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A Phase I Open-label, 2-period Study to Evaluate the Influence of Multiple Oral Doses of Ketoconazole on the Single Dose Pharmacokinetics of Romidepsin in Subjects With Advanced Cancer


Phase 1
18 Years
N/A
Not Enrolling
Both
Hematologic Malignancy, Malignant Lymphoma

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Trial Information

A Phase I Open-label, 2-period Study to Evaluate the Influence of Multiple Oral Doses of Ketoconazole on the Single Dose Pharmacokinetics of Romidepsin in Subjects With Advanced Cancer


Inclusion Criteria:



1. Males and females 18 years of age or older at the time of signing the informed
consent document.

2. Understand and voluntarily sign an informed consent document prior to any study
related assessments/procedures are conducted.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Must have diagnosis of advanced malignancy and must have failed other available
therapies considered standard of care for their disease.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

6. Negative urine or serum pregnancy test on females of childbearing potential; and

7. All females of childbearing potential must use an effective barrier method of
contraception (either an intrauterine contraceptive device [IUCD] or double barrier
method using condoms or a diaphragm plus spermicide) during the treatment period and
for at least 1 month thereafter. Male subjects should use a barrier method of
contraception during the treatment period and for at least 3 months thereafter.
Female subjects should avoid the use of estrogen-containing contraceptives, since
romidepsin may reduce the effectiveness of estrogen-containing contraceptives. An in
vitro binding assay determined that romidepsin competes with β-estradiol for binding
to estrogen receptors.

Exclusion Criteria:

1. Any significant medical condition or psychiatric illness that would prevent the
subject from participating in the study.

2. Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study.

3. Subjects with significant gastrointestinal disease that may impair drug absorption,
such as subjects with a history of Cohn's disease, colectomy, gastrectomy, celiac
disease, or other diseases with known malabsorption.

4. Serum potassium < 3.8 mmol/L or serum magnesium < 0.85 mmol/L (magnesium converts to
2.1 mg/dl or 1.7 mEq/L) (electrolyte abnormalities can be corrected with
supplementation to meet inclusion criteria).

5. Concomitant use of drugs that may cause a significant prolongation of the corrected
measurement of the time between the start of the cardiac Q wave and the end of the T
wave (QTc).

6. Concomitant use of Cytochrome P 450 3A4 (CYP3A4) strong inhibitors within 1 week of
trial medications.

7. Concomitant use of CYP3A4 strong inducers within 2 weeks of trial medications.

8. Concomitant use of therapeutic warfarin due to a potential drug interaction. Use of a
low dose of warfarin or another anticoagulant to maintain patency of venous access
port and cannulas is permitted.

9. Clinically significant active infection.

10. Known infection with Human Immunodeficiency Virus (HIV), hepatitis B, or hepatitis C.

11. Inadequate bone marrow or other organ function as evidenced by:

- Hemoglobin < 9 g/dL (transfusions and/or erythropoietin are permitted);

- Absolute neutrophil count (ANC) ≤ 1.0 * 10^9 cells/L [subjects with neutropenia
(ANC 1-1.5) as a function of their disease may be supported with
granulocyte-colony stimulating factor (G-CSF)];

- Platelet count < 100 * 10^9 cells/L or platelet count < 75 * 10^9 cells/L if
bone marrow disease involvement is documented;

- Total bilirubin > 1.5 * upper limit of normal (ULN) or > 2.0 * ULN in the
presence of demonstrable liver metastases;

- Serum aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT)
and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) > 1.5 *
ULN or > 2.0 * ULN in the presence of demonstrable liver metastases; or

- Serum creatinine > 2.0 * ULN;

12. Prior chemotherapy treatment within 3 weeks prior to the first day of romidepsin
treatment (6 weeks for nitrosoureas) or prior treatment with an investigational agent
within 4 weeks prior to the first day of romidepsin treatment.

13. Prior radiotherapy within 4 weeks prior to the first day of treatment. Subjects who
have not fully recovered or whose acute toxicity related to prior radiotherapy has
not returned to baseline are ineligible.

14. Major surgery within 2 weeks of study entry (day 1).

15. Concomitant use of any other anti-cancer therapy.

16. Concomitant use of any investigational agent.

17. Prior exposure to romidepsin (other histone deacetylase[HDAC] inhibitors are
allowed).

18. Any known cardiac abnormalities, such as:

- Congenital long measure of the time between the start of the Q wave and the end
of the T wave (QT) syndrome;

- . Mean QTc formula (QTcF) interval > 450 msec;

- A myocardial infarction within 12 months of study entry;

- A history of coronary artery disease (CAD), e.g., angina Canadian Class II-IV.
A stress imaging study should be performed for any subject whose cardiac status
is uncertain. If abnormal, an angiography should be completed to define whether
or not CAD is present.

- An electrocardiogram (ECG) recorded at screening showing evidence of cardiac
ischemia (ST depression of ≥ 2 mm, measured from isoelectric line to ST
segment). A stress imaging study should be performed for any subject whose
cardiac status is uncertain. If abnormal, an angiography should be completed to
define whether or not CAD is present.

- Congestive Heart Failure (CHF) that meets the New York Heart Association (NYHA)
Class II to IV definitions (see Appendix F) and/or ejection fraction < 40% by
multi gated acquisition (MUGA) scan or < 50% by echocardiogram and/or magnetic
resonance imaging (MRI);

- A known history of sustained ventricular tachycardia(VT), ventricular
fibrillation (VF), torsades de pointes, or cardiac arrest unless currently
addressed with an automatic implantable cardioverter defibrillator (AICD);

- Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or
other causes (if in doubt, see ejection fraction criteria above);

- Uncontrolled hypertension, i.e., blood pressure (BP) of ≥ 160/95; or

- Any cardiac arrhythmia requiring anti-arrhythmic medication

19. Subjects who are pregnant or breast-feeding.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

Area Under the Plasma Concentration Time-curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t)of Romidepsin

Outcome Description:

AUC0-t: area under the plasma concentration time-curve from Time 0 to the time of the last quantifiable concentration (Ct), calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. For AUC0-t, an analysis of variance (ANOVA) model was used to estimate the ratio of geometric means and its 90% CI between romidepsin alone and romidepsin in the presence to ketoconazole.

Outcome Time Frame:

Days 1 and 8; at 0 (pre-dose) 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.

Safety Issue:

No

Principal Investigator

Ken Takeshita, MD

Investigator Role:

Study Director

Investigator Affiliation:

Celgene Corporation

Authority:

United States: Food and Drug Administration

Study ID:

ROMI-ADVM-001

NCT ID:

NCT01324310

Start Date:

April 2011

Completion Date:

January 2012

Related Keywords:

  • Hematologic Malignancy
  • Malignant Lymphoma
  • ROMI-001
  • romi-001
  • romi
  • ROMI
  • Romidepsin
  • Istodax
  • istodax
  • advanced malignancy
  • PK
  • pharmacokinetics
  • Neoplasms
  • Lymphoma
  • Hematologic Neoplasms

Name

Location

Florida Cancer SpecialistsFort Myers, Florida  33901
Sarah Cannon Research InstituteNashville, Tennessee  37203