Study of Orally Administered Enasidenib (AG-221) in Adults With Advanced Solid Tumors, Including Glioma, or Angioimmunoblastic T-cell Lymphoma, With an IDH2 Mutation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, pharmacokinetics, and clinical activity of enasidenib in adults with advanced solid tumors, including glioma, or with angioimmunoblastic T-cell lymphoma (AITL), with an isocitrate dehydrogenase-2 (IDH2) mutation.

Detailed Description
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The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of enasidenib to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose. The second portion of the study is a planned dose expansion phase where three cohorts of patients will receive enasidenib to further evaluate the safety, tolerability, and clinical activity. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs. Enrollment into the AG221-C-003 study was closed following enrollment of the dose escalation Cohort 4 (650 mg QD) in order to focus resources on the development of other pipeline IDH inhibitors in solid tumors, gliomas, and lymphoma; it was not due to safety reasons. Participants receiving enasidenib at the time of study closure were to be allowed to continue treatment until disease progression or the development of unacceptable toxicity, as outlined in the study protocol.

Official Title
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A Phase 1/2, Multicenter, Open-Label, Dose-Escalation Study of AG-221 in Subjects With Advanced Solid Tumors, Including Glioma, and With Angioimmunoblastic T-cell Lymphoma, That Harbor an IDH2 Mutation

Conditions
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Solid Tumor, Glioma, Angioimmunoblastic T-cell Lymphoma, Intrahepatic Cholangiocarcinoma, Chondrosarcoma

Intervention / Treatment
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* Drug: Enasidenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be ≥ 18 years of age Histologically or cytologically confirmed advanced solid tumor, including glioma, or angioimmunoblastic T-cell lymphoma (AITL) that has recurred or progressed following standard therapy, or that has not responded to standard therapy Subjects must be amenable to peripheral blood sampling, urine sampling, and biopsies during the study. Subjects with AITL must also be amenable to serial bone marrow biopsies Documented IDH2 gene-mutated disease based on local site testing Measurable disease by RECIST v1.1 for subjects with solid tumors without glioma, by modified RANO criteria for subjects with glioma, or by the revised IWG criteria for subjects with AITL Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Adequate bone marrow function (subjects other than those with AITL) as evidenced by: absolute neutrophil count ≥ 1.0 ×10^9/L; hemoglobin > 9 g/dL (subjects may be transfused red blood cells to this level.); platelets ≥ 50 × 10^9/L Adequate hepatic function as evidenced by: serum total bilirubin ≤ 1.5 × upper limit of normal (ULN), unless considered due to Gilbert's disease, a gene mutation in UGT1A1, or disease involvement, following approval by the Medical Monitor; aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≤ 2.5 × ULN, with the exception of subjects with bone metastases and/or suspected disease-related liver or biliary involvement, where ALP must be ≤ 5 × ULN Adequate renal function as evidenced by: serum creatinine ≤ 2.0 × ULN; OR creatinine clearance > 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight in kg) x (0.85 if female)/72 x serum creatinine Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy. Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 90 days (females and males) following the last dose of AG-221 Previous allogeneic stem cell transplant is allowed only if subjects are >100 days from stem cell transplant and do not have uncontrolled acute or chronic graft-vs-host disease Exclusion Criteria: Received systemic anticancer therapy or radiotherapy < 21 days prior to their first day of study drug administration Received an investigational agent < 14 days prior to their first day of study drug administration. In addition, the first dose of AG-221 should not occur before a period ≥ 5 half-lives of the investigational agent has elapsed Subjects taking the following sensitive cytochrome P450 (CYP) substrate medications that have a narrow therapeutic range are excluded from the study unless they can be transferred to other medications prior to enrolling: paclitaxel (CYP2C8), warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline and tizanidine (CYP1A2) Subjects taking the P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) transporter-sensitive substrates digoxin and rosuvastatin should be excluded from the study, unless they can be transferred to other medications prior to enrolling. study unless they can be transferred to other medications prior to enrolling Subjects for whom potentially curative anticancer therapy is available Pregnant or breastfeeding Active severe infection that required anti-infective therapy or with an unexplained fever > 38.5°C during screening visits or on their first day of study drug administration (at the discretion of the Investigator, subjects with tumor fever may be enrolled) Known hypersensitivity to any of the components of AG-221 Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of Cycle 1Day 1 History of myocardial infarction within the last 6 months Subjects with uncontrolled hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg) are excluded. Subjects requiring 2 or more medications to control hypertension are eligible with Medical Monitor approval. Known unstable or uncontrolled angina pectoris Known history of severe and/or uncontrolled ventricular arrhythmias Heart-rate corrected QT (QTc) interval > 450 msec or with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with right bundle branch block and a prolonged QTc interval should be reviewed by the Medical Monitor for potential inclusion Subjects taking medications that are known to prolong the QT interval Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C Any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate, or participate in the study Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally Subjects with brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy, including