NCT02273739

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

Completed Phase 1, PHASE2 Results posted Last updated 23 February 2021

What this trial tests

Phase 1, PHASE2 trial testing Enasidenib in Solid Tumor in 21 participants. Completed in 3 June 2016.

Timeline

8 December 2014

Primary endpoint
3 June 2016

3 June 2016

Quick facts

Lead sponsor	Celgene
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	sequential
Masking	none
Primary purpose	treatment
Enrollment	21
Start date	8 December 2014
Primary completion	3 June 2016
Estimated completion	3 June 2016
Sites	12 locations across France, United States

Drugs / interventions tested

• Enasidenib (ENASIDENIB) — full drug profile →

Conditions studied

• Solid Tumor — all drugs for Solid Tumor →
• Glioma — all drugs for Glioma →
• Angioimmunoblastic T-cell Lymphoma — all drugs for Angioimmunoblastic T-cell Lymphoma →
• Intrahepatic Cholangiocarcinoma — all drugs for Intrahepatic Cholangiocarcinoma →

Sponsor

Celgene — full company profile →

Who can join

18 and older, any sex, with Solid Tumor or Glioma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Treatment-emergent Adverse Events (TEAEs) Primary · 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.

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 inpatien

≥ 1 treatment-emergent adverse event (TEAE)

Group	Value	95% CI
Enasidenib 100 mg	3
Enasidenib 200 mg	4
Enasidenib 400 mg	6
Enasidenib 650 mg	7

≥ 1 treatment-related TEAE

Group	Value	95% CI
Enasidenib 100 mg	3
Enasidenib 200 mg	4
Enasidenib 400 mg	5
Enasidenib 650 mg	5

≥ 1 Grade 3/4 TEAE

Group	Value	95% CI
Enasidenib 100 mg	2
Enasidenib 200 mg	3
Enasidenib 400 mg	5
Enasidenib 650 mg	4

≥ 1 Grade 3/4 treatment-related TEAE

Group	Value	95% CI
Enasidenib 100 mg	0
Enasidenib 200 mg	0
Enasidenib 400 mg	3
Enasidenib 650 mg	3

≥ 1 Grade ≥ 3 TEAE

Group	Value	95% CI
Enasidenib 100 mg	2
Enasidenib 200 mg	3
Enasidenib 400 mg	5
Enasidenib 650 mg	5

≥ 1 Grade ≥ 3 treatment-related TEAE

Group	Value	95% CI
Enasidenib 100 mg	0
Enasidenib 200 mg	0
Enasidenib 400 mg	3
Enasidenib 650 mg	3

≥ 1 Grade 5 TEAE

Group	Value	95% CI
Enasidenib 100 mg	1
Enasidenib 200 mg	0
Enasidenib 400 mg	1
Enasidenib 650 mg	2

≥ 1 Grade 5 treatment-related TEAE

Group	Value	95% CI
Enasidenib 100 mg	0
Enasidenib 200 mg	0
Enasidenib 400 mg	0
Enasidenib 650 mg	0

Number of Participants With Dose-limiting Toxicities Primary · Cycle 1 (28 days)

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 (

Group	Value	95% CI
Enasidenib 100 mg	0
Enasidenib 200 mg	0
Enasidenib 400 mg	1
Enasidenib 650 mg	0

Eastern Cooperative Oncology Group (ECOG) Performance Status at Each Visit Primary · 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

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

Group	Value	95% CI
Enasidenib 100 mg	1.3	± 1.15
Enasidenib 200 mg	0.5	± 0.58
Enasidenib 400 mg	0.9	± 0.90
Enasidenib 650 mg	0.9	± 0.90

Cycle 1 Day 15

Group	Value	95% CI
Enasidenib 100 mg	1.7	± 0.58
Enasidenib 200 mg	1.8	± 1.50
Enasidenib 400 mg	0.8	± 0.84
Enasidenib 650 mg	1.0	± 0.71

Cycle 2 Day 1

Group	Value	95% CI
Enasidenib 100 mg	1.7	± 0.58
Enasidenib 200 mg	0.8	± 0.50
Enasidenib 400 mg	1.2	± 1.30
Enasidenib 650 mg	0.7	± 0.58

Cycle 3 Day 1

Group	Value	95% CI
Enasidenib 100 mg	1.0
Enasidenib 400 mg	1.0	± 0.00
Enasidenib 650 mg	1.0	± 0.00

