A Study of Perpetrator Drug Interactions of Enasidenib in AML Patients

NCT03720366 | Completed Phase 1 FDA Drug

• 2 other identifiers: CC-90007-CP-004U1111-1218-1974
• Study Type: interventional
• Target: 40
• Locations: 2 countries
• Sites: 10

Brief Summary

This is a 2-part, open-label, interventional study conducted in approximately 42 subjects with AML harboring an IDH2 mutation. The overall study is a 3-arm investigation of the PK effects of enasidenib at steady state on the probe compounds. (Part 1), followed by treatment continuation up to 28 months (Part 2). Each arm utilizes different probe compounds; enrolls a separate cohort of approximately 14 subjects; and consists of 2 parts - investigation of the PK effects of enasidenib on the respective probe compound(s) (Part 1), followed by an enasidenib treatment extension (Part 2).

Conditions

Leukemia, Myeloid, Acute

Keywords

Enasidenib; CC-90007; Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Pharmacokinetics - AUC0-30

  Area under the probe plasma concentration-time curve calculated from time zero to 30 hours

  Up to approximately 29 days

• Pharmacokinetics - Cmax

  Observed maximum probe plasma concentration

  Up to approximately 29 days

Secondary Outcomes (6)

• Pharmacokinetics - AUC0-∞

  Up to approximately 29 days

• Pharmacokinetics -t1/2,z

  Up to approximately 29 days

• Pharmacokinetics - CL/F

  Up to approximately 29 days

• Pharmacokinetics - Vz/F

  Up to approximately 29 days

• Complete Response Rate

  Up to approximately 28 months

Study Arms (3)

Arm 1: Administration of enasidenib and Arm 1 probes

EXPERIMENTAL

Part 1: Subjects will receive prescribed doses of Arm 1 probes on Day -1, followed by the first enasidenib dose on Day 1. Subjects will continue to take enasidenib once daily for 27 more days. On Day 28, subjects will receive the Arm 1 probes again together with the Day 28 dose of enasidenib. Part 2: the subjects continue to receive daily doses of enasidenib for the next 28 days (equivalent to a cycle). The subject will continue in subsequent cycles until the end of the study (28 months) or termination

Drug: enasidenib; Drug: Arm 1 probes

Arm 2: Administration of enasidenib and Arm 2 probes

EXPERIMENTAL

Part 1: Subjects will receive prescribed doses of Arm 2 probes on Day -1, followed by the first enasidenib dose on Day 1. Subjects will continue to take enasidenib once daily for 27 more days. On Day 28, subjects will receive the Arm 2 probes again together with the Day 28 dose of enasidenib. Part 2: the subjects continue to receive daily doses of enasidenib for the next 28 days (equivalent to a cycle). The subject will continue in subsequent cycles until the end of the study (28 months) or termination

Drug: enasidenib; Drug: Arm 2 Probes

Arm 3: Administration of Enasidenib and Arm 3 probes

EXPERIMENTAL

Part 1: Subjects will receive prescribed doses of Arm 3 probes on Day -1, followed by the first enasidenib dose on Day 1. Subjects will continue to take enasidenib once daily for 27 more days. On Day 28, subjects will receive the Arm 3 probes again together with the Day 28 dose of enasidenib. Part 2: the subjects continue to receive daily doses of enasidenib for the next 28 days (equivalent to a cycle). The subject will continue in subsequent cycles until the end of the study (28 months) or termination.

Drug: enasidenib; Drug: Arm 3 probes

Interventions

enasidenib DRUG

enasidenib

Also known as: CC-90007, AG-221

Arm 1: Administration of enasidenib and Arm 1 probes; Arm 2: Administration of enasidenib and Arm 2 probes; Arm 3: Administration of Enasidenib and Arm 3 probes

