4 response levels (not at all, a little, quite a bit, and very much). Higher scores indicate better condition.

  17. HRQOL: Patient Global Impression of Change (PGI-C) [ Time Frame: Up to approximately 4 years ]
    The anchor-based questionnaire PGI-C contains the following 3 items (the overall change in the physical functioning since the start of taking the study medication, the overall change in the appetite since the start of taking the study medication, and the overall change in the pain since the start of taking the study medication). The PGI-C is measured using a 7-point Likert scale, with 1 = very much better, 2 = much better, 3 = a little better, 4 = no change, 5 = a little worse, 6 = much worse, and 7 = very much worse.

  18. HRQOL: Patient Global Impression of Severity (PGI-S) [ Time Frame: Up to approximately 4 years ]
    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 is measured using a 7-point Likert scale, with 1 = very much better, 2 = much better, 3 = a little better, 4 = no change, 5 = a little worse, 6 = much worse, and 7 = very much worse.

  19. Health Economic Outcomes: 5-level EuroQol Five Dimensions Questionnaire (EQ-5D-5L) [ Time Frame: Up to approximately 4 years ]
    The EQ-5D-5L contains 5 dimensions (Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression) as well as the EQ visual analogue scale (VAS). EQ-5D-5L consists of 2 components: a descriptive system of the participant's health and a rating of his or her current health state on a 0-100 VAS. The descriptive system comprises the following 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. Rating gets recorded on a vertical VAS in which the endpoints are labeled best imaginable health state is 100 (on the top) and worst imaginable health state is 0 (on the bottom). Higher scores of EQ VAS indicate better health.

  20. Maximum Observed Plasma Concentration (Cmax) of AG-120 [ Time Frame: Day 1 of every cycle up to End of Treatment (EOT) (up to approximately 4 years) ]
  21. Time to Reach Maximal Plasma Concentration (Tmax) of AG-120 [ Time Frame: Day 1 of every cycle up to EOT (up to approximately 4 years) ]
  22. Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) [ Time Frame: Day 1 of every cycle up to EOT (up to approximately 4 years) ]
  23. Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) [ Time Frame: Day 1 of every cycle up to EOT (up to approximately 4 years) ]
  24. Accumulation Ratio Based on AUC0-4 (Racc AUC0-4) [ Time Frame: Day 1 of every cycle up to EOT (up to approximately 4 years) ]
  25. Accumulation Ratio Based on Cmax (Racc Cmax) [ Time Frame: Day 1 of every cycle up to EOT (up to approximately 4 years) ]
  26. Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120 [ Time Frame: Day 1 of every cycle up to EOT (up to approximately 4 years) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02989857


Locations
Show Show 49 study locations
Sponsors and Collaborators
Agios Pharmaceuticals, Inc.
Investigators
Layout table for investigator information
Study Chair: Medical Affairs Servier Pharmaceuticals LLC Servier Pharmaceuticals, LLC
  Study Documents (Full-Text)

Documents provided by Agios Pharmaceuticals, Inc.:
Study Protocol  [PDF] March 5, 2019
Statistical Analysis Plan  [PDF] April 1, 2019

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Agios Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02989857    
Other Study ID Numbers: AG120-C-005
First Posted: December 12, 2016    Key Record Dates
Results First Posted: April 13, 2022
Last Update Posted: April 13, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Agios Pharmaceuticals, Inc.:
IDH1
Additional relevant MeSH terms:
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Cholangiocarcinoma
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Ivosidenib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action