Cycle 4 Day 1

Group	Value	95% CI
Enasidenib 100 mg	1.0
Enasidenib 400 mg	1.0	± 0.00
Enasidenib 650 mg	1.0

Cycle 5 Day 1

Group	Value	95% CI
Enasidenib 400 mg	1.0	± 0.00
Enasidenib 650 mg	1.0

End of Treatment

Group	Value	95% CI
Enasidenib 100 mg	2.5	± 0.71
Enasidenib 200 mg	0.7	± 0.58
Enasidenib 400 mg	1.3	± 1.50
Enasidenib 650 mg	1.7	± 1.15

Maximum Observed Plasma Concentration (Cmax) After a Single Dose of Enasidenib on Day -3 Secondary · Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose.

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.

Group	Value	95% CI
Enasidenib 100 mg	1403.4	± 77.9
Enasidenib 200 mg	1433.0	± 51.2
Enasidenib 400 mg	4540.6	± 63.7
Enasidenib 650 mg	4702.9	± 61.3

Time of Maximum Plasma Concentration (Tmax) of Enasidenib After a Single Dose on Day -3 Secondary · Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose.

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.

Group	Value	95% CI
Enasidenib 100 mg	2.0	2 – 8
Enasidenib 200 mg	6.1	2 – 25
Enasidenib 400 mg	8.0	2 – 10
Enasidenib 650 mg	3.3	2 – 24

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 Secondary · Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, and 10 hours post-dose.

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.

Group	Value	95% CI
Enasidenib 100 mg	10031.7	± 79.0
Enasidenib 200 mg	11040.2	± 55.9
Enasidenib 400 mg	31959.0	± 56.7
Enasidenib 650 mg	29847.8	± 59.6

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 Secondary · Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose.

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.

Group	Value	95% CI
Enasidenib 100 mg	62420.0	± 80.6
Enasidenib 200 mg	86900.7	± 62.5
Enasidenib 400 mg	206214.4	± 65.2
Enasidenib 650 mg	248315.9	± 69.9

Maximum Observed Plasma Concentration (Cmax) of Metabolite AGI-16903 After a Single Dose of Enasidenib on Day -3 Secondary · Day -3 pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose.

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.

Group	Value	95% CI
Enasidenib 100 mg	94.2	± 64.5
Enasidenib 200 mg	71.9	± 70.8
Enasidenib 400 mg	273.0	± 52.9
Enasidenib 650 mg	239.4	± 64.8

Time of Maximum Plasma Concentration (Tmax) of Metabolite AGI-16903 After a Single Dose of Enasidenib on Day -3 Secondary · Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose.

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.

Group	Value	95% CI
Enasidenib 100 mg	70.3	8 – 74
Enasidenib 200 mg	71.7	71 – 73
Enasidenib 400 mg	71.7	2 – 73
Enasidenib 650 mg	72.0	48 – 72

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 Secondary · Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, and 10 hours post-dose.

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.

Group	Value	95% CI
Enasidenib 100 mg	518.6	± 64.5
Enasidenib 200 mg	233.3	± 30.6
Enasidenib 400 mg	1358.2	± 46.5
Enasidenib 650 mg	965.2	± 67.8

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 Secondary · Day -3, pre-dose and at 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose.

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.

Group	Value	95% CI
Enasidenib 100 mg	7556.4	± 42.9
Enasidenib 200 mg	7294.2	± 99999
Enasidenib 400 mg	13752.5	± 57.8
Enasidenib 650 mg	12519.5	± 74.7

Area Under the Plasma Concentration-time Curve From Time 0 to 10 Hours Postdose (AUC0-10) for Enasidenib After Multiple Doses Secondary · Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.

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.