to control symptoms, within 2 months of first dose. Subjects with glioma who are on a stable, steroid-dosing regimen prior to screening magnetic resonance imaging (MRI) may be permitted to enroll with Medical Monitor approval In subjects with AITL, evidence of meningeal or cerebral disease or a history of progressive multifocal leukoencephalopathy Radiotherapy involving < 25% of the hematopoietically active bone marrow within 21 days preceding first dose of study treatment Radiotherapy involving ≥ 25% of the hematopoietically active bone marrow within 42 days preceding first dose of study treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enasidenib<br>During the dose escalation phase, consented eligible participants will be enrolled into sequential cohorts of increasing doses of enasidenib.The starting dose for this study is 100 mg administered every 24 hours, | Drug: Enasidenib<br>* Enasidenib tablets administered orally once a day in 28-day treatment cycles until disease progression or unacceptable toxicities.<br>* Other names: IDHIFA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-emergent adverse events included any adverse events (AEs) occurring or worsening on or after the first dose of study drug and within 28 days after the last dose of the study drug. Severity was graded according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03 or according to the following scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5= Fatal, death related to AE. A serious AE is any AE occurring at any dose that: Resulted in death; Was life-threatening; Required or prolonged existing inpatient hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect; Constituted an important medical event. Relationship to study drug administration was determined by the investigator as not related, possibly related, or probably related; all AEs classified as possibly or probably related were considered treatment-related. | From first dose of study drug to 28 days after last dose; median (minimum, maximum) duration of exposure was 66 (8, 197) days across all cohorts. | 
| Number of Participants With Dose-limiting Toxicities | Toxicities were graded and documented according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. A dose-limiting toxicity (DLT) was defined as an event considered related to enasidenib and meeting 1 of the following criteria: Non-hematologic: - All clinically significant non-hematologic toxicities CTCAE ≥ Grade 3, considered not related to underlying disease or intercurrent illness, with the exception of ≥ Grade 3 blood bilirubin increases in participants with a uridine diphosphate-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) mutation. In participants with a UGT1A1 mutation, blood bilirubin increases of > 5 × upper limit of normal (ULN) were considered a DLT. Hematologic: - Drug-related, prolonged myelosuppression of ≥ Grade 4 neutropenia or thrombocytopenia lasting beyond Day 28 of Cycle 1 unless related to bone marrow involvement by AITL. | Cycle 1 (28 days) | 
| Eastern Cooperative Oncology Group (ECOG) Performance Status at Each Visit | ECOG performance status is used by doctors and researchers to assess how a subjects disease is progressing, assess how the disease affects the daily living activities of the subject and determine appropriate treatment and prognosis. 0 = Fully active (most favorable activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited self-care; 4 = Completely disabled, no self-care (least favorable activity). | Baseline, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, and at end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) After a Single Dose of Enasidenib on Day -3 | The first 3 to 5 participants enrolled in each cohort in the dose escalation phase received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for assessment of enasidenib pharmacokinetics (PK). Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. | Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. | 
| Time of Maximum Plasma Concentration (Tmax) of Enasidenib After a Single Dose on Day -3 | The first 3 to 5 participants enrolled in each cohort in the dose escalation phase received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for assessment of enasidenib pharmacokinetics (PK). Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. | Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. | 
| Area Under the Plasma Concentration Time Curve From Time Zero to 10 Hours Postdose (AUC0-10) of Enasidenib After a Single Oral Dose on Day -3 | The first 3 to 5 participants enrolled in each cohort in the dose escalation phase received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for assessment of enasidenib pharmacokinetics (PK). Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. Area under the plasma concentration-time curve from time 0 to 10 hours post-dose (AUC0-10) was calculated using the linear trapezoidal rule. | Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, and 10 hours post-dose. | 
| Area Under the Plasma Concentration Time Curve From Time Zero to 72 Hours Postdose (AUC0-72) of Enasidenib After a Single Dose on Day -3 | The first 3 to 5 participants enrolled in each cohort in the dose escalation phase received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for assessment of enasidenib pharmacokinetics (PK). Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. Area under the plasma concentration-time curve from time 0 to 72 hours post-dose (AUC0-72) was calculated using the linear trapezoidal rule. | Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. | 
| Maximum Observed Plasma Concentration (Cmax) of Metabolite AGI-16903 After a Single Dose of Enasidenib on Day -3 | The first 3 to 5 participants enrolled in each cohort in the dose escalation phase received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3). AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. | Day -3 pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. | 
