Nonresectable or Metastatic Cholangiocarcinoma MedDRA version: 20.0 Level: LLT Classification code 10008594 Term: Cholangiocarcinoma non-resectable System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10077846 Term: Cholangiocarcinoma metastatic System Organ Class: 100000004864
Conditions
Interventions
Product Name: AG-120
Product Code: AG-120
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ivosidenib
CAS Number: 1448347-49-6
Current Sponsor code: AG-120
Concentration unit: mg milligram
Sponsors
Agios Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion 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) consistent with 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 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 RECIST v1.1. Subjects 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) with progression on the treatment that was most recently given at a minimum. Subjects must have received at least 1 gemcitabine- or 5-FU-containing regimen for advanced cholangiocarcinoma. Systemic adjuvant chemotherapy will be considered a line of treatment if there is documented disease progression during or within 6 months of completing the therapy. 8. Have recovered from toxicities associated with prior anticancer therapy to baseline unless stabilized under medical management. 9. Have adequate bone marrow function as evidenced by: a. Absolute neutrophil count =1,500/mm^3 or 1.5 ×109/L b. Hemoglobin =8 g/dL c. Platelets =100,000/mm^3 or 100 × 109/L 10. Have adequate hepatic function as evidenced by: a. Serum total bilirubin =2 × upper limit of normal (ULN), unless considered due to Gilbert’s disease b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =5 × ULN 11. Have adequate renal 11. function as evidenced by: a. Serum creatinine <1.5 × ULN OR b. Creatinine clearance =50 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) × (weight in kg) × (0.85 if female)/72 × serum creatinine 12. Be able to understand and willing and able to sign the informed consent and comply with scheduled visits, treatment plans, procedures and laboratory tests including serial peripheral blood sampling and urine sampling, during the study. A legally authorized representative may consent on behalf of a subject who is otherwise unable to provide informed consent if acceptable to and approved by the site's Institutional Review Board (IRB)/Independent Ethics Committee (IEC). (Subjects who do not speak one of the languages that the QLQ-C30, QLQ-BIL21, PGI-C, PGI-S, or EQ-5D-5L are provided in at this time will be permitted to enroll and not complete these HRQOL/health economic outcome instruments, assuming all other eligibility criteria are met.) 13. Female subjects with reproductive potential must have a negative serum pregnancy test prior to the start of therapy, or a confirmation from an obstetrician in case of equivocal serum pregnancy results. Females of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated) for at least 24 consec
Exclusion criteria
Exclusion criteria: 1. Received a prior IDH inhibitor. 2. Received systemic anticancer therapy or investigational agent 38.5°C within 7 days of Day 1 (at the discretion of the Investigator, subjects with tumor fever may be enrolled). 12. Have any known hypersensitivity to any of the components of AG-120 or the matched placebo. 13. Have significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) Class III or IV congestive heart failure; myocardial infarction; unstable angina; and/or stroke. 14. Have LVEF <40% by ECHO scan (or by other methods according to institutional practice) obtained within 28 days prior to the start of study treatment. 15. Have a heart-rate corrected QT interval (using Fredericia’s formula) (QTcF) =450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Bundle branch block and prolonged QTcF interval are permitted with approval of the Medical Monitor. 16. Are taking medications that are known to prolong the QT interval, unless they can be transferred to other medications within =5 half-lives prior to dosing or unless the medications can be properly monitored during the study. (If equivalent medication is not available, QTcF should be closely monitored.) 17. Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency syn
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: ongoing basis from randomization until progression of disease or death;Secondary Objective: - To evaluate the safety and tolerability of AG-120 compared to placebo. - To evaluate PFS per Investigator assessment. - To compare the efficacy of AG-120 with placebo based on overall survival (OS), objective response rate (ORR), duration of response (DOR), and time to response (TTR), with response assessed per the Investigator and by the IRC. - To evaluate health related quality of life (HRQOL) with AG-120 compared to placebo as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC QLQ-BIL21), the Patient Global Impression of Change (PGI-C), and the Patient Global Impression of Severity (PGI-S). - To evaluate health economic outcomes as assessed by the EQ-5D-5L instrument. - To evaluate the pharmacokinetics (PK) of AG-120. - To evaluate the PK/pharmacodynamic (PD) relationship of AG-120 and 2-hydroxyglutarate (2-HG) in blood samples.;Main Objective: To demonstrate the efficacy of AG-120 based on progression-free survival (PFS) per Independent Radiology Center (IRC) assessment compared to placebo in subjects with nonresectable or metastatic cholangiocarcinoma with an isocitrate dehydrogenase 1 (IDH1) mutation.;Primary end point(s): The primary endpoint is PFS, the time from date of randomization to date of first documented disease progression (as assessed by the IRC per RECIST v1.1), or date of death due to any cause. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): AEs, SAEs, AEs leading to discontinuation or death. Safety laboratory parameters, vital signs, 12-lead ECGs, evaluation of left ventricular ejection fraction (LVEF), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and concomitant medications. Secondary efficacy endpoints include: - OS, defined as the time from date of randomization to date of death. - ORR, defined as the proportion of subjects with a best overall response defined as CR or PR - DOR, defined as the time from date of first documented complete response (CR) or partial response (PR) to date of first documented disease progression or death due to any cause - PFS as determined by the Investigator. - TTR, defined as the time from date of randomization to date of first documented - CR or PR for responders, as assessed by the Investigator and by the IRC per RECIST v1.1. HRQOL as assessed by validated instruments. Health economic outcomes as assessed by the EQ-5D-5L instrument. Serial or sparse blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters of AG-120. Blood sampling at specified time points for determination of 2-HG levels to characterize the PD effects of AG-120.;Timepoint(s) of evaluation of this end point: Screening D1, D15 and D28 of each cycle end of treatment safety follow-up | — |
Countries
France, Germany, Italy, Korea, Republic of, Spain, United Kingdom, United States
Contacts
Public ContactDirector, Scientific Communications
Agios Pharmaceuticals, Inc.
Outcome results
None listed