Group	Value	95% CI
Enasidenib 100 mg	106522.9	± 46.7
Enasidenib 200 mg	161862.9	± 1.4
Enasidenib 400 mg	154248.7	± 33.3
Enasidenib 650 mg	221865.0	± 10.1

Adverse events — posted to ClinicalTrials.gov

Time frame: 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.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Enasidenib 100 mg

Serious: 2/3 (67%)

Deaths: 1/3

Enasidenib 200 mg

Serious: 2/4 (50%)

Deaths: 0/4

Enasidenib 400 mg

Serious: 3/7 (43%)

Deaths: 1/7

Enasidenib 650 mg

Serious: 4/7 (57%)

Deaths: 2/7

Serious adverse events (30 terms)

Reaction	System	Enasidenib 100 mg	Enasidenib 200 mg	Enasidenib 400 mg	Enasidenib 650 mg
Anaemia	Blood and lymphatic system disorders	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—
Sinus tachycardia	Cardiac disorders	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Death	General disorders	—	—	—	—
Disease progression	General disorders	—	—	—	—
Pyrexia	General disorders	—	—	—	—
Lung infection	Infections and infestations	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—
Septic shock	Infections and infestations	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—
Muscle enzyme increased	Investigations	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—
Hypercalcaemia	Metabolism and nutrition disorders	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—
Mental status changes	Psychiatric disorders	—	—	—	—
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Apnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Aspiration	Respiratory, thoracic and mediastinal disorders	—	—	—	—

Other adverse events (133 terms — click to expand)

Reaction	System	Enasidenib 100 mg	Enasidenib 200 mg	Enasidenib 400 mg	Enasidenib 650 mg
Nausea	Gastrointestinal disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Fatigue	General disorders	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—
Blood bilirubin increased	Investigations	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Somnolence	Nervous system disorders	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—
Leukocytosis	Blood and lymphatic system disorders	—	—	—	—
Dry eye	Eye disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Asthenia	General disorders	—	—	—	—
Pyrexia	General disorders	—	—	—	—
Hyperbilirubinaemia	Hepatobiliary disorders	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—
Hyperkalaemia	Metabolism and nutrition disorders	—	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—
Acute coronary syndrome	Cardiac disorders	—	—	—	—
Palpitations	Cardiac disorders	—	—	—	—
Angina pectoris	Cardiac disorders	—	—	—	—
Sinus tachycardia	Cardiac disorders	—	—	—	—
Supraventricular tachycardia	Cardiac disorders	—	—	—	—
Tachycardia	Cardiac disorders	—	—	—	—
Conjunctivitis	Eye disorders	—	—	—	—
Abdominal discomfort	Gastrointestinal disorders	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—
Abdominal distension	Gastrointestinal disorders	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—
Abdominal tenderness	Gastrointestinal disorders	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—
Flatulence	Gastrointestinal disorders	—	—	—	—
Salivary hypersecretion	Gastrointestinal disorders	—	—	—	—
Chills	General disorders	—	—	—	—

Most-reported serious reactions: Anaemia, Myocardial infarction, Sinus tachycardia, Dysphagia, Nausea, Vomiting, Death, Disease progression.

Data from ClinicalTrials.gov NCT02273739 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Cholangiocarcinoma - evolving concepts and therapeutic strategies.
   Ilyas SI, Khan SA, Hallemeier CL, Kelley RK, et al · · 2018 · cited 1192× · PMID 28994423 · DOI 10.1038/nrclinonc.2017.157
2. Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis.
   Sia D, Villanueva A, Friedman SL, Llovet JM. · · 2017 · cited 864× · PMID 28043904 · DOI 10.1053/j.gastro.2016.11.048
3. New Horizons for Precision Medicine in Biliary Tract Cancers.
   Valle JW, Lamarca A, Goyal L, Barriuso J, et al · · 2017 · cited 475× · PMID 28818953 · DOI 10.1158/2159-8290.cd-17-0245
4. The emerging role and targetability of the TCA cycle in cancer metabolism.
   Anderson NM, Mucka P, Kern JG, Feng H. · · 2018 · cited 404× · PMID 28748451 · DOI 10.1007/s13238-017-0451-1
5. Altered metabolism in cancer: insights into energy pathways and therapeutic targets.
   Tufail M, Jiang CH, Li N. · · 2024 · cited 265× · PMID 39294640 · DOI 10.1186/s12943-024-02119-3
6. Biological Role and Therapeutic Potential of IDH Mutations in Cancer.
   Waitkus MS, Diplas BH, Yan H. · · 2018 · cited 248× · PMID 29805076 · DOI 10.1016/j.ccell.2018.04.011
7. Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances.
   Sirica AE, Gores GJ, Groopman JD, Selaru FM, et al · · 2019 · cited 233× · PMID 30251463 · DOI 10.1002/hep.30289
8. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives.
   Lin H, Liu C, Hu A, Zhang D, et al · · 2024 · cited 232× · PMID 38720342 · DOI 10.1186/s13045-024-01544-7