Ensayos clínicos

Inclusion Criteria:

• Be ≥ 18 years of age.
• 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.
• 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 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 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.
• 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.
• Have recovered from toxicities associated with prior anticancer therapy to baseline unless stabilized under medical management.
• Have adequate bone marrow function as evidenced by:
  • Absolute neutrophil count ≥ 1,500/mm3 or 1.5 ×109/L;
  • Hemoglobin ≥ 8 g/dL;
  • Platelets ≥ 100,000/mm3 or 100 × 109/L.
• Have adequate hepatic function as evidenced by:
  • Serum total bilirubin ≤2 × upper limit of normal (ULN), unless considered due to Gilbert’s disease;
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × ULN.
• Have adequate renal function as evidenced by:
  • Serum creatinine <1.5 × ULN; OR
  • Creatinine clearance ≥ 50 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR) estimation:
  • (140 - Age) x (weight in kg) x (0.85 if female)/72 x serum creatinine
• Be able to understand and willing to sign the informed consent form and to comply with scheduled visits, treatment plans, procedures, and laboratory tests, including serial peripheral blood sampling and urine sampling, during the study. A legally  uthorized 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 IRB/Independent Ethics Committee (IEC). (Subjects who do not speak one of the languages that the EORTC-QLQ-C30, EORTC-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.)
• 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 consecutive months (i.e., have not had menses at any time in the preceding 24 consecutive months). Women with reproductive potential, as well as fertile men with partners who are female with reproductive potential, must agree to use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent throughout the study and for 90 days (both females and males) following the last dose of study drug.  Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal ligation, condoms with spermicide, or male partner sterilization.

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. Subjects 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.
• Have a history of another primary cancer, with the exception of:
  • curatively resected nonmelanoma skin cancer;
  • curatively treated cervical carcinoma in situ; or
  • other primary solid or liquid tumor with no known active disease present that, in the opinion of the Investigator, will not affect subject outcome in the setting of current cholangiocarcinoma diagnosis.
• Underwent major surgery within 4 weeks of Day 1 or have not recovered from post-surgery toxicities.
• Are pregnant or breastfeeding.
• Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic window, unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing.
• Have an active infection requiring systemic anti-infective therapy or with an unexplained fever > 38.5°C within 7 days of Day 1 (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
• Have any known hypersensitivity to any of the components of AG-120 or the matched placebo.
• 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.
• 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.
• Have a heart-rate corrected QT interval (using Fridericia’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.
• 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).
• Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency syndrome (AIDS)-related illness. Subjects with a sustained viral response to HCV treatment or immunity to prior HBV infection will be permitted. Subjects with chronic HBV that is adequately suppressed per institutional practice will be permitted.
• Have any other acute or chronic medical or psychiatric condition, including recent (within 12 months of Day 1) or active suicidal ideation or behavior, or a laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
• Have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential).
• Have been committed to an institution by virtue of an order issued either by the judicial or administrative authorities.
• Are dependent on the Sponsor, Investigator, or study site, per local institution regulations.
• Have known medical history of progressive multifocal leukoencephalopathy (PML).