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Phase I Trial of Romidepsin Given on Days One, Three, and Five in Patients With Thyroid and Other Advanced Cancers

Phase 1
18 Years
Not Enrolling

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Trial Information

Phase I Trial of Romidepsin Given on Days One, Three, and Five in Patients With Thyroid and Other Advanced Cancers


Romidepsin (NSC 630176, FR901228, FK228, formerly referred to as depsipeptide) is a histone
deacetylase inhibitor with potent cytotoxic activity against human tumor cell lines and in
vivo efficacy against both human tumor xenografts and murine tumors (1-3).

Laboratory studies suggest that longer exposure to non-toxic doses of romidepsin can enhance
its molecular effects to a greater degree than short toxic doses that rapidly cause cell

NIS is responsible for enabling uptake of RAI in thyroid cancer, with decreased levels in
tumors resistant or refractory to RAI therapy.

Our group has demonstrated that NIS expression is upregulated by romidepsin, resulting in
increased sensitivity to RAI.


To determine the MTD of romidepsin when administered on days 1, 3 and 5.

To examine the effect of a multi-day regimen of romidepsin on surrogate markers and the
expression of molecular targets.

To determine whether thyroid cancers that do not have detectable uptake of RAI will have
detectable uptake after treatment.


- Age 18 and over

- Evaluable disease

- Performance status ECOG 0-2

- Excluding patients that are pregnant, HIV positive, have CNS metastasis, or acute

- Left ventricular ejection fraction within normal limits. Additional cardiac criteria
are noted in protocol


- Phase I

- Romidepsin administered as a 4-hour intravenous infusion on days 1, 3 and 5

- Dose escalation

- Enrollment of additional cohort of 10 patients with thyroid cancer at MTD

Inclusion Criteria


1. Patients must have histologic or cytologic confirmation of cancer (excluding
acute leukemia) for which there is no known standard therapy capable of
extending life expectancy.

2. Patients must:

- Be age greater than or equal to 18 years.

- Have evaluable disease.

- Have a performance status of ECOG 0-2.

- Have no serious or intercurrent illness that can not be medically controlled and have
a have a life expectancy of greater than 12 weeks.

- Give written informed consent.

- Be willing to return to National Cancer Institute for follow-up.

- Female patients of childbearing potential must have a negative pregnancy test within
1 week and must use effective contraception (hormonal or barrier methods) while being
treated on protocol.

3. Laboratory values:

- Within 7 days prior to registration: absolute neutrophil count greater than or equal
to 1000/microL, platelets greater than or equal to l00,000/microL, bilirubin (total
and direct) less than or equal to 1.5x upper limit of normal, and AST less than or
equal to 3x upper limit of normal, creatinine less than or equal to1.5x upper limit
of normal, or documented creatinine clearance of greater than or equal to 60mL/min.

- Within 4 weeks of registration: ejection fraction of greater than 50% by
echocardiogram or cardiac MRI, or 45% by MUGA scan.

4. Criteria for cohort of patients with RAI refractory non-medullary thyroid cancer
to be enrolled after the MTD has been defined:

- Non-medullary thyroid carcinoma.

- progressive disease following total or near-total thyroidectomy and RAI therapy.

- Documented evidence of no, or minimally ( faint ), RAI uptake on RAI whole body scan.

- no RAI therapy within 3 months prior to study entry.

- no history of administration of IV iodinated contrast or other large iodine loads
(i.e. CT, amiodarone, SSKI) during the previous 3 months.

- 24 hr urinary iodine values less than or equal to150 microg/day.


1. Patients with unconfirmed diagnosis will be excluded.

2. Prior or concurrent malignancies that have not been curatively treated.

3. Current or previous CNS metastasis.

4. Chemotherapy within 4 weeks, 6 weeks for nitrosoureas or mitomycin C, and 8 weeks for

5. HIV seropositivity.

6. Pregnant or breast-feeding patients.

7. Uncontrolled infection.

8. Patients with the following cardiac risk factors will be excluded from the study:

- Patients with known cardiac abnormalities such as: Congenital long QT syndrome
and -QTc interval greater than 480 milliseconds

- Patients who have had a myocardial infarction within 12 months of study entry.

- Patients who have active coronary artery disease, e.g. angina as defined by
Canadian Class II-IV

- Patients with an ECG recorded at screening showing evidence of cardiac ischemia
(ST depression of greater than or equal to 2 mm).

- Any patient in whom coronary artery disease is suspected should be referred for
a cardiology consultation and if active myocardial ischemia is demonstrated, the
patient should be excluded. If a noninvasive imaging study is equivocal, it may
be necessary to proceed to coronary angiography.

- Patients with congestive heart failure that meets NYHA Class II to IV
definitions and/or ejection fraction less than 45% by MUGA scan or less than 50%
by echocardiogram and/or MRI.

- Patients with a history of sustained VT, VF, Torsade de Pointes, or cardiac
arrest unless currently addressed with an automatic implantable cardioverter
defibrillator (AICD). Patients with a history of arrhythmia should have Holter
monitoring and evaluation by cardiology.

- Patients with dilated, hypertrophic, or restrictive cardiomyopathy from prior
treatment or other causes (in doubt, see ejection fraction criteria above).
Patients with left ventricular hypertrophy should be discussed with the
Principal Investigator or Study Chairman.

- Patients with uncontrolled hypertension, i.e. SBP greater than or equal to 160
mm Hg or DBP greater than or equal to 95 mm Hg.

- Patients with cardiac arrhythmia requiring anti-arrhythmic medication other than
beta blocker or calcium channel blocker. Patients in whom digitalis cannot be
discontinued are excluded from study.

- Patients with Mobitz II second degree heart block who do not have a pacemaker.
Patients with first degree or Mobitz I second degree heart block,
bradyarrhythmias or sick sinus syndrome require Holter monitoring and evaluation
by cardiology.

- Patients with other cardiac disease may be excluded at the discretion of the PI
following consultation with cardiology.

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

To define the MTD of romidepsin when administered on a multi-daly regimen of days 1, 3, and 5.

Principal Investigator

Richard L Piekarz, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

October 2002

Completion Date:

April 2010

Related Keywords:

  • Neoplasms
  • Histone Acetylation
  • Cancer
  • Neoplasms



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892