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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 10/25/2020.

A Study of Perpetrator Drug Interactions of Enasidenib in AML Patients

Clinicaltrials.gov identifier NCT03720366

Recruitment Status Recruiting

First Posted October 25, 2018

Last update posted July 23, 2020

Study Description

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).

  • Condition or Disease:Leukemia, Myeloid, Acute
  • Intervention/Treatment: Drug: enasidenib
    Drug: Arm 1 probes
    Drug: Arm 2 Probes
    Drug: Arm 3 probes
  • Phase: Phase 1
Detailed Description

Subjects can only be enrolled in one treatment arm. The probes (which are given twice) used in the study are approved for use in the countries where the study will be conducted. The probes in Arm 1 consist of single doses of caffeine (100mg), dextromethorphan (30 mg), flurbiprofen (50 mg), midazolam (0.03 mg/kg), and omeprazole (40 mg). Arm 2 probes consist of digoxin (0.25 mg), and rosuvastatin (10 mg). Arm 3 probe is pioglitazone (15 mg). Enasidenib is administered orally. All probes, except for midazolam, are administered orally. Midazolam will be administered intravenously. In Part 1 (equivalent to Cycle 1), eligible subjects will receive the probes on Day -1, followed by the first dose of enasidenib on Day 1. Enasidenib will continue to be taken once daily for 28 days. Blood samples for pharmacokinetic analysis will be collected according to a set schedule. Subjects will receive the probes a second time on Day 28. Part 2 of the study begins the next day when the subject begins a second round of daily enasidenib doses (equivalent to Cycle 2). Safety assessment s and procedures consistent with AML standard of care will continue.

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 40 participants
  • Allocation: Non-Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase 1, 2-Part, Multicenter, Open-Label, 3-Arm Study to Determine the Effect of Enasidenib (CC-90007) on the Pharmacokinetics of Single Oral Doses of Caffeine, Dextromethorphan, Fexofenadine, Flurbiprofen, Midazolam, Omeprazole, Pioglitazone, and Rosuvastatin in Patients With Acute Myeloid Leukemia
  • Actual Study Start Date: December 2018
  • Estimated Primary Completion Date: July 2022
  • Estimated Study Completion Date: July 2022
Arms and interventions
Arm Intervention/treatment
Experimental: Arm 1: Administration of enasidenib and Arm 1 probes
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
enasidenib

Drug: Arm 1 probes
caffeine, dextromethorphan, flurbiprofen, midazolam, and omeprazole
Experimental: Arm 2: Administration of enasidenib and Arm 2 probes
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
enasidenib

Drug: Arm 2 Probes
digoxin and rosuvastatin
Experimental: Arm 3: Administration of Enasidenib and Arm 3 probes
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
enasidenib

Drug: Arm 3 probes
pioglitazone
Outcome Measures
  • Primary Outcome Measures: 1. Pharmacokinetics - AUC0-30 [ Time Frame: Up to approximately 29 days ]
    Area under the probe plasma concentration-time curve calculated from time zero to 30 hours
  • 2. Pharmacokinetics - Cmax [ Time Frame: Up to approximately 29 days ]
    Observed maximum probe plasma concentration
  • Secondary Outcome Measures: 1. Pharmacokinetics -t1/2,z [ Time Frame: Up to approximately 29 days ]
    Terminal elimination half life for the probes
  • 2. Pharmacokinetics - CL/F [ Time Frame: Up to approximately 29 days ]
    Apparent clearance of probes from plasma
  • 3. Pharmacokinetics - AUC0-∞ [ Time Frame: Up to approximately 29 days ]
    Area under the probe plasma concentration time curve from time zero to infinity
  • 4. Pharmacokinetics - Vz/F [ Time Frame: Up to approximately 29 days ]
    Apparent total volume of distribution of the probes, based on the terminal phase
  • 5. Complete Response Rate [ Time Frame: Up to approximately 28 months ]
    Measurement of tumor size reduction by a predefined amount over the defined time period
  • 6. Adverse Events (AEs) [ Time Frame: Up to approximately 28 months ]
    Number of participants with adverse events
Eligibility Criteria
  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No
Criteria

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

1. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.

2. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.

3. Subject is ≥ 18 years of age at the time of signing the ICF.

4. 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.

5. 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.

6. Subject has the following disease status:

1. 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

2. 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

7. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

8. 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.