Arm 1 probes DRUG

caffeine, dextromethorphan, flurbiprofen, midazolam, and omeprazole

Arm 1: Administration of enasidenib and Arm 1 probes

Arm 2 Probes DRUG

digoxin and rosuvastatin

Arm 2: Administration of enasidenib and Arm 2 probes

Arm 3 probes DRUG

pioglitazone

Arm 3: Administration of Enasidenib and Arm 3 probes

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must satisfy the following criteria to be enrolled in the study:
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• Subject is ≥ 18 years of age at the time of signing the ICF.
• Subject has either primary (ie, de novo) or secondary (associated with myelodysplastic syndrome \[MDS\], myeloproliferative neoplasms \[MPN\], or prior therapy with hematotoxins and/or radiation {ie, therapy-related disease}) AML according to the WHO classification.
• Subject either:
• a. has received at least first line of AML therapy and any number of subsequent lines/regimens Note: For subjects having AML secondary to prior higher risk \[Intermediate-2 or High risk according to the International Prognostic Scoring System\] MDS treated with a hypomethylating agent \[eg, azacitidine or decitabine\], the hypomethylating therapy can be counted as a line/regimen if there is disease progression to AML during or shortly \[eg, within 60 days\] after the hypomethylating therapy.); or b. has never been treated for AML, but has declined standard of care chemotherapy.
• Subject has the following disease status:
• Refractory to, or relapsed after first, second, or third line regimen of intensive therapy for AML (eg, the "7 + 3" protocol) with at least 5% leukemic blasts in bone marrow (the minimum number of treatment cycles of the intensive therapy is per the investigator's discretion); or
• Refractory to, or relapsed after first, second or third line low-intensity AML therapy (eg, low dose cytarabine (LDAC), azacitidine or decitabine) with at least 5% leukemic blasts in bone marrow after at least 2 treatment cycles; or
• Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• Subject has IDH2 gene mutations revealed by local testing in samples of bone marrow aspirate and/or peripheral blood, and confirmed positive in bone marrow aspirate and/or peripheral blood. Local testing may be performed during screening or within two months prior to screening with appropriate documentation and concurrence of Sponsor's Medical Monitor.
• Subject has adequate organ function defined as:
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 3 x upper limit of normal (ULN), unless considered to be due to leukemic organ involvement, following review by the Sponsor's Medical monitor; and
• Serum total bilirubin ≤ 1.5 x ULN, unless considered due to Gilbert's syndrome (eg, a gene mutation in UGT1A1) or leukemic organ involvement, following review by the Investigator and the Sponsor's Medical Monitor; and

You may not qualify if:

• Presence of any of the following will exclude a subject from enrollment:
• Subject is suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype.
• Subject has AML secondary to chronic myeloid leukemia (CML).
• Subject has received a targeted agent against an IDH2 mutation.
• a. Prior treatment with an IDH2-targeted agent is acceptable if such treatment was interrupted for bone marrow or stem cell transplantation AND the patient was responsive to IDH2 treatment without progressive disease prior to transplantation.
• Subject has received systemic anticancer therapy or radiotherapy \< 14 days prior to the start of study treatment. Note that hydroxyurea is allowed prior to the start of study treatment for the control of leukocytosis (however, hydroxyurea should not be given within 72 hours prior to and after administration of azacitidine).
• Subject has received non-cytotoxic or investigational agents \< 14 days or 5 half-lives, whichever is longer, prior to the start of study treatment.
• Subject has undergone hematopoietic stem cell transplantation (HSCT) within 60 days prior to the start of study treatment, or on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD).
• a. The use of a stable dose of oral steroid post-HSCT and/or topical steroids for ongoing skin GVHD is permitted.
• Subject has persistent, clinically significant non-hematologic toxicities from prior therapies.
• Subject has or is suspected of having central nervous system (CNS) leukemia.
• a. Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is suspected during screening.
• Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
• Subject has immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
• Subject has 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; acute coronary syndrome (ACS); and/or stroke; or left ventricular ejection fraction (LVEF) \< 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 6 months starting study treatment.

Sponsors & Collaborators

• Celgene: lead

Study Sites (10)

Local Institution - 103

Concord, New South Wales, 2139, Australia

Location

Local Institution - 107

Adelaide, South Australia, 5000, Australia

Location

Local Institution - 106

Clayton, Victoria, 3168, Australia

Location

Local Institution - 102

Heidelberg, Victoria, 3084, Australia

Location

Local Institution - 105

Nedlands, Western Australia, 6009, Australia

Location

Local Institution - 101

Melbourne, 3141, Australia

Location

Local Institution - 104

Waratah, NSW, Australia

Location

Local Institution - 203

Seoul, 06351, South Korea

Location

Local Institution - 202

Seoul, 110-744, South Korea

Location

Local Institution - 201

Seoul, 5505, South Korea

Location

Related Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

enasidenib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: October 24, 2018
• First Posted: October 25, 2018
• Study Start: October 4, 2018
• Primary Completion: September 22, 2023
• Study Completion: December 22, 2023
• Last Updated: February 28, 2024

Record last verified: 2024-02

Locations

KR (3); AU (7)