| Time of Maximum Plasma Concentration (Tmax) of Metabolite AGI-16903 After a Single Dose of Enasidenib on Day -3 | The first 3 to 5 participants enrolled in each cohort in the dose escalation phase received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3). AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. | Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 10 Hours Postdose (AUC0-10) for Metabolite AGI-16903 After a Single Dose of Enasidenib on Day -3 | The first 3 to 5 participants enrolled in each cohort in the dose escalation phase received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3). AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. Area under the plasma concentration-time curve from time 0 to 10 hours post-dose (AUC0-10) was calculated using the linear trapezoidal rule. | Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, and 10 hours post-dose. | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose (AUC0-72) for AGI-16903 After a Single Dose of Enasidenib on Day -3 | The first 3 to 5 participants enrolled in each cohort in the dose escalation phase received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3). AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. Area under the plasma concentration-time curve from time 0 to 72 hours post-dose (AUC0-72) was calculated using the linear trapezoidal rule. | Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 10 Hours Postdose (AUC0-10) for Enasidenib After Multiple Doses | Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. Area under the plasma concentration-time curve from time 0 to 10 hours post-dose (AUC0-10) was calculated using the linear trapezoidal rule. | Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. | 
| Maximum Observed Plasma Concentration (Cmax) of Enasidenib After Multiple Doses | Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. | Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. | 
| Time of Maximum Plasma Concentration (Tmax) of Enasidenib After Multiple Doses | Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. | Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 10 Hours Postdose (AUC0-10) for Metabolite AGI-16903 After Multiple Doses of Enasidenib | AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. Area under the plasma concentration-time curve from time 0 to 10 hours post-dose (AUC0-10) was calculated using the linear trapezoidal rule. | Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. | 
| Maximum Observed Plasma Concentration (Cmax) of Metabolite AGI-16903 After Multiple Doses of Enasidenib | AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. | Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. | 
| Time of Maximum Plasma Concentration (Tmax) of Metabolite AGI-16903 After Multiple Doses of Enasidenib | AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. | Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. | 
| Percentage of Participants With Solid Tumors (Excluding Glioma) Who Achieved an Objective Response | Response was assessed based on radiographic evaluations according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria for participants with solid tumors without glioma. An objective response was defined as the percentage of participants with complete response (CR) or partial response (PR), confirmed no less than 4 weeks after the criteria for response were first met based on RECIST 1.1. Complete response: Disappearance of all target and non-target lesions, pathological lymph nodes must have reduction in short axis to < 10 mm, and no new lesions. Partial response: Disappearance of all target lesions with persistence of one or more non-target lesion(s) and/or maintenance of tumor marker levels above the normal limits, or, at least a 30% decrease in the size of target lesions and no progression of existing non-target lesions and no new lesions. | Response assessments were performed every 56 days up to the end of treatment; median (minimum, maximum) duration of treatment was 50.0 (34, 112), 51.5 (41, 57), 40.0 (4, 170), and 27.0 (3, 126) days in each treatment group respectively. | 
| Percentage of Participants With Glioma Who Achieved an Objective Response | Response was assessed based on modified Response Assessment in Neuro-Oncology (RANO) working group criteria in participants with glioma. An objective response is defined as the percentage of participants with a CR or PR, confirmed no less than 4 weeks based on the modified RANO) criteria. CR: Complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks, stable or improved non-enhancing (T2/FLAIR) lesions, no new lesions, participants must be off corticosteroids (or on physiologic replacement doses only), and clinically stable or improved. PR: At least 50% decrease compared to Baseline in the size of all measurable enhancing lesions sustained for at least 4 weeks, no progression of non-measurable disease or any new lesions, stable of lower dose of corticosteroids than Baseline dose, and stable or improved non-enhancing (T2/FLAIR) lesions. | Response assessments were performed every 56 days up to the end of treatment; median (minimum, maximum) duration of treatment was 50.0 (34, 112), 51.5 (41, 57), 40.0 (4, 170), and 27.0 (3, 126) days in each treatment group respectively. | 
| Percentage of Participants With AITL Who Achieved an Objective Response | Response assessments for participants with AITL were based on the revised International Working Group (IWG) Response criteria for Malignant Lymphoma. Overall response was defined as the percentage of participants who achieved a CR or PR based on IWG criteria. CR: Disappearance of all evidence of disease, including nodal masses, extra nodal masses, and bone marrow. PR: Regression of measurable disease and no new sites (≥ 50% decrease in size from Baseline of all index lesions (both nodal and extranodal lesions), no obvious increase in non-index lesions/disease, fludeoxyglucose (FDG)-avid or positron emission tomography (PET) positive prior to therapy; one or more PET positive at previously involved site, variably FDG-avid or PET negative; regression on computed tomography (CT), no increase in size of liver or spleen). | Response assessments were performed every 56 days up to the end of treatment; median (minimum, maximum) duration of treatment was 50.0 (34, 112), 51.5 (41, 57), 40.0 (4, 170), and 27.0 (3, 126) days in each treatment group respectively. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AITL, IDH, angioimmunoblastic T-cell lymphoma, glioma, solid tumor, including intrahepatic cholangiocarcinoma and chondrosarcoma, solid tumor, intrahepatic cholangiocarcinoma, chondrosarcoma