Depsipeptide to Treat Thyroid and Other Advanced Cancers
| Status: | Completed |
|---|---|
| Conditions: | Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/5/2019 |
| Start Date: | October 26, 2002 |
| End Date: | April 1, 2010 |
Phase I Trial of Romidepsin Given on Days One, Three, and Five in Patients With Thyroid and Other Advanced Cancers
This phase I study will evaluate the experimental drug Romidepsinin patients with advanced
cancer. The study will: 1) determine how well patients tolerate Romidepsin; 2) measure blood
levels of Romidepsin during treatment; 3) analyze the cellular and molecular effects of the
drug; and 4) determine if Romidepsin can shrink tumors. Romidepsin has been shown to kill
cancer cells growing in the laboratory and to shrink tumors in animals with various tumor
types. In preliminary studies, several patients with a type of lymphoma and one patient with
kidney cancer responded to treatment.
Patients 18 years of age and older with advanced cancer (excluding acute leukemia) may be
eligible for this study. Candidates are screened with a medical history and physical
examination, x-rays and CT scans, and blood and urine tests. Patients with thyroid cancer may
also have magnetic resonance imaging (MRI). This test uses a magnetic field instead of x-rays
to obtain images or body organs and tissues.
Participants receive three infusions of Romidepsin administered through an intravenous line
over 4 hours on days 1, 3 and 5 of a 21-day treatment cycle. The intravenous line is a
catheter (plastic tube) placed in a vein and may be a peripheral line, inserted in a vein in
the arm, or a central line, in which the tube is placed under the skin of the chest or neck
into a major vein. Patients are hospitalized for the first 6 days of the first cycle to
monitor heart rate. Those who tolerate the treatment well may continue as an outpatient.
In addition to drug therapy, participants undergo the following procedures:
- Blood tests: Small amounts of blood are drawn frequently during the first five days of
treatment to measure Romidepsin levels and to see how the body uses and excretes the
drug. A heparin lock (an indwelling device to keep the vein open) may be put in the vein
to prevent the need for repeated needle sticks.
- Biopsies (removal of a small sample of tumor tissue): Tumors that are accessible may be
biopsied at the start of the study and at different times during treatment. Biopsies are
done no more than three times per cycle, and no more than nine biopsies are done within
a year. The samples are examined for the effects of Romidepsin on proteins that control
the way cells divide and stay alive.
- Apheresis: This procedure is done to collect white blood cells and cancer cells for
research. Blood is collected through a needle in an arm vein and directed into a machine
that separates it into its components by centrifugation (spinning). The white cells are
removed and the red cells are returned to the patient through the same needle or through
another needle in the other arm.
- Scans and x-rays: Imaging studies are usually done before starting treatment. Some of
them are repeated at every 2 cycles (6 weeks), and some at the end of the patient's
participation in the study. The tests may include chest x-rays, plain x-rays of affected
bones, CT scans of the chest, abdomen, and pelvis, bone scans, and a MUGA scan (special
X-ray of the heart) or echocardiogram (ultrasound of the heart) to test heart function
before and during the study. MRI or positron emission tomography (PET) scans may also be
done to detect tumors. PET scans use a small amount of a radioactive substance injected
into a vein. The radioactivity is detected by a special camera during scanning to detect
cancer cells.
- Other tests include an electrocardiogram (recording of the electrical activity of the
heart) before and after each dose of depsipeptide. Eye exams are done if there are
vision changes or if the doctor recommends an eye test.
cancer. The study will: 1) determine how well patients tolerate Romidepsin; 2) measure blood
levels of Romidepsin during treatment; 3) analyze the cellular and molecular effects of the
drug; and 4) determine if Romidepsin can shrink tumors. Romidepsin has been shown to kill
cancer cells growing in the laboratory and to shrink tumors in animals with various tumor
types. In preliminary studies, several patients with a type of lymphoma and one patient with
kidney cancer responded to treatment.
Patients 18 years of age and older with advanced cancer (excluding acute leukemia) may be
eligible for this study. Candidates are screened with a medical history and physical
examination, x-rays and CT scans, and blood and urine tests. Patients with thyroid cancer may
also have magnetic resonance imaging (MRI). This test uses a magnetic field instead of x-rays
to obtain images or body organs and tissues.
Participants receive three infusions of Romidepsin administered through an intravenous line
over 4 hours on days 1, 3 and 5 of a 21-day treatment cycle. The intravenous line is a
catheter (plastic tube) placed in a vein and may be a peripheral line, inserted in a vein in
the arm, or a central line, in which the tube is placed under the skin of the chest or neck
into a major vein. Patients are hospitalized for the first 6 days of the first cycle to
monitor heart rate. Those who tolerate the treatment well may continue as an outpatient.
In addition to drug therapy, participants undergo the following procedures:
- Blood tests: Small amounts of blood are drawn frequently during the first five days of
treatment to measure Romidepsin levels and to see how the body uses and excretes the
drug. A heparin lock (an indwelling device to keep the vein open) may be put in the vein
to prevent the need for repeated needle sticks.
- Biopsies (removal of a small sample of tumor tissue): Tumors that are accessible may be
biopsied at the start of the study and at different times during treatment. Biopsies are
done no more than three times per cycle, and no more than nine biopsies are done within
a year. The samples are examined for the effects of Romidepsin on proteins that control
the way cells divide and stay alive.
- Apheresis: This procedure is done to collect white blood cells and cancer cells for
research. Blood is collected through a needle in an arm vein and directed into a machine
that separates it into its components by centrifugation (spinning). The white cells are
removed and the red cells are returned to the patient through the same needle or through
another needle in the other arm.
- Scans and x-rays: Imaging studies are usually done before starting treatment. Some of
them are repeated at every 2 cycles (6 weeks), and some at the end of the patient's
participation in the study. The tests may include chest x-rays, plain x-rays of affected
bones, CT scans of the chest, abdomen, and pelvis, bone scans, and a MUGA scan (special
X-ray of the heart) or echocardiogram (ultrasound of the heart) to test heart function
before and during the study. MRI or positron emission tomography (PET) scans may also be
done to detect tumors. PET scans use a small amount of a radioactive substance injected
into a vein. The radioactivity is detected by a special camera during scanning to detect
cancer cells.
- Other tests include an electrocardiogram (recording of the electrical activity of the
heart) before and after each dose of depsipeptide. Eye exams are done if there are
vision changes or if the doctor recommends an eye test.
BACKGROUND:
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
death.
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.
OBJECTIVES:
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.
ELIGIBILITY:
- Age 18 and over
- Evaluable disease
- Performance status ECOG 0-2
- Excluding patients that are pregnant, HIV positive, have CNS metastasis, or acute
leukemia
- Left ventricular ejection fraction within normal limits. Additional cardiac criteria are
noted in protocol
DESIGN:
- 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
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
death.
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.
OBJECTIVES:
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.
ELIGIBILITY:
- Age 18 and over
- Evaluable disease
- Performance status ECOG 0-2
- Excluding patients that are pregnant, HIV positive, have CNS metastasis, or acute
leukemia
- Left ventricular ejection fraction within normal limits. Additional cardiac criteria are
noted in protocol
DESIGN:
- 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.
EXCLUSION CRITERIA
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
UCN-01.
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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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