| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nonresectable or Metastatic Cholangiocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bile duct that has metastasized or can't be removed with surgery |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008594 |
| E.1.2 | Term | Cholangiocarcinoma non-resectable |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077846 |
| E.1.2 | Term | Cholangiocarcinoma metastatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
- 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 consecutive months (i.e., have not had menses at any time in the preceding 24 consecutive months). Women of reproductive potential, as well as fertile men and their partners who are female with reproductive potential, must agree to use 2 effective forms of contraception (including at least one barrier form) from the time of giving informed consent througout 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. |
|
| E.4 | Principal exclusion criteria |
1. Received a prior IDH inhibitor.
2. Received systemic anticancer therapy or 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. 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, havediscontinued 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.
6. Have a history of another primary cancer, with the exception 6. of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) 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.
7. Underwent major surgery within 4 weeks of Day 1 or have not recovered from postsurgery toxicities.
8. Are pregnant or breastfeeding.
9. Are taking known strong CYP3A4 inducers or inhibitors, 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.
10. Are taking P-gp transporter-sensitive substrate medications with a narrow therapeutic window, unless they can be transferred to other medications within ≥5 half-lives prior to administration of study treatment.
11. 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).
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 syndrome (AIDS) related illness. Subjects with a sustained viral response to HCV or immunity to prior HBV infection will be permitted. Subjects with chronic HBV that is adequately suppressed per institutional practice will be permitted.
18. 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.
19. 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).
20. Have been committed to an institution by virtue of an order issued either by the judicial or administrative authorities.
21. Are dependent on the Sponsor, Investigator, or study site, per local institution regulations. |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| ongoing basis from randomization until progression of disease or death |
|
| E.5.2 | 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening
D1, D15 and D28 of each cycle
end of treatment
safety follow-up |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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