9. 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

- Estimated glomerular filtration rate (GFR) > 30 mL/min based on the Modification
of Diet in Renal Disease (MDRD) formula: GFR (mL/min/1.73 m2) = 175 × (serum
creatinine)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)

10. Females of childbearing potential (FCBP)2 may participate, providing they meet the
following conditions:

- Agree to practice true abstinence from sexual intercourse or to use highly
effective contraceptive methods (eg, combined [containing estrogen and
progestogen] or progestogen-only associated with inhibition of ovulation, oral,
injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral
tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or
male partner sterilization [note that vasectomized partner is a highly effective
birth control method provided that partner is the sole sexual partner of the FCBP
trial participant and that the vasectomized partner has received medical
assessment of the surgical success]) at screening and throughout the study, and
for 4 months following the last study treatment; and

- Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG) pregnancy
test (sensitivity of at least 25 mIU/mL) at screening; and

- Have a negative serum β-hCG pregnancy test (sensitivity of at least 25 mIU/mL)
within 72 hours prior to the start of study treatment in the Treatment Phase
(note that the screening serum pregnancy test can be used as the test prior to
the start of study treatment in the Treatment Phase if it is performed within the
72-hour timeframe).

11. Male subjects must agree to practice true abstinence from sexual intercourse or to the
use of highly effective contraceptive methods with non-pregnant female partners of
childbearing potential at screening and throughout the course of the study, and should
avoid conception with their partners during the course of the study and for 4 months
following the last study treatment.

Exclusion Criteria:

Presence of any of the following will exclude a subject from enrollment:

1. Subject is suspected or proven to have acute promyelocytic leukemia based on
morphology, immunophenotype, molecular assay, or karyotype.

2. Subject has AML secondary to chronic myeloid leukemia (CML).

3. 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.

4. 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). 5. Subject has received non-cytotoxic or investigational agents < 14 days or 5 half-lives, whichever is longer, prior to the start of study treatment. 6. 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. 7. Subject has persistent, clinically significant non-hematologic toxicities from prior therapies. 8. 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. 9. 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). 10. Subject has immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation. 11. 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) 180 mmHg or
diastolic BP > 100 mmHg).

15. Subject is a pregnant or lactating female.

16. Subject is known or suspected to have hypersensitivity to any of the components of PK
probe compounds or study treatment.

Note: A subject may be enrolled into an alternate arm of the study to which the
subject does not have hypersensitivity if that alternate arm has not been filled, and
if the alternate arm is available in the respective country. Subject is planning, or
has reasonable probability, to violate the restrictions. Note in particular the
medication restrictions.

17. Subject has QTc interval (ie, Fridericia's correction [QTcF]) ≥ 480 ms or other
factors that increase the risk of QT prolongation or arrhythmic events (eg, heart
failure, hypokalemia, family history of long QT interval syndrome) at screening.
Reversible factors such as hypokalemia or hypomagnesemia may be corrected prior to
dosing if the Investigator and Sponsor's Medical Monitor concur.

18. In conjunction with the restrictions, subject is taking the following CYP-sensitive
substrate medications that have a narrow therapeutic range are excluded from the study
unless the subject can be transferred to other medications at least 5 halflives prior
to the start of study treatment: paclitaxel and docetaxel (CYP2C8), phenytoin
(CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and tizanidine
(CYP1A2).

19. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that places the subject at unacceptable risk or would prevent the subject from
participating in the study.

20. Subject has any condition that confounds the ability to interpret data from the study.

Contacts and Locations
Contacts

Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

Locations

Australia, New South Wales
Concord Repatriation General Hospital
Concord

Australia, South Australia
Royal Adelaide Hospital Institute of Medical and Veterinary Science
Adelaide

Australia, Victoria
Monash Medical Centre
Clayton

Australia, Victoria
Austin Health - Austin Hospital
Heidelberg

Australia, Western Australia
Linear Clinical Research
Nedlands

Australia
The Alfred Hospital
Melbourne

Australia
Calvary Mater New Castle
Waratah

Korea, Republic of
Seoul National University Hospital
Seoul

Korea, Republic of
Samsung Medical Center
Seoul

Korea, Republic of
Asan Medical Center
Seoul

Sponsors and Collaborators

Celgene

Investigators

Study Director: Leon Carayannopoulos, MD Celgene

More Information
  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT03720366 History of Changes
  • Other Study ID Numbers: CC-90007-CP-004, U1111-1218-1974
  • First Posted: October 25, 2018 Key Record Dates
  • Last Update Posted: July 23, 2020
  • Last Verified: July 2020
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Celgene: Enasidenib
    CC-90007
    Acute Myeloid Leukemia
  • Additional relevant MeSH terms: Leukemia
    Leukemia, Myeloid
    Leukemia, Myeloid, Acute